SK283715B6 - Novel erythromycin derivatives, method for preparing them and their use as medicine - Google Patents
Novel erythromycin derivatives, method for preparing them and their use as medicine Download PDFInfo
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Abstract
Description
Predložený vynález sa týka derivátov erytromycínu, spôsobu a medziproduktov na ich prípravu, ich použitia ako liečiv a farmaceutických kompozícií s ich obsahom.The present invention relates to erythromycin derivatives, a process and intermediates for their preparation, their use as medicaments and pharmaceutical compositions containing them.
Doterajší stav technikyBACKGROUND OF THE INVENTION
EP-A-680967 opisuje deriváty erytromycínu, ktorc sú v polohách 11 a 12 substituované cyklickým karbamátom, pričom atóm dusíka je substituovaný skupinou (CH2)n-Ar, kde n znamená číslo 3, 4 alebo 5 a Ar predstavuje heterocyklus, napríklad |4-(p-pyndyľ)-l -H-imidazol- 1-yl]-(CH,)2-CH2-CH2-skupinu.EP-A-680967 discloses erythromycin derivatives which are substituted at the 11 and 12 positions by a cyclic carbamate, the nitrogen atom being substituted by (CH 2 ) n -Ar, where n is 3, 4 or 5 and Ar is a heterocycle, for example | 4- (p-pyridyl) -1-H-imidazol-1-yl] - (CH 2 ) 2 -CH 2 -CH 2 -group.
V EP-A-0487411 sú opísané okrem iných deriváty erytromycínu, ktoré sú v polohách 11 a 12 substituované cyklickým karbamátom, pričom atóm dusíka je substituovaný alkyl alebo aralkylskupinou, napríklad fenyl-(CH2)2-CH2-CH2-skupinou alebo alkoxyskupinou.EP-A-0487411 discloses, among other erythromycin derivatives, which are at positions 11 and 12 substituted cyclic carbamate, wherein the nitrogen is substituted with an alkyl or aralkyl group, e.g., phenyl (CH 2) 2 CH 2 CH 2 or a group joining alkoxy.
V EP-A-0596802 sú opísané okrem iných deriváty erytromycínu, ktoré sú v polohách 11 a 12 substituované cyklickým karbamátom, pričom atóm dusíka je substituovaný skupinou (CH2)„-Ar|, kde Aij je substituovaná karbocyklická alebo prípadne substituovaná heterocyklická arylová skupina; alebo skupinou X-Ar2, kde X znamená alkylskupinu, ktorá je prerušená kyslíkom (okrem iných možnosti) a Ar2 znamená pripadne substituovanú heterocyklickú alebo karbocyklickú arylovú skupinu.EP-A-0596802 discloses among others erythromycin derivatives substituted at the 11 and 12 positions by a cyclic carbamate wherein the nitrogen atom is substituted by a (CH 2 ) n -Ar 1 group, wherein Aij is a substituted carbocyclic or optionally substituted heterocyclic aryl group ; or X-Ar 2 where X is an oxygen-interrupted alkyl group (among other options) and Ar 2 is an optionally substituted heterocyclic or carbocyclic aryl group.
Predložený vynález uvádza deriváty erytromycínu, ktoré sú v polohách 11 a 12 substituované cyklickým karbamátom, pričom atóm dusíka je substituovaný skupinou -CH2-O-R, ktorou môže byť okrem iných skupina [4-(3-pyridinyl)-]-H-imidazol-l-ylj-(CH2)2-0-CH2- alebo fenyl-(CH2)2-O-CH2-, a ktoré sa získajú postupom syntézy, ktorý sa odlišuje od postupov navrhnutých v doterajšom stave techniky. Zlúčeniny podľa vynálezu okrem toho majú antibiotické vlastnosti, ktoré sú zaujímavejšie ako vlastnosti zlúčenín až dosiaľ známych z doterajšieho stavu techniky.The present invention provides erythromycin derivatives which are substituted at the 11 and 12 positions by a cyclic carbamate wherein the nitrogen atom is substituted by a -CH 2 -OR group which may be, inter alia, [4- (3-pyridinyl) -] - H-imidazole- 1-yl] - (CH 2 ) 2 -O-CH 2 - or phenyl- (CH 2 ) 2 -O-CH 2 -, and which are obtained by a synthesis process that differs from those suggested in the prior art. In addition, the compounds of the invention have antibiotic properties that are more interesting than those of the prior art compounds.
Podstata vynálezuSUMMARY OF THE INVENTION
Predmetom vynálezu sú deriváty erytromycínu vzorca (DThe present invention provides erythromycin derivatives of formula (D)
kdewhere
R predstavuje buď lineárny, rozvetvený, alebo cyklický alkyl, alkenyl alebo alkinyl obsahujúci až 18 atómov uhlíka, prípadne substituovaný aspoň jedným substituentom, ktorým sú atómy halogénu, lineárny rozvetvený alebo cyklický O-alkyl, O-alkenyl alebo O-alkinyl, S-alkyl, S-alkenyl ale bo S-alkinyl obsahujúci až 12 atómov uhlíka, NO2, C=N skupina, ďalej skupinyR represents either linear, branched or cyclic alkyl, alkenyl or alkynyl containing up to 18 carbon atoms, optionally substituted with at least one substituent being halogen, linear branched or cyclic O-alkyl, O-alkenyl or O-alkynyl, S-alkyl , S-alkenyl or S-alkynyl containing up to 12 carbon atoms, NO 2 , C = N group, further groups
Ra R a
kde Ra a Rb, identické alebo rozdielne predstavujú atóm vodíka, lineárny alebo rozvetvený alkyl obsahujúci až 4 atómy uhlíka, nasledujúce skupinywherein R a and R b , identical or differently represent a hydrogen atom, a linear or branched alkyl having up to 4 carbon atoms, the following groups
Rc R c
kde Rc, Rd a Rf, identické alebo rozdielne, predstavujú lineárny rozvetvený alebo cyklický alkyl obsahujúci až 4 atómy uhlíka, prípadne substituované aspoň jedným atómom halogénu, alebo (CH2)nAr skupinu, v ktorej n predstavuje celé číslo v rozmedzí od 0 do 6 a Ar predstavuje aryl alebo heteroaryl, prípadne substituované aspoň jedným uvedeným substituentom,wherein R c , R d and R f , identical or different, represent a linear branched or cyclic alkyl of up to 4 carbon atoms, optionally substituted with at least one halogen atom, or a (CH 2 ) n Ar group in which n represents an integer in the range from 0 to 6 and Ar represents aryl or heteroaryl, optionally substituted with at least one of said substituents,
Z predstavuje atóm vodíka alebo acylový zvyšok obsahujúci až 12 atómov uhlíka, rovnako ako ich adičné soli s kyselinami.Z represents a hydrogen atom or an acyl radical containing up to 12 carbon atoms, as well as their acid addition salts.
Arylová skupina môže byť fenyl alebo naftyl.The aryl group may be phenyl or naphthyl.
Arylová skupina môže byť tiež heterocyklická skupina substituovaná alebo nesubstituovaná, ako je tienyl, furyl, pyrolyl, tiazolyl, oxazolyl, imidazolyl, tiadiazolyl, pyrazolyl alebo izopyrazolyl, pyridyl, pyrimidyl, pyridazinyl alebo pyrazinyl, alebo tiež indolyl, benzofuranyl, benzotiazyl alebo chinolinyl.The aryl group may also be a heterocyclic group substituted or unsubstituted such as thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, pyrazolyl or isopyrazolyl, pyridyl, pyrimidyl, pyridazinyl or pyrazinyl, or also indolyl, benzofuranyl, benzothiazyl or benzothiazyl.
Tieto arylové skupiny môžu obsahovať aspoň jednu skupinu zvolenú zo skupiny, ktorú tvorí hydroxyl, atómy halogénu, NH2, NO2, ON skupina, alkyl, alkenyl alebo alkinyl, O-alkyl, O-alkenyl alebo O-alkinyl, S-alkyl, S-alkenyl alebo S-alkinyl, alebo N-alkyl, N-alkenyl alebo N-akinyl. obsahujúcu až 12 atómov uhlíka prípadne substituovanú aspoň jedným atómom halogénu, skupinuThese aryl groups may contain at least one group selected from the group consisting of hydroxyl, halogen atoms, NH 2 , NO 2 , ON, alkyl, alkenyl or alkynyl, O-alkyl, O-alkenyl or O-alkynyl, S-alkyl, S-alkenyl or S-alkynyl, or N-alkyl, N-alkenyl or N-alkynyl. containing up to 12 carbon atoms optionally substituted by at least one halogen atom
Ra R a
kde Ra a Rb identické alebo rozdielne, predstavujú atóm vodíka alebo alkyl obsahujúci až 12 atómov uhlíka, skupinuwherein R a and R b are identical or different, represent a hydrogen atom or an alkyl of up to 12 carbon atoms, a group
OABOUT
IIII
- C - R3 - C - R 3
SK 283715 Β6 kde R3 predstavuje alkyl obsahujúci až 12 atómov uhlíka alebo prípadne substituovaný aryl alebo heteroaryl, karboxylový aryl, O-aryl alebo S-aryl, heterocyklický aryl, O-aryl alebo S-aryl s 5 alebo 6 členmi obsahujúcimi aspoň jeden heteroatóm, prípadne substituovaný aspoň jedným z ďalej uvedených substituentov.Wherein R 3 represents alkyl of up to 12 carbon atoms or optionally substituted aryl or heteroaryl, carboxyl aryl, O-aryl or S-aryl, heterocyclic aryl, O-aryl or S-aryl of 5 or 6 members containing at least one heteroatom optionally substituted with at least one of the following substituents.
Ako výhodný heterocyklus môžu byť zmienené medzi inými:As a preferred heterocycle, the following may be mentioned:
a heterocyklické skupiny uvádzané v európskej patentovej prihláške 487411, 596802, 676409 a 680967. Tieto výhodné heterocyklické skupiny sú schopné byť substituované jednou alebo viacerými funkčnými skupinami.and heterocyclic groups disclosed in European Patent Application 487411, 596802, 676409 and 680967. These preferred heterocyclic groups are capable of being substituted with one or more functional groups.
Hal výhodne predstavuje fluór, chlór alebo atóm brómu.Hal preferably represents a fluorine, chlorine or bromine atom.
Medzi adičnými soľami s kyselinami môžu byť zmienené soli tvorené s nasledujúcimi kyselinami: octovou, propiónovou, trifluóroctovou, jablčnou, vínnou, metánsulfónovou, benzénsulťónovou, p-toluénsulfónovou a najmä stearovou, etyl-jantárovou alebo laurylsulfónovou kyselinou.Among the acid addition salts, mention may be made of salts formed with the following acids: acetic, propionic, trifluoroacetic, malic, tartaric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, and in particular stearic, ethylsuccinic or laurylsulfonic acid.
Predmetom vynálezu sú najmä zlúčeniny vzorca (I), kde Z predstavuje atóm vodíka, zlúčeniny vzorca (I), kde R predstavuje skupinu (CH2)nAr, v ktorej n predstavuje celé číslo v rozmedzí od 1 do 4 a Ar predstavuje prípadne substituovaný aryl alebo heteroaryl a osobitne tie, v ktorých Ar je prípadne substituovaný fenyl, rovnako ako tie, v ktorých R predstavuje prípadne substituovanú skupinuIn particular, the present invention provides compounds of formula (I) wherein Z represents a hydrogen atom, compounds of formula (I) wherein R represents a (CH 2 ) n Ar group in which n represents an integer ranging from 1 to 4 and Ar represents an optionally substituted aryl or heteroaryl, and especially those in which Ar is optionally substituted phenyl, as well as those in which R represents an optionally substituted group
Úplne osobitným podmetom vynálezu sú zlúčeniny, ktorých príprava je uvedená ďalej v experimentálnej časti a najmä produkty príkladov rozpracovania 2 a 3.A very particular subject of the invention are the compounds whose preparation is given below in the experimental part, and in particular the products of embodiments 2 and 3.
Produkty všeobecného vzorca (I) majú veľmi dobrú antibiotickú aktivitu na grampozitívne baktérie ako sú stafylokoky, streptokoky a pneumokoky.The products of formula (I) have very good antibiotic activity on Gram positive bacteria such as staphylococci, streptococci and pneumococci.
Zlúčeniny tohto vynálezu môžu byť preto použité ako liečivá pri infekciách vyvolaných citlivými choroboplodnými zárodkami a najmä pri stafylokokii ako je stafylokoková septikémia, malígna stafylokokia tváre alebo kože, pyodermatitída, septické alebo hnisajúce rany, vredy, antrax, ílegmóny, erysipel a akné, stafylokokii ako je akútna primárna alebo pochrípková angína, bronchopneumónia, pulmonálna supurácia, streptokokii ako je akútna angína, otitída, sinusitída, spala, pneumokokii ako je pneumónia, bronchitída, brucelóza, diftéria a gonokokálna infekcia.The compounds of the invention can therefore be used as medicaments in infections caused by susceptible germs and in particular in staphylococci such as staphylococcal septicemia, malignant staphylococcus of the face or skin, pyodermatitis, septic or purulent wounds, ulcers, anthrax, erythelemias, erociples and erysipelgias, acute primary or influenza angina, bronchopneumonia, pulmonary supuration, streptococia such as acute angina, otitis, sinusitis, sleep, pneumococia such as pneumonia, bronchitis, brucellosis, diphtheria and gonococcal infection.
Produkt}' predloženého vynálezu sú tiež účinné proti infekciám vyvolaným choroboplodnými zárodkami, ako je Haemophiltus influenzae, Rickettsie, Mycoplasnia pneumoniae, Chlamydia, Legionella, Ureaplasma, Toxoplasma alebo zárodky rodu Mycobacterium.The products of the present invention are also effective against infections caused by germs such as Haemophiltus influenzae, Rickettsia, Mycoplasnia pneumoniae, Chlamydia, Legionella, Ureaplasma, Toxoplasma or Mycobacterium.
Predmetom predloženého vynálezu sú preto tiež ako liečivá a najmä antibiotické liečivá, produkty' vzorca (I) definovaného skôr rovnako ako ich adičné soli s farmaceutický akceptovateľným minerálnymi alebo organickými kyselinami.Accordingly, the present invention also provides, as medicaments and in particular antibiotic medicaments, the products of formula (I) as defined above, as well as their addition salts with pharmaceutically acceptable mineral or organic acids.
Osobitným predmetom vynálezu sú, ako liečivá a najmä antibiotické liečivá, produkty príkladov 2 alebo 3 a ich farmaceutický prijateľné soli.A particular object of the invention are, as medicaments and in particular antibiotic medicaments, the products of Examples 2 or 3 and pharmaceutically acceptable salts thereof.
Predmetom vynálezu sú tiež farmaceutické kompozície obsahujúce aspoň jedno z definovaných liečiv ako účinnú zložku.The present invention also provides pharmaceutical compositions comprising at least one of the defined drugs as an active ingredient.
Tieto kompozície môžu byť podávané bukálnou, rektálnou, parenterálnou cestou alebo lokálnou cestou ako je topická aplikácia na kožu a mukózne membrány, ale výhodným spôsobom podania je bukálna cesta.These compositions may be administered by the buccal, rectal, parenteral, or topical route such as topical application to the skin and mucous membranes, but the preferred route of administration is the buccal route.
Kompozície môžu byť tuhé alebo kvapalné a môžu byť uvádzané vo farmaceutických formách bežne používaných v humánnej medicíne, ako sú napríklad prosté alebo cukrom potiahnuté tablety, tobolky, granuly, čapíky, injektovateľné prípravky, masti, krémy, gély. Môžu byť pripravované zvyčajnými spôsobmi.The compositions may be solid or liquid and may be presented in pharmaceutical forms commonly used in human medicine, such as, for example, plain or sugar-coated tablets, capsules, granules, suppositories, injectables, ointments, creams, gels. They can be prepared by conventional methods.
Aktívna zložka alebo zložky môžu byť začlenené s excipientmi zvyčajne používanými v týchto farmaceutických zmesiach ako je talk, arabská guma, laktóza, škrob, stearan horečnatý', kakaové maslo, vodné alebo nevodné vehikulá,The active ingredient (s) may be incorporated with excipients commonly used in these pharmaceutical compositions such as talk, acacia, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles,
SK 283715 Β6 tukové látky živočíšneho alebo rastlinného pôvodu, parafínové deriváty, glykoly, rôzne namáčacie, dispergačné alebo amulgačné prostriedky a konzervačné látky.286 fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and preservatives.
Tieto kompozície môžu byť tiež uvádzané vo forme prášku určeného na rozpustenie v čase potreby, vo vhodnom vehikule, napríklad apyrogénnej, sterilnej vode.The compositions may also be presented in the form of a powder to be dissolved at the time of need, in a suitable vehicle, for example pyrogen-free, sterile water.
Podávaná látka je variabilná podľa liečenej choroby pacienta, spôsobu podávania a uvažovaného produktu. Môže byť napríklad zahrnutá medzi 50 mg a 300 mg na deň pri orálnom spôsobe pre dospelého pre produkt z príkladu 2.The agent to be administered is variable according to the patient's disease to be treated, the mode of administration and the product contemplated. For example, it may be included between 50 mg and 300 mg per day in an adult oral route for the product of Example 2.
Predmetom vynálezu je tiež spôsob prípravy zlúčenín vzorca (1) vyznačujúci sa tým, že zlúčenina vzorca (11)The invention also provides a process for the preparation of compounds of formula (1), characterized in that the compound of formula (11)
kde Z' predstavuje zvyšok karboxylovej kyseliny obsahujúci až 12 atómov uhlíka, sa podrobí pôsobeniu chrániaceho prostriedku ketónovej skupiny v polohe 3 vo forme enoléteru alebo enolesteru, aby sa získala zlúčeniny vzorca (III)wherein Z 'is a carboxylic acid residue of up to 12 carbon atoms, is treated with a ketone protecting group at the 3-position in the form of an enol ether or an enol ester to provide a compound of formula (III)
kde E predstavuje zvyšok enoléteru alebo enolesteru a Z' má skôr uvedený význam, sa podrobí pôsobeniu zlúčeniny vzorca (IV)wherein E represents a residue of an enol ether or an enol ester and Z 'is as defined above, is treated with a compound of formula (IV)
Hal-CH2OR (IV), kde Hal predstavuje atóm halogénu, aby sa získala zodpovedajúca zlúčenina vzorca (V)Hal-CH 2 OR (IV) wherein Hal represents a halogen atom to obtain the corresponding compound of formula (V)
ktorá sa podrobí, keď je to potrebné, pôsobeniu prostriedku, ktorý' uvoľňuje ketónovú skupinu v polohe 3 a/alebo pôsobeniu prostriedku, ktorý uvoľňuje hydroxyl v polohe 2', čím sa získa zodpovedajúca zlúčenina vzorca (I)which is subjected, if necessary, to a composition which 'releases the ketone group at the 3-position and / or a composition which releases the hydroxyl at the 2' position to give the corresponding compound of formula (I)
kde R a Z zachovávajú ich skorší význam.where R and Z retain their earlier meaning.
Produkty vzorca (II) použité ako východiskové produkty sú známe produkty, ktoré môžu byť pripravené spôsobom opísaným v EP 487411 alebo WO 9321199.The products of formula (II) used as starting products are known products which can be prepared as described in EP 487411 or WO 9321199.
Ako chrániaci prostriedok ketónovej skupiny v polohe 3 vo forme enoléteru, halogénmetyléter môže byť použitý najmä chlórmetetyléter, ako napríklad MEM-chlorid alebo 2-metoxyetoxychlorid, alebo tiež SEM-chlorid, alebo 2-(trimetylsilyjetoxymetylchlorid, ako chrániaci prostriedok ketónovej zlúčeniny vo forme enolesteru môže byť tiež použitý benzyloxymetyléter (BOM), pričom Hal výhodne predstavuje atóm chlóru, Z' výhodne predstavuje acetylovú skupinu alebo prostriedok na uvoľnenie ketónovej skupiny v polohe 3, uvoľnenie hydroxylu v polohe 2' sa vykonáva metanolýzou.As the protecting agent of the ketone group at the 3-position in the form of an enol ether, the halomethyl ether may in particular be a chloromethyl ether, such as MEM-chloride or 2-methoxyethoxy chloride, or SEM-chloride, or 2- (trimethylsilyjetoxymethyl chloride). benzyloxymethyl ether (BOM) may also be used, wherein Hal preferably represents a chlorine atom, Z 'preferably represents an acetyl group or a means for releasing the ketone group at the 3-position, the release of the hydroxyl at the 2-position is performed by methanolysis.
Zlúčeniny vzorcov (III) a (V) použité počas spôsobu prípravy sú nové a samotné sú predmetom predloženého vynálezu.The compounds of formulas (III) and (V) used in the preparation process are novel and are themselves subject to the present invention.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad 1 l,12-Dideoxy-3-de[(2,6-dideoxy-3-C-metyl-3-O-metyl-alfa-L-ribohexopyranozyl)oxy]-6-0-metyl-3-oxo-12,11-[oxykarbonyl[[(2-metoxyetoxy)metyl]imino]]erytromycínExample 11,12-Dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy] -6-O-methyl-3-oxo- 12,11- [oxycarbonyl [[(2-methoxyethoxy) methyl] imino]] erythromycin
Stupeň AGrade A
2,3-Didehydro-11,12-dideoxy-3-0-de[(2,6-dideoxy-3-C-metyl-3-0-metyl-alfa-L-ribohexopyranozyl)-6-0-metyl-11,12-(iminokarbonyloxy)-3-O-[[(2-trimetylsilyl)etoxy]metyl]erytromýcín-2'-acetát2,3-didehydro-11,12-dideoxy-3-0-de [(2,6-dideoxy-3-C-methyl-3-0-methyl-.alpha.-L-ribo-hexopyranosyl) -6-0-methyl- 11,12 (iminokarbonyloxy) -3-O - [[(2-trimethylsilyl) ethoxy] methyl] erythromycin 2'-acetate
Roztok obsahujúci 6 ml DMF, 0,654 g 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-metyl-alfa-L-ribohexopyranozyl)oxy]-6-O-metyl-3-oxo-11,12-(iminokarbonyloxy)erytromycín-2'-acetátu a 0,57 g hydridu sodného v 50 % koncentrácii v oleji sa mieša počas 10 minút. Reakčná zmes sa zahreje na 40 °C. Po ochladení na teplotu -5 °C sa zavedie po kvapkách 0,177 mikrolitra CISEM v 5 ml DMF. Miešanie sa vykonáva pri 0 °C počas 30 minút (pH 9).Solution containing 6 ml DMF, 0.654 g 11,12-dideoxy-3-de [(2,6-dideoxy-3-C-methyl-alpha-L-ribohexopyranosyl) oxy] -6-O-methyl-3-oxo- 11,12- (Iminocarbonyloxy) erythromycin-2'-acetate and 0.57 g of sodium hydride at 50% oil concentration are stirred for 10 minutes. The reaction mixture was heated to 40 ° C. After cooling to -5 ° C, 0.177 microliter of CISEM in 5 ml of DMF is introduced dropwise. Stirring is performed at 0 ° C for 30 minutes (pH 9).
Médium sa naleje na ľad, potom sa vykoná extrakcia etylacetátom, premyje sa vodou, vysuší, sfiltruje a koncentruje. Získa sa 0,785 g produktu, ktorý sa rozpustí v izopropyléteri.The medium is poured onto ice, then extracted with ethyl acetate, washed with water, dried, filtered and concentrated. 0.785 g of product is obtained, which is dissolved in isopropyl ether.
Iniciuje sa kryštalizácia, potom nasleduje separácia, premytie a vysušenie pri teplote 70 °C. Žiadaný produkt sa získa topením pri 100 °C.Crystallization is initiated, followed by separation, washing and drying at 70 ° C. The desired product is obtained by melting at 100 ° C.
NMR CDClj ppm možná štruktúra:NMR CDCl 3 ppm possible structure:
0,07 (s): Si(Me)3; 0,87 (t): CH3-CH2; J,03: CH2-Si; 1,10 (d) - 1,12 (d) - 1,14 (d) - 1,24 (d) CH3; 1,24 (s) - 1,43 (s): 6 a 12 CH3; 1,95 (s): 2-Me; 2,08 (s): OAc; 2,27 (s): N(Me)2; 2,47 (m): H8; 2,68 (m): H'3; 2,82 (s): 6-OMe; 3,04 (q): Hlo; 3,31 (dq): H4; 3,48 (m): H'5; 3,73 (d, J = 2,5): H5; 3,80 - 3,92: OCH2; 3,89 (s): Hn; 4,69 (d): Hi; 4,78 (dd): H2; 4,99 (d) - 5,04, (d): OCH2O; 5,29 (dd): H13.0.07 (s): Si (Me) 3 ; 0.87 (t): CH 3 -CH 2 ; J, 03: CH2 -Si; 1.10 (d) - 1.12 (d) - 1.14 (d) - 1.24 (d) CH 3 ; 1.24 (s) - 1.43 (s): 6 and 12 CH 3 ; 1.95 (s): 2-Me; 2.08 (s): OAc; 2.27 (s): N (Me) 2; 2.47 (m): H8; 2.68 (m): H- 3 ; 2.82 (s): 6-OMe; 3.04 (q): H1o ; 3.31 (dq): H4; 3.48 (m): H- 5 ; 3.73 (d, J = 2.5): H5; 3.80 to 3.92: OCH2; 3.89 (s): H n ; 4.69 (d): H1 ; 4.78 (dd): H2; 4.99 (d) - 5.04, (d) OCH 2 O; 5.29 (dd): H 13 .
Stupeň BGrade B
12,1 l-dideoxy-3-de[(2,6-dideoxy-3-C-metyl-3-O-rnetyl-alfa-L-ribohexapyranozyl)oxy-6-0-metyl-3-oxo-l 1,12-(oxykarbony 1 [[metoxymetyl)] imino] erytromycín12,1 1-dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexapyranosyl) oxy-6-O-methyl-3-oxo-11 12- (oxycarbonyl [[methoxymethyl)] imino] erythromycin
0,150 g zmesi obsahujúcej 0,150 g produktu zo stupňa 11 sa rozpustí v 1,5 ml DMF.0.150 g of a mixture containing 0.150 g of the product of step 11 is dissolved in 1.5 ml of DMF.
Reakčná zmes sa ochladí na +10 °C a pridá sa 14 mg hydridu sodného v 50 % koncentrácii v oleji. Reakčná zmes sa ochladí na 0 °C a zavedie sa 26 mikrolitrov MEM-chloridu v roztoku v 0,5 ml DMF. Vykonáva sa miešanie počas 25 minút pri 0 °C, potom nasleduje naliatie zmesi na ľad, koncentrácia, vyzdvihnutie v etylacetáte, premytie vodou, extrakcia etylacetátom, vysušenie, filtrácia a koncentrácia. Získa sa produkt, ktorý sa zriedi v 4 ml metanolu.The reaction mixture was cooled to + 10 ° C and 14 mg of sodium hydride at 50% oil concentration was added. The reaction mixture was cooled to 0 ° C and 26 µL of MEM-chloride in solution in 0.5 mL of DMF was introduced. Stirring is carried out for 25 minutes at 0 ° C, followed by pouring the mixture on ice, concentration, collection in ethyl acetate, washing with water, extraction with ethyl acetate, drying, filtration and concentration. The product is diluted with 4 ml of methanol.
Roztok sa podrobí refluxu počas 2 hodín, potom sa vráti na teplotu okolia. Pridá sa 1 ml 6,5 M roztoku kyseliny chlorovodíkovej v metanole. Metanol sa odparí a nasleduje vyzdvihnutie v etylacetáte, premytie hydroxidom amónnym, zriedenie, extrakcia etylacetátom, vysušenie, filtrácia a koncentrácia. Získa sa 0,11 g produktu, ktorý vykryštalizuje. Po vyčistení sa získa surový žiadaný produkt. T.t. = 238 - 240 °C.The solution is refluxed for 2 hours, then returned to ambient temperature. Add 1 ml of a 6.5 M solution of hydrochloric acid in methanol. The methanol was evaporated, followed by collection in ethyl acetate, washing with ammonium hydroxide, dilution, extraction with ethyl acetate, drying, filtration and concentration. 0.11 g of product is obtained, which crystallizes. After purification, the crude desired product is obtained. MP: Mp = 238-240 ° C.
NMR CDClj ppmNMR CDCl3 ppm
0,88 (t): CH3-CH2; 1,03 (d): 10-Me; 1,16 (d): 8Me; 1,25 (d): 5'Me; 1,32 (d): 4Me; 1,38 (d): 2Me; 1,34 a 1,51: O a 12Me; J,57 a 1,38 CH2 v polohe 4; .1,60 a 1,84: CH2 v polohe 7; J,67 a 1,25: CH2 v polohe 4'; 2,27 (s): N(Me)2; 2,44 (m): H'3; 2,62 (m): H8; 2,67 (s): 6-OMe; 3,09 (ql): H10; 3,12 (m): H4; 3,18 (dd): H'2; 3,36 (s): OMe; .3,47: OH; 3,86 (q): H2; 3,87 (s): H,,; 4,24 (d): H',; 4,93 (d) - 5,27 (d): NCH2O; 5,05 (dd): H13.0.88 (t): CH 3 -CH 2 ; 1.03 (d) 10-Me; 1.16 (d): 8 Me; 1.25 (d): 5'Me; 1.32 (d): 4 Me; 1.38 (d): 2 Me; 1.34 and 1.51: 0 and 12Me; J, 57, and 1.38 CH2 at position 4; .1,60 and 1.84: CH2 in position 7; J, 67 and 1.25: CH2 in position 4 '; 2.27 (s): N (Me) 2 ; 2.44 (m): H- 3 ; 2.62 (m): H 8; 2.67 (s): 6-OMe; 3.09 (ql): H10; 3.12 (m): H 4 ; 3.18 (dd): H- 2 ; 3.36 (s): OMe; 3.47: OH; 3.86 (q): H2; 3.87 (s): H1; 4.24 (d): H '; 4.93 (d) - 5.27 (d): H 2 NCH; 5.05 (dd): H 13 .
Príklad 2 l,12-dideoxy-3-de[(2,6-dideoxy-3-C-metyl-3-O-metyl-alfa-L-ribohexapyranozyl)oxy]-6-0-metyl-3-oxo-12,11-[oxykarbonyl[[[2-[4-(3-pyridinyl)-lH-imidazol-l-yl]etoxy] metyl] -imino]] erytromycínExample 2 1,1-Dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexapyranosyl) oxy] -6-O-methyl-3-oxo- 12,11- [oxycarbonyl [[[2- [4- (3-pyridinyl) -1H-imidazol-1-yl] ethoxy] methyl] imino]] erythromycin
Stupeň AGrade A
2,3-didehydro-l l,12-dideoxy-3-O-de(2,6-dideoxy-3-C-metyl-3-O-metyl-alfa-L-ribohexapyranozyl)-6-O-metyl-12,l 1 -[oxykarbonyl[[(2-brómetoxy)metyl]imino]]-3-0-[[2-(trimetylsilyl)etoxy]metyl]erytromycín-2'-acetát2,3-didehydro-1,1,12-dideoxy-3-O-de (2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexapyranosyl) -6-O-methyl- 12,11- [oxycarbonyl [[(2-bromoethoxy) methyl] imino]] - 3-O - [[2- (trimethylsilyl) ethoxy] methyl] erythromycin-2'-acetate
0,278 g hydridu sodného v 50 % koncentrácii v oleji sa mieša v 2 ml THF. Zmes sa ochladí na 0 °C a pridá sa 510 mg produktu stupňa A z príkladu 1 v roztoku v 8 ml THF. Reakčné médium sa vráti na okolitú teplotu a zavedie sa 100 mikrolitrov ClCH2OCH2CH2Br v roztoku v 4 ml THF. Reakčné médium sa vráti na 0 °C, naleje na ľad, extrahuje etylacetátom, premyje soľným roztokom, vysuší, sfiltruje a koncentruje sa. Získa sa 0,709 g požadovaného produktu.0.278 g of sodium hydride at 50% concentration in oil was stirred in 2 ml of THF. The mixture was cooled to 0 ° C and 510 mg of the product of Step A of Example 1 in solution in 8 mL of THF was added. The reaction medium is returned to room temperature and introduced into 100 microliters of ClCH 2 OCH 2 CH 2 Br in solution in 4 mL of THF. The reaction medium is returned to 0 ° C, poured onto ice, extracted with ethyl acetate, washed with brine, dried, filtered and concentrated. 0.709 g of the expected product is obtained.
Stupeň BGrade B
2.3- Didehydro-11,12-dideoxy-3-0-de(2,6-dideoxy-3TC-metyl-3-0-metyl-alfa-L-ribohexopyranozyl)-6-0-metyl-12,11 -[oxykarbonyl[[2-[4-(3-pyridinyl)-1 H-imidazol-1-yl]etoxy]metyl]imino]]-3-0-[[2-(trimetylsilyl)etoxy]mety 1] erytromycín-2'-acetát2,3-Didehydro-11,12-dideoxy-3-O-de (2,6-dideoxy-3TC-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) -6-O-methyl-12,11 - [ oxycarbonyl [[2- [4- (3-pyridinyl) -1H-imidazol-1-yl] ethoxy] methyl] imino]] - 3-O - [[2- (trimethylsilyl) ethoxy] methyl] erythromycin-2 'acetate
Roztok 3 ml DMF a 0,377 g de-4-(3-pyridinyl)-lH-imidazolu sa zavedie do roztoku obsahujúceho 2 ml DMF a 0,162 g hydridu sodného v 50 % koncentrácii v oleji. Miešanie sa uskutočňuje počas 1/4 hodiny a zavedie sa 0,709 g produktu zo stupňa A, príkladu 2 v roztoku v 8 ml DMF. Mieša sa 3 hodiny pri okolitej teplote a počas 15 minút pri 60 °C. Reakčné médium sa naleje na ľad, extrahuje etylacetátom, premyje soľným roztokom, potom vodou, vysuší sa, sfiltruje a skoncentruje. Získa sa 0,644 g produktu.A solution of 3 ml of DMF and 0.377 g of de-4- (3-pyridinyl) -1H-imidazole is introduced into a solution containing 2 ml of DMF and 0.162 g of sodium hydride at 50% concentration in oil. Stirring is carried out for 1/4 hour and 0.709 g of the product from Step A, Example 2 are introduced in solution in 8 ml of DMF. Stir 3 hours at ambient temperature and for 15 minutes at 60 ° C. The reaction medium is poured onto ice, extracted with ethyl acetate, washed with brine, then water, dried, filtered and concentrated. 0.644 g of product is obtained.
Stupeň CGrade C
11,12-Dideoxy-3-de[(2,6-dideoxy-3-C-metyl-3-O-metyl-alfa-L-ribohexopyranozyl)oxy]-6-O-metyl-3 -oxo-12,11-[oxykarbonyl-[[[2-[4-(3-pyridinyl)-1 H-imidazol-1 -yl]etoxy]metyl]imino]]erytromycín11,12-Dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy] -6-O-methyl-3-oxo-12, 11- [oxycarbonyl - [[[2- [4- (3-pyridinyl) -1H-imidazol-1-yl] ethoxy] methyl] imino]] erythromycin
Roztok obsahujúci 0,644 g produktu zo stupňa B a 8 ml metanolu sa mieša počas 48 hodín pri teplote okolia, potom sa 0,565 g získaného produktu zriedi v 5 ml etylacetátu. Reakčné médium sa ochladí na 0 “C a zavedie sa 2,5 ml 2, IN roztoku chlorovodíkovej kyseliny v metanole a celok sa vráti na teplotu okolia. Miešanie sa udržuje pri okolitej teplote počas 1 hodiny.A solution containing 0.644 g of the product of Step B and 8 ml of methanol is stirred for 48 hours at ambient temperature, then 0.565 g of the product obtained is diluted in 5 ml of ethyl acetate. The reaction medium is cooled to 0 DEG C. and 2.5 ml of a 2.0N hydrochloric acid / methanol solution are introduced and the whole is returned to ambient temperature. Stirring is maintained at ambient temperature for 1 hour.
Rozpúšťadlo sa odparí, potom nasleduje zriedenie vodou, naliatie do nasýteného vodného roztoku uhličitanu sodného extrakcia etylacetátom, premytie vodou, vysušenie, filtrácia a koncentrácia. Získa sa 0,508 g oleja, ktorý sa chromatografuje na silikagéli pomocou zmesi CH2Cl2/MeOH (93-7), potom CH2Cl2/MeOH/NH4OH (93-7-0,5). Homogénne frakcie sa koncentrujú pomocou chromatografie na tenkej vrstve a potom nasleduje vyzdvihnutie v etylacetáte, premytie hydroxidom amónnym, zriedenie, extrakcia etylacetátom a vodou, vysušenie, filtrácia a koncentrácia. Získa sa 66 mg žiadaného produktu. CDC13 ppmThe solvent was evaporated, followed by dilution with water, pouring into saturated aqueous sodium carbonate solution, extraction with ethyl acetate, washing with water, drying, filtration and concentration. To give 0.508 g of an oil which was chromatographed on silica gel using CH 2 Cl 2 / MeOH (93-7), and CH 2 Cl 2 / MeOH / NH 4 OH (93-7-0,5). The homogeneous fractions were concentrated by thin layer chromatography followed by collection in ethyl acetate, washing with ammonium hydroxide, dilution, extraction with ethyl acetate and water, drying, filtration and concentration. 66 mg of the expected product are obtained. CDCl 3 ppm
0,85 (t): CH3-CH2; 1,00 (d) - 1,15 (d) - 1,25 (d) 1,31 (d) - 1,40 (d): CH3-CH; 1,34 a 1,51: 6 a 12 Me; 2,26 (s): N(Me)2; 2,44 (m): H'4; 2,60 (m): H8; 2,68 (s): 6-OMe; 3,03 (m): H4 a Hlo; 3,18 (dd): H'2; 3,55 (m): H'5; 3,76 (s) - 3,92 (m) - 4,38 (m): OCH2CH2N; 3,87 (s): Hn; 3,83 (q): H2; 4,24 (d): H5; 4,31 (d): H',; 4,96 (dd): H13; 4,99 (d) - 5,37 (d): NCH2O; 7,36 (d) - 7,54 (d): H imidazol; 7,30 (ddd): H5; 8,08 (dt): H4 - 8,45 (dd): H6 - 8,95 (ddd): pyridín.0.85 (t): CH3 --CH2; 1.00 (d) - 1.15 (d) - 1.25 (d) 1.31 (H) - 1.40 (d): the CH3 --CH; 1.34 and 1.51: 6 and 12 Me; 2.26 (s): N (Me) 2; 2.44 (m): H- 4 ; 2.60 (m): H8; 2.68 (s): 6-OMe; 3.03 (m): H 4 and H lo; 3.18 (dd): H- 2 ; 3.55 (m): H- 5 ; 3.76 (s) - 3.92 (m) - 4.38 (m): OCH 2 CH 2 N; 3.87 (s): H n ; 3.83 (q): H2; 4.24 (d): H5; 4.31 (d): H '; 4.96 (dd): H 13 ; 4.99 (d) - 5.37 (d): H 2 NCH; 7.36 (d) - 7.54 (d): H imidazole; 7.30 (ddd): H5; 8.08 (dt): H 4-8.45 (dd): H 6-8.95 (ddd): pyridine.
Príklad 3Example 3
11,12-Dideoxy-3-de[(2,6-dideoxy-3-C-metyl-3-O-metyl-alfa-L-ribohexapyranozyl)oxy]-6-0-metyl-3 -oxo-12,11-[oxykarbonyl-[[(2-fenyletoxy)metyl]imino]] erytromycín11,12-Dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexapyranosyl) oxy] -6-O-methyl-3-oxo-12, 11- [oxycarbonyl - [[(2-phenylethoxy) methyl] imino]] erythromycin
Stupeň AGrade A
2.3- Didehydro-l l,12-dideoxy-3-0-de(2,6-dideoxy-3-C-metyl-3-O-metyl-alfa-L-ribohexapyranozyl)-6-O-metyl-12,1 l-[oxykarbonyl[[(2-fenyletoxy)metyl]imino]]-3-0-[[2-(trimetylsilyl-etoxy]metyl]erytromycín-2'-acatát mg hydridu sodného v 50 % koncentrácii v oleji sa pridá pri teplote 10 °C do roztoku obsahujúceho 2 ml DMF a 203 mg produktu získaného v stupni A, príkladu 1.2,3-Didehydro-1,1,12-dideoxy-3-O-de (2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexapyranosyl) -6-O-methyl-12; 11- [oxycarbonyl [[(2-phenylethoxy) methyl] imino]] - 3-O - [[2- (trimethylsilyl-ethoxy) methyl] erythromycin-2'-acatate mg sodium hydride at 50% concentration in oil is added at 10 ° C to a solution containing 2 ml DMF and 203 mg of the product obtained in Step A, Example 1.
Miešanie sa vykonáva počas 15 minút a potom nasleduje ochladenie na -5 °C a pridá sa 46 mikrolitrov chlórmetylfenyléteru v roztoku v 0,5 ml DMF.Stirring is carried out for 15 minutes, followed by cooling to -5 ° C, and 46 microliters of chloromethylphenyl ether in solution in 0.5 ml of DMF is added.
DMF sa odparí a nasleduje vyzdvihnutie v etylacetáte, premytie vodou, vysušenie, filtrácia a koncentrácia. Získa sa 0,277 g žiadaného produktu.The DMF was evaporated, followed by collection in ethyl acetate, washing with water, drying, filtration and concentration. 0.277 g of the expected product is obtained.
Stupeň B l,12-Dideoxy-3-de[(2,6-dideoxy-3-C-metyl-3-O-metyl-alfa-L-ribohexapyranozyl)oxy]-6-O-metyl-3-oxo-12,l 1-[oxykarbonyl-[[(2-fenyletoxy)metyl]imino]]erytromycínStep B 1,12-Dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexapyranosyl) oxy] -6-O-methyl-3-oxo 12,1- [oxycarbonyl - [[(2-phenylethoxy) methyl] imino]] erythromycin
0,227 g produktu získaného v stupni A sa zavedie naraz do 0,33 ml 0,19N roztoku kyseliny chlorovodíkovej v etylacetáte ochladenom na +5 °C. Reakčné médium sa vráti na teplotu okolia a miešanie sa vykonáva počas 2 hodín. Po ochladení na 0 °C sa pridá voda, pH sa nastaví na hodnotu 9 až 10 koncentrovaným roztokom hydroxidu amónneho, potom nasleduje extrakcia etylacetátom, premytie vodou, vysušenie, filtrácia a koncentrácia. Získa sa 0,201 g produktu, ktorý· sa zriedi v 2,5 ml metanolu. Celok sa privedie k refluxu počas 2 hodín 30 minút. Metanol sa odparí a získa sa 0,88 mg produktu, ktorý sa chromatografuje na silikagéli elúciou zmesou metylénchlorid-izopropanol-hydroxid amónny (95-5-0,5). Po koncentrácii sa zvyšok vyzdvihne v metylénchloride, pridá sa kvapka koncentrovaného hydroxidu amónneho a potom nasleduje miešanie, sušenie, filtrácia a koncentrácia. Získa sa 55 mg produktu, ktorý sa separuje a vysuší pri 80 °C. Získa sa 36 mg produktu.0.227 g of the product obtained in Step A is introduced in one portion into 0.33 ml of a 0.19N solution of hydrochloric acid in ethyl acetate cooled to + 5 ° C. The reaction medium is returned to ambient temperature and stirring is performed for 2 hours. After cooling to 0 ° C, water is added, the pH is adjusted to 9-10 with concentrated ammonium hydroxide solution, followed by extraction with ethyl acetate, washing with water, drying, filtration and concentration. 0.201 g of product is obtained, which is diluted in 2.5 ml of methanol. The whole is brought to reflux for 2 hours 30 minutes. Methanol was evaporated to give 0.88 mg of product which was chromatographed on silica gel eluting with methylene chloride-isopropanol-ammonium hydroxide (95-5-0.5). After concentration, the residue is taken up in methylene chloride, a drop of concentrated ammonium hydroxide is added, followed by stirring, drying, filtration and concentration. 55 mg of product are obtained, which product is separated and dried at 80 ° C. 36 mg of product are obtained.
T.t. = 210-212 °C.MP: MP 210-212 ° C.
NMR CDC13 ppmNMR CDCl 3 ppm
0,88 (t): CH3-CH2; 1,02 (d) - 1,15 (d) - 1,25 (d) - 1,31 (d) - 1,39 (d): CH3-CH; 1,33 - 1,51: 6 a 12 Me; 2,27 (s): N(Me)2; 2,45 (m): H',; 2,62 (m): Hs; 2,70 (s): 6-OMe; 2,91 (m): CH2tó; 3,08 (ql): Hlo; -3,15 (m): H4; 3,18 (dd) H'2; -3,58 (m): H'5; -3,58 a 3,77: OCH2; 3,87 (q): H2; 3,91 (s): Hn; 4,25 (d): H5; 4,32 (d): Hj; 5,00 (d) - 5,33 (d): NCH2O; 5,05 (dd): H13; 7,13 to,7,30: fenyl, éter (-0,3 mol).0.88 (t): CH 3 -CH 2 ; 1.02 (d) - 1.15 (d) - 1.25 (d) - 1.31 (d) - 1.39 (d): the CH3 --CH; 1.33-1.51: 6 and 12 Me; 2.27 (s): N (Me) 2 ; 2.45 (m): H '; 2.62 (m): H s ; 2.70 (s): 6-OMe; 2.91 (m): CH2 lake; 3.08 (ql): H10 ; -3.15 (m): H 4 ; 3.18 (dd) H '2; -3.58 (m): H- 5 ; -3.58 and 3.77: OCH 2 ; 3.87 (q): H2; 3.91 (s): H n ; 4.25 (d): H5; 4.32 (d): H1; 5.00 (d) - 5.33 (d): NCH 2 O; 5.05 (dd): H 13 ; 7.13 to, 7.30: phenyl, ether (-0.3 mol).
Spracovaním, ako je uvedené, bol pripravený nasledujúci produkt.Working up as described gave the following product.
Príklad 4Example 4
11,12-Dideoxy-3-de[(2,6-dideoxy-3-C-metyl-3-0-metyl-alfa-L-ribohexopyranozyl)oxy]-6-0-metyl-3-oxo-12,l 1 -[oxykarbonyl-[[(2-(trimetylsilyl)etoxy]metyl]imino]]erytromycín11,12-dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3-0-methyl-.alpha.-L-ribohexopyranosyl) oxy] -6-0-methyl-3-oxo-12, 11 - [oxycarbonyl - [[(2- (trimethylsilyl) ethoxy] methyl] imino]] erythromycin
T. t. = 141 -143 °C, Rf = 0,38 (AcOEt-TEA 95-5).T. t. = 141-143 ° C, R f = 0.38 (AcOEt-TEA 95-5).
Príklad farmaceutickej kompozícieAn example of a pharmaceutical composition
Bola pripravená kompozícia obsahujúca produkt z príkladu 2 150 mg excipient s.q.f. 1 g zložky excipientu: škrob, talk, stearan horečnatý. Farmakologická štúdia produktov podľa tohto vynálezu Spôsob riedenia v kvapalnom médiuA composition containing the product of Example 21 of 150 mg excipient s.q.f. was prepared. 1 g excipient component: starch, talk, magnesium stearate. Pharmacological Study of Products of the Invention Dilution method in liquid medium
Pripraví sa séria skúmaviek, v ktorých sa rozdelí rovnaké množstvo sterilného živného média. Rozmiestni sa rastúce množstvo produktu, ktorý má byť študovaný, do každej skúmavky, potom sa každá skúmavka naočkuje bakteriálnym kmeňom. Po inkubácii počas 24 hodín v termostate pri 37 °C sa vyhodnotí inhibícia rastu transilumináciou, ktorá umožňuje určiť minimálne inhibičné koncentrácie (M.I.C.), vyjadrené v mikrogramoch/cm3.A series of tubes are prepared in which an equal amount of sterile nutrient medium is distributed. Spread an increasing amount of the product to be studied in each tube, then inoculate each tube with a bacterial strain. After incubation for 24 hours in a thermostate at 37 ° C, growth inhibition is evaluated by transilumination, which makes it possible to determine the minimum inhibitory concentrations (MIC), expressed in micrograms / cm 3 .
Boli získané nasledujúce výsledky.The following results were obtained.
Navyše produkt z príkladu 1 mal užitočnú aktivitu na nasledujúce gramnegatívne bakteriálne kmene: Haemophilus influenzae 351HT3, 351CB12, 351CA1 a 351GR6.In addition, the product of Example 1 had useful activity on the following gram-negative bacterial strains: Haemophilus influenzae 351HT3, 351CB12, 351CA1 and 351GR6.
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FR9615271A FR2757168B1 (en) | 1996-12-12 | 1996-12-12 | NOVEL ERYTHROMYCIN DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS |
PCT/FR1997/002254 WO1998025942A1 (en) | 1996-12-12 | 1997-12-10 | Novel erythromycin derivatives, method for preparing them and their use as medicine |
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KR (1) | KR100490074B1 (en) |
CN (2) | CN1238364C (en) |
AP (1) | AP997A (en) |
AT (1) | ATE217008T1 (en) |
AU (1) | AU721732B2 (en) |
BG (1) | BG63124B1 (en) |
BR (1) | BR9714007A (en) |
CA (1) | CA2273985C (en) |
CZ (1) | CZ292403B6 (en) |
DE (1) | DE69712361T2 (en) |
DK (1) | DK0946579T3 (en) |
EA (1) | EA001733B1 (en) |
ES (1) | ES2174323T3 (en) |
FR (1) | FR2757168B1 (en) |
GE (1) | GEP20012518B (en) |
HU (1) | HUP0001180A3 (en) |
ID (1) | ID21873A (en) |
IL (1) | IL130420A (en) |
NO (1) | NO314040B1 (en) |
NZ (1) | NZ335325A (en) |
PT (1) | PT946579E (en) |
SK (1) | SK283715B6 (en) |
TR (1) | TR199901301T2 (en) |
WO (1) | WO1998025942A1 (en) |
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FR2771008B1 (en) * | 1997-11-17 | 2000-04-28 | Hoechst Marion Roussel Inc | USE OF KETOLIDES FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS FOR PREVENTING ARTERIAL THROMBOTIC COMPLICATIONS LINKED TO ATHEROSCLEROSIS |
ATE344269T1 (en) * | 1998-12-10 | 2006-11-15 | Pfizer Prod Inc | CARBAMAT AND CARBAZATE KETOLIDE ANTIBIOTICS |
BR9916969A (en) | 1999-01-27 | 2001-11-06 | Pfizer Prod Inc | Ketolide antibiotics |
KR100710605B1 (en) * | 1999-04-16 | 2007-04-24 | 코산 바이오사이언시즈, 인코포레이티드 | Macrolide antiinfective agents |
AU3832100A (en) | 1999-05-24 | 2000-12-12 | Pfizer Products Inc. | 13-methyl-erythromycin derivatives |
US6472372B1 (en) * | 2000-12-06 | 2002-10-29 | Ortho-Mcneil Pharmaceuticals, Inc. | 6-O-Carbamoyl ketolide antibacterials |
DK200201957A (en) * | 2002-12-20 | 2003-01-20 | Alpharma Aps | 10-substituted erythromycin ketolides and methods of making |
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US4742049A (en) * | 1986-06-04 | 1988-05-03 | Abbott Laboratories | Semisynthetic erythromycin antibiotics |
IL114589A (en) * | 1990-11-21 | 1999-12-22 | Roussel Uclaf | Intermediates for the preparation of erythromycin derivatives |
DK0638584T3 (en) * | 1992-04-22 | 1996-04-15 | Taisho Pharmaceutical Co Ltd | 5-O-desosaminyl-erythronolide A derivative |
US5527780A (en) * | 1992-11-05 | 1996-06-18 | Roussel Uclaf | Erythromycin derivatives |
JP3709997B2 (en) * | 1994-03-29 | 2005-10-26 | 日東電工株式会社 | Heat resistant negative photoresist composition, photosensitive substrate, and negative pattern forming method |
FR2718450B1 (en) * | 1994-04-08 | 1997-01-10 | Roussel Uclaf | New erythromycin derivatives, their preparation process and their use as drugs. |
FR2719587B1 (en) * | 1994-05-03 | 1996-07-12 | Roussel Uclaf | New erythromycin derivatives, their preparation process and their use as drugs. |
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1996
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- 1997-12-10 GE GEAP19974895A patent/GEP20012518B/en unknown
- 1997-12-10 SK SK750-99A patent/SK283715B6/en unknown
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- 1997-12-10 JP JP52629898A patent/JP4363666B2/en not_active Expired - Lifetime
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