SK146497A3 - Esters of carbapenems, pharmaceutical composition containing the same, method for producing the same and their use - Google Patents

Esters of carbapenems, pharmaceutical composition containing the same, method for producing the same and their use Download PDF

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SK146497A3
SK146497A3 SK1464-97A SK146497A SK146497A3 SK 146497 A3 SK146497 A3 SK 146497A3 SK 146497 A SK146497 A SK 146497A SK 146497 A3 SK146497 A3 SK 146497A3
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methyl
compound
ethyl
carbapenem
formula
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SK1464-97A
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Slovak (sk)
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George Burton
Stephen F Moss
Alfred J Eglington
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Smithkline Beecham Plc
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Priority claimed from GBGB9508957.9A external-priority patent/GB9508957D0/en
Priority claimed from GBGB9508955.3A external-priority patent/GB9508955D0/en
Priority claimed from GBGB9508956.1A external-priority patent/GB9508956D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Publication of SK146497A3 publication Critical patent/SK146497A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/14—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/02—Preparation
    • C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C07D477/08—Modification of a carboxyl group directly attached in position 2, e.g. esterification
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

A compound of formula (I), wherein R is selected from the group consisting of isobutyryloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, and benzoyloxymethyl, is useful in the treatment of bacterial infections.

Description

Oblasť technikyTechnical field

Vynález sa týka nových antibakteriálnych zlúčenín, spôsobov ich prípravy, farmaceutických a veterinárnych zmesí s ich obsahom a ich použitia v antibakteriálnej terapii.The invention relates to novel antibacterial compounds, processes for their preparation, pharmaceutical and veterinary compositions containing them and their use in antibacterial therapy.

Doterajší stav technikyBACKGROUND OF THE INVENTION

Karbapenémy tak ako imipenémy vzorca (A):Carbapenems as well as imipenems of formula (A):

majú účinné široké spektrum antibakteriálnej aktivity (pozri US 3 950 357 a US 4 194 047; Merck a spol.) Tieto karbapenémy však majú tendenciu hydrolyzovať enzýmom renálnej dehydropeptidázy-1 (DHP-1) a táto skutočnosť limituje ich použitie v chemoterapii. V prípade imipenému tento problém môže byť prekonaný pomocou inhibítora DHP-1.however, these carbapenems tend to hydrolyze with the enzyme renal dehydropeptidase-1 (DHP-1), and this limits their use in chemotherapy. In the case of imipenem, this problem can be overcome by a DHP-1 inhibitor.

Stabilita voči DHP-1 môže byť tiež dosiahnutá chemickou modifikáciou karbapenémového jadra, napríklad začlenením Ιβ-metyl substituentu, ako v zlúčenine meropenému, zlúčenina vzorca (B):Stability towards DHP-1 can also be achieved by chemical modification of the carbapenem nucleus, for example by incorporating a β-methyl substituent, such as in the meropenem compound, a compound of formula (B):

- 2 (pozri Shih D.H., Heterocycles,1984, 21, 29 a Sunagawa M., J. Antibiotics, 1990, 43, 519). Dávnejšie, tieto zlúčeniny boli rozšírené o Ιβ-aminoalkylový substituent (pozri EP 0 433 759, Bristol-Meyers Squibb).2 (see Shih D.H., Heterocycles, 1984, 21, 29 and Sunagawa M., J. Antibiotics, 1990, 43, 519). More recently, these compounds have been extended by a β-aminoalkyl substituent (see EP 0 433 759, Bristol-Meyers Squibb).

Alternatívny prístup zvýšenia stability voči DHP-1 využíva 2-C-substituované karbapenémy, napríklad, 2-aryl, 2-heteroaryl a 2-heteroaromatické karbapenémy (US 4 543 257, US 4 260 627, US 4 962 101, US 4 978 659, EP 0 14 493, EP 0 414 489, EP 0 010 316 a EP 0 030 032 Merck a spol.) a 2-(substituovaný)metyl karbapenémy (Schmidt a spol, Antibiotics, 41,1988, 780).An alternative approach to enhance DHP-1 stability utilizes 2-C-substituted carbapenems, for example, 2-aryl, 2-heteroaryl and 2-heteroaromatic carbapenems (US 4,543,257, 4,260,627, US 4,962,101, US 4,978,659 , EP 0 14 493, EP 0 414 489, EP 0 010 316 and EP 0 030 032 (Merck et al.) And 2- (substituted) methyl carbapenems (Schmidt et al., Antibiotics, 41, 1988, 780).

UK Patent 1 593 524, Merck a spol. opisuje 5-členné heteroaromatické karbapenémové deriváty zahrňujúce zlúčeniny, diazolu a tetrazolu. Avšak, v prípade derivátov pyrazolu heterocyklická zlúčenina je pripojená na jadro karbapenému cez pozíciu C-4.UK Patent 1,593,524 to Merck et al. discloses 5-membered heteroaromatic carbapenem derivatives including diazole and tetrazole compounds. However, in the case of pyrazole derivatives, the heterocyclic compound is attached to the carbapenem nucleus via the C-4 position.

Ďalšie štrukturálne modifikácie predstavené v pozícii-2 zahrňujú substituovanú vinylovú skupinu -C(Ra)=CHRb, v ktorej napríklad Raje vodík alebo metyl a Rb je vodík alebo nižší alkyl (EP 0 330 108; Fujisawa) alebo Ra a Rb sú vybrané zo skupiny vodík, nižší alkyl, aminokarbonyl, nižší alkoxy, cyano, nitro ,a nižší alkoxykarbonyl (EP 0 430 037, Banyu Pharmaceutical Co.). V neprítomnosti 1βmetyl substituentu taká modifikácia však neposkytuje stabilitu voči DHP-1.Other structural modifications introduced at position-2 include a substituted vinyl group -C (R a ) = CHR b , wherein, for example, R a is hydrogen or methyl and R b is hydrogen or lower alkyl (EP 0 330 108; Fujisawa) or R a and R b are selected from hydrogen, lower alkyl, aminocarbonyl, lower alkoxy, cyano, nitro, and lower alkoxycarbonyl (EP 0 430 037, Banyu Pharmaceutical Co.). However, in the absence of the 1β-methyl substituent, such modification does not provide stability to DHP-1.

Medzinárodná prihláška vynálezu č. PCT/GB94/02347 opisuje zlúčeninu všeobecného vzorca (C):International patent application no. PCT / GB94 / 02347 discloses a compound of formula (C):

v ktorom R znamená:wherein R stands for:

- 3 kde- 3 where

R“ je vodík, voliteľne substituovaný (C^gjalkyl alebo voliteľne substituovaný aryl;R 'is hydrogen, optionally substituted (C 1-6 alkyl or optionally substituted aryl;

Rp je vodík, voliteľne substituovaný^Jalkyl alebo voliteľne substituovaný aryl;R p is hydrogen, optionally substituted C 1-4 alkyl or optionally substituted aryl;

alebo R“ a Rp spolu tvoria voliteľne substituovaný 5 až 6 členný heterocyklický reťazec s alebo bez dodatočných heteroatómov;or R 1 and R p together form an optionally substituted 5 to 6 membered heterocyclic chain with or without additional heteroatoms;

Rc je (C1.6)alkyl, ktorý je nesubstituovaný alebo substituovaný atómom fluóru, hydroxyskupinou, ktorá je voliteľne chránená ľahko odstrániteľnou chrániacou hydroxyskupinou alebo aminoskupinou, ktorá je voliteľne chránená ľahko odstrániteľnou amino chrániacou skupinou;R c is (C first 6) alkyl which is unsubstituted or substituted by fluoro, hydroxy, which is optionally protected by a readily removable protecting hydroxyl or amino group which is optionally protected by a readily removable amino protecting group;

Rd je vodík alebo metyl;R d is hydrogen or methyl;

-C02Re je karboxy alebo karboxylovaný anión alebo skupina R® je ľahko odstrániteľná karboxy chrániacou skupinou.-CO 2 R e is a carboxy or carboxylated anion or the group R 8 is an easily removable carboxy protecting group.

Podstata vynálezuSUMMARY OF THE INVENTION

Ŕodľa vynálezu zlúčeninou vzorca (I) je: , ’According to the invention, the compound of formula (I) is: '

kde R je vybrané zo skupiny obsahujúcej izobutyryloxymetyl, (5-metyl-2-oxo-1,3dioxolen-4-yl) metyl a benzoyloxymetyl.wherein R is selected from the group consisting of isobutyryloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl and benzoyloxymethyl.

Konkrétnymi zlúčeninami podľa predmetného vynálezu sú najmä: izobutyryloxymetyl (5R,6S)-2-[1 -ety l-5-mety I py razol-3-yl]-6-[( 1 R)-1 -hydroxyetyl]-karbapen-2-ém-3-karboxylát, (5-metyl-2-oxo-1,3dioxolen-4-yl)metyl(5R,6S)-2-[1-etyl-5-metylpyrazol~3-yl]-6[(1 R)-1-hydroxyetyl]-karbapen-2-em-3-karboxylát aParticular compounds of the present invention are in particular: isobutyryloxymethyl (5R, 6S) -2- [1-ethyl-5-methylpyrazol-3-yl] -6 - [(1R) -1-hydroxyethyl] -carbapen- 2-em-3-carboxylate, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl (5R, 6S) -2- [1-ethyl-5-methylpyrazol-3-yl] -6 [ (1R) -1-hydroxyethyl] -carbapen-2-em-3-carboxylate a

- 4 benzoyloxymetyl (5R,6S)-2-[1 -etyl-5-metylpyrazol-3-yl]-6-[(1 R)-1 -hydroxyetyl]-karbapen-2-em-3-karboxylát.4-Benzoyloxymethyl (5R, 6S) -2- [1-ethyl-5-methylpyrazol-3-yl] -6 - [(1R) -1-hydroxyethyl] carbapen-2-em-3-carboxylate.

Každá zlúčenina karbapenému podľa vynálezu je určená na použitie vo farmaceutických kompozíciách, rozumie sa, že je pripravená v podstate v čistej forme, napríklad najmenej 50 % čistá, viac vhodná najmenej 75 % čistá a výhodne najmenej 95 % čistá (% hmotn./hmotn). Nečisté prípravky zlúčenín môžu byť použité na prípravu čistejších foriem používaných vo farmaceutických kompozíciách. Výhodne, vždy keď je to možné, každá zlúčenina vynálezu je získaná v kryštalickej forme.Each carbapenem compound of the invention is intended for use in pharmaceutical compositions, it is understood that it is prepared in substantially pure form, for example at least 50% pure, more preferably at least 75% pure and preferably at least 95% pure (% w / w) . Unclean formulations of the compounds can be used to prepare cleaner forms used in pharmaceutical compositions. Preferably, whenever possible, each compound of the invention is obtained in crystalline form.

Keďže každá zlúčenina tohto vynálezu môže byť získaná kryštalizáciou alebo rekryštalizáciou z organických rozpúšťadiel, rozpúšťadlo z kryštalizácie môže byť prítomné v kryštalickom produkte. Vynález zahŕňa tiež rozsah možných rozpúšťadiel. Podobne zlúčeniny podľa vynálezu môžu byť kryštalizované alebo re kryštalizované z rozpúšťadiel obsahujúcich vodu. V týchto prípadoch hydrátová voda môže byť prítomná v kryštalickom produkte. Vynález tiež zahŕňa rozsah stechiometrických hydrátov. , · ’ 'Since each compound of the invention may be obtained by crystallization or recrystallization from organic solvents, the solvent from the crystallization may be present in the crystalline product. The invention also encompasses a range of possible solvents. Similarly, the compounds of the invention may be crystallized or re-crystallized from water-containing solvents. In these cases, hydrate water may be present in the crystalline product. The invention also encompasses a range of stoichiometric hydrates. "·"

Karbapenémové antibiotické zlúčeniny podľa vynálezu môžu byť pripravené vhodným spôsobom na použitie v ľudskej alebo veterinárnej medicíne, podľa techník a spôsobov známych v technike s odvolaním sa na ďalšie antibiotiká. Preto do rozsahu vynálezu spadajú tiež farmaceutické kompozície obsahujúce antibiotické zlúčeniny podľa vynálezu spolu s farmaceutický akceptovateľným nosičom alebo vehikulom.The carbapenem antibiotic compounds of the invention may be prepared by a suitable method for use in human or veterinary medicine, according to techniques and methods known in the art with reference to other antibiotics. Accordingly, the invention also includes pharmaceutical compositions comprising the antibiotic compounds of the invention together with a pharmaceutically acceptable carrier or vehicle.

Kompozície môžu byť pripravené na aplikáciu akoukoľvek vhodnou cestou, takou ako orálnou, parenterálnou alebo lokálnou aplikáciou, hoci orálna cesta je výhodnejšia. Kompozície môže byť vo forme tabletiek, kapsúl, práškov, granúl, pastiliek, krémov alebo tekutých prípravkov takých, ako orálne alebo sterilné parenterálne roztoky alebo suspenzie. Tabletky a kapsuly na orálnu aplikáciu môžu byť jednotlivo dávkované v uvedenej forme a môžu obsahovať zvyčajné vehikulum také ako spojivá, napríklad, akáciový sirup, želatína, sorbitol, kozinec (tragant) alebo polyvinylpyrolidón; plnivá, napríklad laktózu, cukor, kukuričný škrob, fosforečnan vápenatý, sorbitol alebo glycín; tabletovacie lubrikanty, napríklad stearan horečnatý, mastenec, polyetylén glykolu alebo oxid kremičitý: dezintegrantyThe compositions can be prepared for administration by any suitable route, such as oral, parenteral or topical administration, although the oral route is more preferred. The composition may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations such as oral or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be individually dosed in the form indicated and may contain a conventional vehicle such as a binder, for example, acacia syrup, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tableting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica: disintegrants

- 5 ako napríklad zemiakový škrob; alebo prijateľné zvlhčujúce činidlá, také ako lauryl sulfát sodný. Tablety môžu byť potiahnuté spôsobmi dobre známymi vo farmaceutickom priemysle. Orálne tekuté prípravky môžu byť napríklad vo forme vodných alebo olejových suspenzií, roztokov, emulzií, sirupov alebo elixírov alebo môžu byť pripravené ako suché produkty vhodné na riedenie vodou alebo inými vhodnými nosičmi pred použitím. Tieto tekuté prípravky môžu obsahovať bežné aditíva také ako suspenzačné činidlá, napríklad sorbitol, metylcelulózu, glukózový sirup, želatínu, hydroxyetylcelulózu, karboxymetyicelulózu, gél stearátu hliníka alebo hydrogenované jedlé tuky; emulzifikačné činidlá napríklad lecitín, sorbitan, monooleáty alebo klovatina; nevodné nosiče (ktoré môžu obsahovať jedlé oleje), napríklad mandľový olej, olejové estery, glycerín, propylénglykol alebo etylalkohol; konzervačné prísady, napríklad metyl alebo propyl-p-hydroxybenzoát alebo kyselina sorbová; pokiaľ je to požadované tiež bežné arómy alebo farbivá. Čapíky môžu obsahovať bežný čapíkový základ ako napríklad kakaové maslo alebo iné glyceridy.- 5 such as potato starch; or acceptable wetting agents, such as sodium lauryl sulfate. The tablets may be coated by methods well known in the pharmaceutical industry. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be prepared as a dry product suitable for dilution with water or other suitable carriers before use. These liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, methylcellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyicellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan, monooleate or acacia; non-aqueous carriers (which may contain edible oils), for example, almond oil, oily esters, glycerin, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; if desired also conventional flavorings or coloring agents. The suppositories may contain a conventional suppository base such as cocoa butter or other glycerides.

Tekúté formy na parenterálne dávkovanie sú pripravené zo zlúčeniny a sterilného· nosiča,, výhodne vody. Zlúčenina v závislosti ód nosiča a použitejLiquid forms for parenteral dosage are prepared from a compound and a sterile carrier, preferably water. Compound depending on carrier and used

I koncentrácie, môže byť tiež suspendovaná alebo rozpustená v nosiči. Pri príprave roztokov zlúčenina môže byť rozpustená v injekčnej vode a sterilizovaná pred naplnením do vhodnej nádobky alebo ampulky a utesnená. Výhodne, činitele, také ako lokálne anestetiká, konzervačné a pufrujúce činitele, môžu byť rozpustené v nosiči. Kompozícia môže byť zmrazená po naplnení do ampuliek a voda odstránená pod vákuom za účelom zvýšenia stability. Suchý lyofilizovaný prášok je potom uzatvorený v ampulkách. K týmto ampulkám je možné priložiť osobitne vodu v ampulke potrebnú na prípravu tekutej dávky pred použitím. Parenterálne suspenzie sú pripravované v podstate podobným spôsobom okrem toho, že zlúčenina je suspendovaná v nosiči namiesto toho, aby bola rozpustená a sterilizovaná, nemôže byť ustálená filtráciou. Zlúčenina môže byť sterilizovaná expozíciou oxidu etylénu pred suspendovaním v sterilnom nosiči. Výhodne povrchovo aktívna látka alebo zmáčadlo je obsiahnuté v kompozícii s cieľom dosiahnutia rovnomernej distribúcie zlúčeniny.Also, the concentration may also be suspended or dissolved in the carrier. In preparing solutions, the compound may be dissolved in injection water and sterilized prior to filling into a suitable vial or ampoule and sealed. Preferably, agents, such as local anesthetics, preservatives and buffering agents, can be dissolved in the carrier. The composition can be frozen after filling into ampoules and water removed under vacuum to increase stability. The dry lyophilized powder is then encapsulated in ampoules. These ampoules may in particular be accompanied by the water in the ampoule required to prepare the liquid dose before use. Parenteral suspensions are prepared in a substantially similar manner except that the compound is suspended in the carrier instead of being dissolved and sterilized cannot be stabilized by filtration. The compound may be sterilized by exposure to ethylene oxide prior to suspension in a sterile carrier. Preferably, the surfactant or wetting agent is included in the composition to achieve a uniform distribution of the compound.

Kompozícia môže obsahovať 0,1% až 99,5% hmotnostných, výhodne 10 až 60% hmotnostných účinnej látky v závislosti na spôsobe dávkovania. KeďThe composition may contain 0.1% to 99.5% by weight, preferably 10 to 60% by weight, of active ingredient, depending on the method of dosing. When

-(5kompozície pozostávajú z dávkovacích jednotiek, každá jednotka bude výhodne obsahovať 50 až 500 mg aktívnej zložky. Dávka na použitie pri liečbe dospelých ľudí bude výhodne v rozsahu 100 mg až 12 g za deň pre priemerného dospelého pacienta (telesná váha 70 kg), napríklad 1500 mg na deň v závislosti na spôsobe a frekvencii dávkovania. Takéto dávky zodpovedajú približne od 1,5 až 170mg/kg za deň. Vhodné dávkovanie je 1 až 6 g za deň.(5 compositions consist of dosage units, each unit will preferably contain 50 to 500 mg of active ingredient. The dose for use in the treatment of adult humans will preferably be in the range of 100 mg to 12 g per day for an average adult patient (body weight 70 kg). 1500 mg per day, depending on the mode and frequency of dosing, such dosages are from about 1.5 to 170 mg / kg per day, preferably 1 to 6 g per day.

Výhodne denná dávka zlúčeniny podľa vynálezu je podávaná niekoľkokrát za 24 hodín. Obyčajne 250 mg je podávané 4-krát za deň, hoci v praxi jednotlivá dávka a frekvencia jej podávania sa môže meniť v závislosti od individuálneho pacienta a to s vekom, váhou a reakciou pacienta. V závislosti od prípadu lekár môže stanoviť vyššiu alebo nižšiu dávku a rôznu frekvenciu podávania lieku. Tieto dávkované množstvá spadajú do rozsahu predmetu tohto vynálezu.Preferably, the daily dose of the compound of the invention is administered several times per 24 hours. Usually 250 mg is administered 4 times a day, although in practice the single dose and frequency of administration may vary depending on the individual patient, with the patient's age, weight and response. Depending on the case, the physician may determine a higher or lower dose and a different frequency of administration. These dosages are within the scope of the present invention.

Žiadne toxikologické účinky neboli indikované, keď zlúčenina podľa vynálezu bola podávaná vo vyššie uvedenom rozsahu dávkovania.No toxicological effects were indicated when the compound of the invention was administered in the above dosage range.

Predmetom vynálezu je tiež spôsob liečenia bakteriálnych infekcií u ľudí a zvierat, ktorý zahrňuje dávkovanie terapeuticky účinného množstva antibiotickej zlúčeniny podľa vynálezu vzorca (I).The invention also provides a method of treating bacterial infections in humans and animals, comprising administering a therapeutically effective amount of an antibiotic compound of the invention of formula (I).

Ďalším aspektom predmetného vynálezu je použitie zlúčeniny vzorca (I) na výrobu liečiv na liečenie bakteriálnych infekcií.Another aspect of the present invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment of bacterial infections.

Zlúčeniny podľa vynálezu vzorca (I) sú účinné proti širokému rozsahu Grampozitívnych a Gram-negatívnych baktérií a môžu byť použité na liečenie širokého rozsahu bakteriálnych infekcií zahrňujúcich infekcie imunitné oslabených pacientov.The compounds of the invention of formula (I) are effective against a wide range of Gram-positive and Gram-negative bacteria and can be used to treat a wide range of bacterial infections including immune-compromised infections.

Medzi mnohé ďalšie použitia zlúčenín podľa predmetného vynálezu patrí liečba kože, mäkkého tkaniva, liečba infekcií dýchacieho a močového traktu ľudí. Zlúčeniny podľa vynálezu môžu byť tiež použité na liečenie mastitidy dobytka.Many other uses of the compounds of the present invention include treatment of skin, soft tissue, treatment of human respiratory and urinary tract infections. The compounds of the invention may also be used to treat cattle mastitis.

Výhodou antibakteriálne účinných zlúčenín podľa vynálezu je ich stabilita na enzýmy β-laktamázy, a preto sú účinné proti β-laktamáze produkovanej organizmom.An advantage of the antibacterially active compounds of the invention is their stability to β-lactamase enzymes and therefore they are effective against β-lactamase produced by the organism.

Predmetom vynálezu je dalej spôsob prípravy zlúčeniny vzorca (I), kde R je izobutyryloxymetyl alebo benzoyloxymetyl, pričom na príslušnú zlúčeninu vzorca (I), kde R je alkalický kovový katión sa pôsobí zlúčeninou vzorca XCH2OCOCHMe2 The invention further provides a process for the preparation of a compound of formula (I) wherein R is isobutyryloxymethyl or benzoyloxymethyl, wherein the corresponding compound of formula (I) wherein R is an alkali metal cation is treated with a compound of formula XCH 2 OCOCHMe 2

- 7 alebo XCH2OCOC6H5, kde X je východisková skupina taká ako halogén, výhodne bróm alebo jód.7 or XCH 2 OCOC 6 H 5 , wherein X is a starting group such as halogen, preferably bromine or iodine.

Reakcia je obyčajne uskutočňovaná pri 0 až 60 °C, napríklad pri teplote okolia, v inertnej atmosfére, napríklad argóne, vo vhodnom organickom rozpúšťadle, napríklad N-metyl-2-pyrolidinóne. Ďalšie vhodné rozpúšťacie systémy zahrňujú Ν,Ν’-dimetylformamid a N,N’-dimetylacetamid.The reaction is conveniently carried out at 0 to 60 ° C, for example at ambient temperature, under an inert atmosphere, for example argon, in a suitable organic solvent, for example N-methyl-2-pyrrolidinone. Other suitable solvent systems include Ν, Ν´-dimethylformamide and N, N´-dimethylacetamide.

Predmetom vynálezu je tiež spôsob prípravy zlúčeniny podľa vzorca (I), kde R je (5-metyl-2-oxo-1,3-dioxolen-4-yl)metyl, pričom na príslušnú zlúčeninu vzorca (I), kde R je alkalický kovový katión, sa pôsobí zlúčeninou vzorca:The present invention also provides a process for the preparation of a compound of formula (I) wherein R is (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl, wherein the corresponding compound of formula (I) wherein R is alkali a metal cation is treated with a compound of the formula:

kde X východisková skupina taká ako halogén; výhodne bróm alebo jód.wherein X is a starting group such as halogen; preferably bromine or iodine.

Reakcia je obyčajne vedená pri teplote 0 až 60 °C, napríklad pri teplote okolia, vo vhodnom organickom rozpúšťadle, napríklad N-metyl-2-pyrrolidinon a v prítomnosti kyslého spojiva ako napr. 2,6-lutidin. Ďalšie vhodné kyslé spojivá zahrnujú pyridín a diizopropyletylamin. Ďalšie vhodné rozpúšťadlá zahrnujú Ν,Ν’dimetylformamid a N,N’-dimetylacetamid.The reaction is conveniently conducted at a temperature of 0 to 60 ° C, for example at ambient temperature, in a suitable organic solvent, for example N-methyl-2-pyrrolidinone, and in the presence of an acidic binder such as e.g. 2,6-lutidine. Other suitable acidic binders include pyridine and diisopropylethylamine. Other suitable solvents include Ν, Ν´dimethylformamide and N, N´-dimethylacetamide.

Zlúčeniny vzorca (I), kde R je alkalický kovový katión ako napríklad sodík, sú opísané v medzinárodnej prihláške vynálezu č. PCT/ GB94/02347 a nižšie v Príprave 1.,Compounds of formula (I) wherein R is an alkali metal cation such as sodium are disclosed in International Patent Application Ser. PCT / GB94 / 02347 and below in Preparation 1.,

Zlúčenina vzorca ICH2OCOCHMe2 (jódmetylizobutyrát) a jódmetylbenzoát môže byť pripravená z príslušných chloridov prostredníctvom Finkelsteinovej reakcie, ktorá je dobre známa v odborných kruhoch.The compound of formula ICH 2 OCOCHMe 2 (iodomethylisobutyrate) and iodomethylbenzoate can be prepared from the corresponding chlorides via a Finkelstein reaction, which is well known in the art.

Chlórmetyiizobutyrát a chlórmetylbenzoát môžu byť pripravované esterifikáciou kyseliny maslovej alebo kyseliny benzoovej jednotlivo z chlórmetyichlórsulfátu (Binderup a spol., Synthetic Commun., 14(9), 857 až 864 (1984)).Chloromethyl isobutyrate and chloromethyl benzoate can be prepared by esterifying butyric acid or benzoic acid individually from chloromethylchlorosulfate (Binderup et al., Synthetic Commun., 14 (9), 857-864 (1984)).

Všeobecné inštrukcie - Roztoky boli sušené použitím bezvodého síranu horčíka a rozpúšťadlá boli odstránené odparovaním pri zníženom tlaku s použitím rotačnej odparky. Stĺpcová chromatografia na silikagéli s použitím Merckovho silikágeluGeneral Instructions - The solutions were dried using anhydrous magnesium sulfate and the solvents were removed by evaporation under reduced pressure using a rotary evaporator. Silica gel column chromatography using Merck silica gel

60, častice rozmeru < .0,063 mm.60, particle size <.0.063 mm.

Príklad 1Example 1

Príklady uskutočnenia vynálezu lzobutyryloxymetyl-(5R,6S)-2-(1-etyl-5-metylpyrazol-3-yl)-6-[(1R)-1-hydroxyetyl]karbapen-2-ém-3-karboxylátEXAMPLES Isobutyryloxymethyl (5R, 6S) -2- (1-ethyl-5-methylpyrazol-3-yl) -6 - [(1R) -1-hydroxyethyl] carbapen-2-em-3-carboxylate

Produkt z Prípravy 1 (200 mg 0,61 mmol) bol rozpustený v N-metyl-2pyrolidinóne (2ml). Bol pridaný roztok izobutyryloxymetyljodidu (360 mg, 1,6 mmol) v N-metyl-2-pyrolidinóne (0,5 ml) pri izbovej teplote v atmosfére argónu a po 0,5 hodipe reakčná zmes bola zriedená etylacetátom (15 ml). Roztok bol premývaný vodou (3 x 15 ml), 5% roztokom thiosulfátu sodného (15ml) a potom saturovaný soľným vodným roztokom (15 ml). Organický extrakt bol vysušený (Na2SO4) a koncentrovaný na olej, ktorý bol čistený chromatografický na silikágeli, eluovaný zmesou acetónom/toluénom až do získania bledožltého produktu, ktorý bol skryštalizovaný z dietyléteru, čím sa získala zlúčenina ako bledožlté mikroihly (100 mg, 40 %), teplota topenia107 až 108 °C; (Zistené: M+,405.1899.The product of Preparation 1 (200 mg 0.61 mmol) was dissolved in N-methyl-2-pyrrolidinone (2ml). A solution of isobutyryloxymethyl iodide (360 mg, 1.6 mmol) in N-methyl-2-pyrrolidinone (0.5 mL) was added at room temperature under argon and after 0.5 h the reaction mixture was diluted with ethyl acetate (15 mL). The solution was washed with water (3 x 15 mL), 5% sodium thiosulfate solution (15 mL) and then saturated with brine (15 mL). The organic extract was dried (Na 2 SO 4 ) and concentrated to an oil which was purified by chromatography on silica gel, eluting with acetone / toluene to give a pale yellow product which was crystallized from diethyl ether to give the compound as pale yellow micro-needles (100 mg, 40%), m.p. 107-108 ° C; (Found: M @ + , 405.1899).

C20H27N3O6 vyžaduje M 405.1900); vmax (CHCI3) 3458,3019,1772 a 1734 cm·1; ÓH(CDCL3) 1,19 (6H, d, J7,1 Hz), 1,36 (3H, d, J6,1 Hz), 1,40 (3H, t, J7,2 Hz), 1,76 (1H, d, J4, 9Hz), 2,29 (3H, s), 2,62 (1H, septet, J7,1 Hz), 3,18 (1H, dd, J2.7, 6,5Hz), 3,30 (1H, dd, J9,0, 18,8Hz), 3,64 (1H, dd, J9,8, 18,8Hz), 4,08 (2H, q, J7,2 Hz), 4,16-4,30 (2H,m), 5,92 (1 H, d, J5,6 Hz), 5,98 (1 H, d, J5,6 Hz) a 7,02 (1 H,s).C 20 H 27 N 3 O 6 requires M 405.1900); ν max (CHCl 3 ) 3458, 3019, 1772, and 1734 cm -1 ; Δ H (CDCl 3 ) 1.19 (6H, d, J 7.1 Hz), 1.36 (3H, d, J 6.1 Hz), 1.40 (3H, t, J 7.2 Hz), 1, 76 (1H, d, J 4, 9Hz), 2.29 (3H, s), 2.62 (1H, septet, J7.1 Hz), 3.18 (1H, dd, J2.7, 6.5Hz) 3.30 (1H, dd, J9.0, 18.8Hz), 3.64 (1H, dd, J9.8, 18.8Hz), 4.08 (2H, q, J7.2 Hz), 4 16-4.30 (2H, m), 5.92 (1H, d, J5.6 Hz), 5.98 (1H, d, J5.6 Hz) and 7.02 (1H, s) ).

-9Príklad 2 (5-Metyl-2-oxo-1,3-dioxolen-4-yl)metyl-(5R,6S)-6-[(R)-1-hydroxyetyl]-2-(1-etyl-5metyl-pyrazoI-3-yl)karbapen-2-ém-3-karboxylát (5R,6S)-6-[(R)-1-hydroxyetyl]-2-(1-etyl-5-metylpyrazol-3-yl)karbapen-2-ém-3karboxylát sodný (300 mg) v N-metylpyrolidinóne (4 ml) bol spracovaný s 2,6lutidínom (cca 30 mg) následne bol pridaný 4-brómmetyl-5-metyl-1,3-dioxol-2-ón (290 mg) [F.Sakamoto, S.lkeda a G. Tsukamoto, Chem.Pharm. Bull.32, (6), 2241 až 2248 (1984) ] v tetrahydrofuráne (1 ml). Zmes bola miešaná 1,25 hodiny. Bol dodaný etylacetát a voda a vrstvy boli odseparované. Vodná fáza bola reextrahovaná s etylacetátom a zlúčené etylacetátové fázy boli premývané vodou, nasledovalo saturovannie soľným vodným roztokom a potom nasledovalo sušenie (MgSO4). Prefiltrovaný roztok bol uskladnený cez noc v chladničke a potom odparený a chromatografovaný na silikagéli (230 až 400 otvorov ASTM) (2,5 x 12 cm kolóna) v CH2CI2/hexáne. Eluovanie bolo vykonané' pomocou etylacetátu. Frakcie obsahujúce produkt boli spojené a odparené za účelom získania bezfarebnej látky, ktorá bola rekryštalizovaná z acetónu za účelom získania kryštálov (5-metyl-oxo-1,3-dioxolen-4-yl)metyl-(5R,6S)-6-[(R)-1-hydroxyetyl]-2-(1etyl-5-metylpyrazol-3-yl)karbapen-2-ém-3-karboxylátu, teplota topenia je 148 až 151 °C; vmax (CH2CI2) 3605, 2975, 1823, 1776, 1737 (sh), 1721, 1598, 1546, 1314, 1231 a 1182 crn'1;Xmax (EtOH/nm 325(s/dm3mol'1cm'1 14,654), 260,5 (ε/ dm3moľ1cm‘1 3404); δ (CDCI3) 1,36 (3H, d, J6,2 Hz), 1.40 (3H, t, J cca 7,3 Hz), 1,76 (1H, d, J 4,9 Hz), 2,21 (3H, s), 2,30 (3H,s), 3,19 (1H, dd, J2,7& 6,5 Hz), 3.31 (1H, dd, J9,0 & 18,7 Hz), 3,61 (1H, dd, J 9,9 & 18,7 Hz), 4,08 (2H, q J7,3 Hz), 4,16 - 4,30 (2H, m), 5,00 & 5,07 (2H, ABq, J13,9Hz), 6,88 (1H, s) ppm; zistené (El ms) m/z 417 (M+).-9 Example 2 (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl- (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2- (1-ethyl-5-methyl) (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2- (1-ethyl-5-methylpyrazol-3-yl) carbapen-pyrazol-3-yl) carbapen-2-ene Sodium -2-em-3-carboxylate (300 mg) in N-methylpyrrolidinone (4 ml) was treated with 2,6-glutidine (ca. 30 mg) followed by 4-bromomethyl-5-methyl-1,3-dioxol-2-one (290 mg) [F. Sakamoto, S.lkeda and G. Tsukamoto, Chem. Bull. 32, (6), 2241-2248 (1984)] in tetrahydrofuran (1 mL). The mixture was stirred for 1.25 hours. Ethyl acetate and water were added and the layers were separated. The aqueous phase was re-extracted with ethyl acetate, and the combined ethyl acetate phases were washed with water, followed by saturation with brine, followed by drying (MgSO 4 ). The filtered solution was stored in a refrigerator overnight and then evaporated and chromatographed on silica gel (230-400 ASTM holes) (2.5 x 12 cm column) in CH 2 Cl 2 / hexane. Elution was carried out with ethyl acetate. Product containing fractions were combined and evaporated to give a colorless material which was recrystallized from acetone to give (5-methyl-oxo-1,3-dioxolen-4-yl) methyl- (5R, 6S) -6- [ (R) -1-hydroxyethyl] -2- (1-ethyl-5-methylpyrazol-3-yl) carbapen-2-em-3-carboxylate, m.p. 148-151 ° C; v max (CH 2 Cl 2 ) 3605, 2975, 1823, 1776, 1737 (sh), 1721, 1598, 1546, 1314, 1231 and 1182 cm -1 ; Xmax (EtOH / nm 325 (s / dm 3 mol -1) cm -1 11.654), 260.5 (ε / dm 3 m 1 cm -1 1,340); δ (CDCl 3) 1.36 (3H, d, J 6.2 Hz), 1.40 (3H, t, J ca. 7, 3 Hz), 1.76 (1H, d, J 4.9 Hz), 2.21 (3H, s), 2.30 (3H, s), 3.19 (1H, dd, J2.7 &amp; 6, 5 Hz), 3.31 (1H, dd, J9.0 & 18.7 Hz), 3.61 (1H, dd, J 9.9 & 18.7 Hz), 4.08 (2H, q J7.3 Hz) ), 4.16-4.30 (2H, m), 5.00 & 5.07 (2H, ABq, J 13.9Hz), 6.88 (1H, s) ppm, found (EI ms) m / z 417 (M &lt; + &gt; ).

Príklad 3Example 3

Produkt z Prípravy 1 (200 mg 0,61 mmol) bol rozpustený v N-metyl-2pyrolidinóne (2 ml). Bol pridaný roztok benzoyloxymetyljodidu (336 mg, 1,28 mmol)The product of Preparation 1 (200 mg 0.61 mmol) was dissolved in N-methyl-2-pyrrolidinone (2 mL). Benzoyloxymethyl iodide solution (336 mg, 1.28 mmol) was added.

- 10 v N-metyl-2-pyrolidinóne (0,5 ml) pri izbovej teplote v atmosfére argónu a po 0,5 hodine reakčná zmes bola zriedená etylacetátom (15 ml). Roztok bol premývaný vodou (3 x 15ml), 5% roztokom thiosulfátu sodného (15 ml) a potom saturovaný soľným vodným roztokom (15 ml). Organický extrakt bol vysušený (Na2SO4) a koncentrovaný na olej, ktorý bol čistený chromatograficky na silikagéli, eluovaný zmesou acetón/toluén až do získania bledožltého produktu, ktorý bol rekryštaiizovaný z dietyléteru, čím bola získaná zlúčenina - biela látka (143 mg, 53 %), teplota topenia131 až 134 °C; (zistené: M+,439.1743. C22H25N3O6 vyžaduje M 439.1743); vmax (CHCI3) 3021, 1740,1602, 1452 a 1440 cm'1; ÔH(CDCL3) 1,34 (6H,10 in N-methyl-2-pyrrolidinone (0.5 mL) at room temperature under argon and after 0.5 h the reaction mixture was diluted with ethyl acetate (15 mL). The solution was washed with water (3 x 15 mL), 5% sodium thiosulfate solution (15 mL) and then saturated with brine (15 mL). The organic extract was dried (Na 2 SO 4 ) and concentrated to an oil which was purified by silica gel chromatography, eluting with acetone / toluene until a pale yellow product was obtained, which was recrystallized from diethyl ether to give a white compound (143 mg, 53%), m.p. 131-134 ° C; (Found: M + , 439.1743. C22H25N3O6 requires M 439.1743); ν max (CHCl 3) 3021, 1740, 1602, 1452 and 1440 cm -1 ; ÔH (CDCL 3 ) 1.34 (6H,

m), 1,70 (1H, d, J4,9 Hz), 2,25 (3H, s), 3,19 (1H, dd, J2,4, 6,3Hz), 3,30 (1H, dd, J8,8, 18,8Hz), 3,64 (1H, dd, J10,1, 18,8 Hz), 4,07 (2H, q, J7,2Hz), 4,18-4,31 (2H, m), 6,20 (2H, s), 7,42-7,48 (2H, m), 7,56-7,61 (1H,m) a 8,0 (2H, d, J7,1 Hz) ppm.m), 1.70 (1H, d, J 4.9 Hz), 2.25 (3H, s), 3.19 (1H, dd, J2.4, 6.3Hz), 3.30 (1H, dd) , J8.8, 18.8Hz), 3.64 (1H, dd, J10.1, 18.8 Hz), 4.07 (2H, q, J7.2Hz), 4.18-4.31 (2H , m), 6.20 (2H, s), 7.42-7.48 (2H, m), 7.56-7.61 (1H, m), and 8.0 (2H, d, J7.1) Hz) ppm.

Príprava 1 (5R,6S)-6-[(R)-1-hydroxyetyl]-2-(1-etyl-5-metylpyrazol-3-yl)karbapen-2-ém-3- karboxylát (a) Etyl 1-etyl-5-metylpyrazol-3-karboxylátPreparation 1 (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2- (1-ethyl-5-methylpyrazol-3-yl) carbapen-2-em-3-carboxylate (a) Ethyl 1- ethyl-5-methylpyrazole-3-carboxylate

N-Etylhydrazín oxalát (12 g) v ľadovej kyseline octovej (100 ml) bol ochladený v ľadovom kúpeli a spracovaný s etyl 2,4-dioxovaleranom (11,24 ml). Následne zmes bola miešaná pri izbovej teplote; po cca 45 minútach zmes bola zahrievaná s cieľom rozpustiť nerozpustený etylhydrazin oxalát. Zmes bola miešaná ďalšie 2 hodiny a potom naliata do vody (cca 3000 ml)/etylacetátu (cca 700 ml), opatrne počas miešania bol dodávaný tuhý K2CO3 až pH bolo neutrálne. Po oddelení vodná fáza bola reextrahovaná etylacetátom. Zmiešané etylacetátové extrakty boli usušené (MgSOJ a rozpúšťadlá boli odstránené z oleja.N-Ethylhydrazine oxalate (12 g) in glacial acetic acid (100 mL) was cooled in an ice bath and treated with ethyl 2,4-dioxovalerate (11.24 mL). Subsequently, the mixture was stirred at room temperature; after about 45 minutes the mixture was heated to dissolve the undissolved ethylhydrazine oxalate. The mixture was stirred for an additional 2 hours and then poured into water (ca. 3000 ml) / ethyl acetate (ca. 700 ml), solid K 2 CO 3 was added carefully while stirring until the pH was neutral. After separation, the aqueous phase was re-extracted with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4 and solvents removed from the oil).

Chromatografia na silikágeli v CH2CL2/hexáne a stupňovité vymývanie zmesou etylacetát/hexán (pomer od 2:8 ku 1:1) poskytlo 1-etyl-5-metylpyrazol-3karboxylát ako olej (13,2g); vmax (CH2CI2) 1717, 1446, 1389 a 1219 cm'1, Ô(CDCI3)Chromatography on silica gel in CH 2 Cl 2 / hexane and stepwise elution with ethyl acetate / hexane (2: 8 to 1: 1 ratio) gave 1-ethyl-5-methylpyrazole-3-carboxylate as an oil (13.2g); v max (CH 2 Cl 2 ) 1717, 1446, 1389 and 1219 cm -1 , Ô (CDCl 3 )

- 11 1,38 (3Η, t, J7,2 Hz), 1,42 (3H, t, J7,3 Hz), 2,30 (3H, s), 4,17 (2H, q, J 7,3 Hz), 4,38 (2H q, J 7,1 Hz), 6,55 (1H,s), (Zistené m/z 182.1055.C9H14N2O2 vyžaduje m/z 182.1055).Δ 11 1.38 (3Η, t, J 7.2 Hz), 1.42 (3H, t, J 7.3 Hz), 2.30 (3H, s), 4.17 (2H, q, J 7), 3 Hz), 4.38 (2H q, J 7.1 Hz), 6.55 (1H, s), (Found m / z 182.1055. 9 H 14 N 2 O 2 requires m / z 182.1055).

(b) Kyselina 1-etyl-5-metylpyrazol-3-karboxylová(b) 1-Ethyl-5-methylpyrazole-3-carboxylic acid

Etyl 1-etyl-5-metylpyrazol-3-karboxylát (10,39 g) v etanole (70 ml) bol spracovaný s KOH (3,69 g), následne bola pridaná voda (30 ml) a zmes bola miešaná a zahrievaná pod refluxom počas 6 hodín. Etanol bol odsunutý pomocou rotačnej odparky a bol pridaný etylacetát/voda. pH zmesi bolo upravené na 3,0 a fázy boli oddelené. Vodná vrstva bola reextrahovaná s etylacetátom. Spojené etylacetátové fázy boli extrahované nadbytkom vodného roztoku NaHCO3. NaHCO3 extrakt bol zaliaty nadbytkom kyseliny, pričom pH bolo upravené na 3. Do roztoku bol pridaný NaCI. Zmes bola potom opakovane extrahovaná etylacetátom a zmiešané extrakty boli vysušené (MgSO4) a odparené. Zvyšok bol rozotretý s dietyléterom s cieľom získať kyselinu ako tuhú látku (5.65 g), vmax (CH2CI2) -2754, 2598, 1698,1498,1387 a 1233 cm·1; 6(CDCI3) 1,40 (3H, t, J7,3Hz), 2,32 (3H, s), 4,19 (2H, q, J7,3Hz), 6,61 (1H, s) ppm; (Zistené m/z 154.0740 C7H10N2O2 vyžaduje m/z 154.0742).Ethyl 1-ethyl-5-methylpyrazole-3-carboxylate (10.39 g) in ethanol (70 ml) was treated with KOH (3.69 g), followed by addition of water (30 ml) and stirring and heating under reflux for 6 hours. Ethanol was removed by rotary evaporation and ethyl acetate / water was added. The pH of the mixture was adjusted to 3.0 and the phases were separated. The aqueous layer was re-extracted with ethyl acetate. The combined ethyl acetate phases were extracted with excess aqueous NaHCO 3 solution. The NaHCO 3 extract was quenched with excess acid while adjusting the pH to 3. NaCl was added to the solution. The mixture was then repeatedly extracted with ethyl acetate and the combined extracts were dried (MgSO 4 ) and evaporated. The residue was triturated with diethyl ether to give the acid as a solid (5.65 g), in max (CH 2 Cl 2 ) -2754, 2598, 1698, 1498, 1387, and 1233 cm -1 ; Δ (CDCl 3 ) 1.40 (3H, t, J 7.3 Hz), 2.32 (3H, s), 4.19 (2H, q, J 7.3 Hz), 6.61 (1H, s) ppm; (Found m / z 154.0740 C 7 H 10 N 2 O 2 requires m / z 154.0742).

(c) N-Metoxy-N-metyl-1 -etyl-5-metylpyrazol-3-karboxamid(c) N-Methoxy-N-methyl-1-ethyl-5-methylpyrazole-3-carboxamide

Kyselina 1-etyl-5-metylpyrazol-3-karboxylová (5,25 g) v suchom dichlórmetáne (100 ml) obsahujúca N,N-dimetylformamid (0,26 ml) bola chladená v ľadovom kúpeli a upravená roztokom oxalylchloridu (3,27 ml) v dichlórmetáne (25 ml), ktorý bol dodaný po kvapkách. Zmes bola miešaná 25 minút v chlade a potom zahriata na izbovú teplotu, pričom bol zistený vznik plynu. Po 10 minútach rozpúšťadlo bolo odstránené odparovaním vo vákuu a bol dodaný toulén a odstránený (2x), aby boli odstránené zbytky HCI a oxalyl chloridu. Výsledná chlorid kyseliny bol opätovne rozpustený v suchom dichlórmetáne a následne spracovaný s Ν,Ο-dimetylhydroxylamínom hydrochloridu (3,61 g). Zmes bola ochladená v ľadovom kúpeli a bol pridaný pyridín (6 ml). Zmes bola potom miešaná v izbovej1-Ethyl-5-methylpyrazole-3-carboxylic acid (5.25 g) in dry dichloromethane (100 mL) containing N, N-dimethylformamide (0.26 mL) was cooled in an ice bath and treated with a solution of oxalyl chloride (3.27) ml) in dichloromethane (25 ml), which was added dropwise. The mixture was stirred in the cold for 25 minutes and then warmed to room temperature for gas evolution. After 10 minutes the solvent was removed by evaporation in vacuo and toluene was added and removed (2x) to remove the HCl residue and oxalyl chloride. The resulting acid chloride was redissolved in dry dichloromethane and then treated with Ν, Ο-dimethylhydroxylamine hydrochloride (3.61 g). The mixture was cooled in an ice bath and pyridine (6 mL) was added. The mixture was then stirred at room temperature

- 12 teplote počas 1,5 hodiny a následne zriedená éterom (100 ml) a premytá soľným vodným roztokom. Organická fáza bola vysušená (MgSOJ a odparená s cieľom vylúčenia oleja. Chromatografia bola uskutočnená na silikágeli za použitia dichlórmetán/hexánu a vymývania zmesou etylacetát/hexán, aby po odparení potrebných frakcií sa získal hydroxamát (5,2 g) ako tuhá látka;- temperature for 1.5 h and then diluted with ether (100 mL) and washed with brine. The organic phase was dried (MgSO 4 and evaporated to give an oil. Chromatography on silica gel using dichloromethane / hexane and eluting with ethyl acetate / hexane to give the hydroxamate (5.2 g) as a solid after evaporation of the necessary fractions;

vmax (CH2CI2) 2982, 2937, 1641,1489,1445 1379 a 975 cm’1; Ô(CDCI3) 1,43 (3H, t, J7,3Hz), 2,29 (3H, s), 3,42 (3H, s), 3,76 (3H, s), 4,13 (2H, q, J7,3 Hz), 6,49 (1H, s); (zistené m/z 197.1164. C9H15N3O2 vyžaduje m/z 197.1164). ν max (CH 2 Cl 2 ) 2982, 2937, 1641, 1489, 1445, 1379, and 975 cm -1 ; Δ (CDCl 3 ) 1.43 (3H, t, J 7.3 Hz), 2.29 (3H, s), 3.42 (3H, s), 3.76 (3H, s), 4.13 (2H , q, J 7.3 Hz), 6.49 (1H, s); (found m / z 197.1164. C 9 H 15 N 3 O 2 requires m / z 197.1164).

(d) 3-Acetyl-1 -etyl-5-metylpyrazol(d) 3-Acetyl-1-ethyl-5-methylpyrazole

N-Metoxy-N-metyl-1-etyl-5-metylpyrazol-3-karboxyamid (3,12 g) v suchom tetrahydrofuráne (60 ml) bol chladený v ľadovom kúpeli a upravený 3M roztokom metylmagnéziumbromidu v éteri (11,8 ml). Zmes bola miešaná 1,5 hodiny a následne naliata do zmesi metanolu (100 ml) a 5M vodného roztoku HCI (10 ml) v ľadovom kúpeli. Zmes-bola odparená na nízky objem a bola' pridaná zmes dichlórmetánu, vody a nasýteného soľného roztoku. Po oddelení vodná fáza bola reextrahovaná dichlórmetánom. Spojené dichlórmetanové extrakty boli sušené (MgSOJ a odparené, aby sa výlučil olej, .(2,26 g), ktorý tuhol stáním.N-Methoxy-N-methyl-1-ethyl-5-methylpyrazole-3-carboxyamide (3.12 g) in dry tetrahydrofuran (60 mL) was cooled in an ice bath and treated with a 3M solution of methylmagnesium bromide in ether (11.8 mL) . The mixture was stirred for 1.5 hours and then poured into a mixture of methanol (100 mL) and 5M aqueous HCl (10 mL) in an ice bath. The mixture was evaporated to low volume and a mixture of dichloromethane, water and saturated brine was added. After separation, the aqueous phase was re-extracted with dichloromethane. The combined dichloromethane extracts were dried (MgSO 4 and evaporated to give an oil (2.26 g) which solidified on standing.

vmax (CH2CI2) 1680,1446,1425,1380,1324,1280 a 945 cm·1; Ô(CDCI3) 1,44 (3H, t, J7,3Hz), 2,30 (3H, s), 2,53 (3H, s), 4,13 (2H, q, J7,3 Hz), 6,61 (1H, s); (zistené m/z 152.0949. C8H12N2O vyžaduje m/z 152.090).v max (CH 2 Cl 2 ) 1680, 1446, 1425, 1380, 1324, 1280, and 945 cm -1 ; Δ (CDCl 3 ) 1.44 (3H, t, J 7.3 Hz), 2.30 (3H, s), 2.53 (3H, s), 4.13 (2H, q, J7.3 Hz), 6.61 (1 H, s); (found m / z 152.0949. C 8 H 12 N 2 O requires m / z 152.090).

(e) (3S,4R)-4-[(1-etyl-5-metylpyrazol-3-yl)karbonylmetyl]-3-[(R)-1-terc-butyldimetylsilyloxyetyl]-2-azetidinón(e) (3S, 4R) -4 - [(1-Ethyl-5-methylpyrazol-3-yl) carbonylmethyl] -3 - [(R) -1-tert-butyldimethylsilyloxyethyl] -2-azetidinone

3-Acetyl-1-etyl-5-metylpyrazol (3.51 g) v suchom tetrahydrofuráne (THF) (150 ml) v atmosfére argónu bol chladený v kúpeli acetón/tuhý dioxid uhlíka a potom spracovaný 1M roztokom lítium-bis(trimetylsilyl)amidu (50 ml). Zmes bola miešaná 45 minút a potom bol pridaný (3R,4R)-4-acetoxy-3-[(1R)-1-terc-butyldimetylsilyloxyetyljazetidinón (6,6 g) ako tuhá látka pod pokrývkou alebo argónom. Zmes3-Acetyl-1-ethyl-5-methylpyrazole (3.51 g) in dry tetrahydrofuran (THF) (150 mL) under an argon atmosphere was cooled in an acetone / solid carbon dioxide bath and then treated with 1M lithium bis (trimethylsilyl) amide solution ( 50 ml). The mixture was stirred for 45 minutes, and then (3R, 4R) -4-acetoxy-3 - [(1R) -1-tert-butyldimethylsilyloxyethyljazetidinone (6.6 g) was added as a solid under a blanket or argon. mixture

- 13bola 3,5 hodiny miešaná v chlade. Bol pridaný nasýtený vodný roztok chloridu amónneho, následne etylacetát a zmes bola zahriata na izbovú teplou. Bolo dodané malé množstvo vody a fázy boli oddelené. Vodná fáza bola reextrahovaná etylacetátom. Zmiešané etylacetátové extrakty boli premyté nasýteným soľným roztokom, vysušené a odparené. Chromatografia na silikágeli a eluovanie zmesou etylacetát/ hexán poskytuje zlúčeninu (3,65 g), vmax(CH2CI2) 3411, 1761, 1678, 1376, 1151 a 838 cm·1, ô(CDCI3), 0.064(6H, s), 0,86 (9H,s), 1,20 (3H, d, J6,3 Hz), 1,44 (3H, t, J7,3 Hz), 2,31 (3H,s), 2,89 (1H, dd, J1,8 & 4,9 Hz), 3,15 (1 H, dd, J10,0 & 17,1 Hz), 3,50 (1H, dd, J3,5 & 17,0 Hz), 4,06-4,25 (4H, m), 6,11 (1H, s), 6,53 (1H, s). (Zistené m/z 379.2296. C19H33N3O3Si vyžaduje m/z 379.2291).The mixture was stirred in the cold for 3.5 hours. Saturated aqueous ammonium chloride solution was added, followed by ethyl acetate, and the mixture was warmed to room temperature. A small amount of water was added and the phases were separated. The aqueous phase was re-extracted with ethyl acetate. The combined ethyl acetate extracts were washed with saturated brine, dried and evaporated. Silica gel chromatography eluting with ethyl acetate / hexane gave the compound (3.65 g), in max (CH 2 Cl 2 ) 3411, 1761, 1678, 1376, 1151 and 838 cm -1 , δ (CDCl 3 ), 0.064 (6H). , s), 0.86 (9H, s), 1.20 (3H, d, J 6.3 Hz), 1.44 (3H, t, J 7.3 Hz), 2.31 (3H, s), 2.89 (1H, dd, J1.8 & 4.9 Hz), 3.15 (1H, dd, J10.0 & 17.1 Hz), 3.50 (1H, dd, J3.5 & 17) 0.04 Hz, 4.06-4.25 (4H, m), 6.11 (1H, s), 6.53 (1H, s). (Found m / z 379.2296. C 19 H 3 N 3 O 3 Si requires m / z 379.2291).

(f) Alyl (2R a 2S)-2-[(3S,4R)-4-[(1-etyl-5-metylpyrazol-3-yl)karbonylmetyl]-3-[(R)-1terc-butyldimetylsilyloxyetyl]-2-oxo-azetidinyl]-2-hydroxyacetát (3S,4R)-4-[(1-Etyl-5-metylpyrazol-3-yl)karbonylmetyl]-3-[(R)-1-terc-butyldimetyl-silyloxýetyl]-2-azetidinón (3,6 g) a hydrát alylglyoxylátu (1,66, g) v toluéne (100 ml) boli zahrievané pod refluxom v Deanovom a Starkovom prístroji v atmosfére argónu počas 3,5 hodiny. T.l.c. reakčnej zmesi ukázalo, že reakcia nedobehla do konca, takže ďalší hydrát alylglyoxylátu (190 g) bol dodaný a zmes bola zohrievaná pod refluxom ďalších 45 minút. Zmes bola ochladená, toluén bol odstránený s cieľom získania surového alyl (2R a 2S)-2-[(3S,4R)-4-[(1-etyl-5metylpyrazol-3-yl)karbonylmetyl]-3-[[(R)-1-terc-butyldimetylsilyloxyetyl]-2-oxo-azetidinyl]-2-hydroxyacetátu, ktorý bol použitý v ďalšom stupni;(f) Allyl (2R and 2S) -2 - [(3S, 4R) -4 - [(1-ethyl-5-methylpyrazol-3-yl) carbonylmethyl] -3 - [(R) -1-tert-butyldimethylsilyloxyethyl] - 2-Oxo-azetidinyl] -2-hydroxyacetate (3S, 4R) -4 - [(1-Ethyl-5-methylpyrazol-3-yl) carbonylmethyl] -3 - [(R) -1-tert-butyldimethylsilyloxyethyl] -2-azetidinone (3.6 g) and allyl glyoxylate hydrate (1.66 g) in toluene (100 mL) were heated under reflux in a Dean and Stark apparatus under an argon atmosphere for 3.5 hours. T.l.c. The reaction mixture showed that the reaction was not complete, so additional allyl glyoxylate hydrate (190 g) was added and the mixture was heated under reflux for an additional 45 minutes. The mixture was cooled, the toluene was removed to give crude allyl (2R and 2S) -2 - [(3S, 4R) -4 - [(1-ethyl-5-methylpyrazol-3-yl) carbonylmethyl] -3 - [[(R) -1-tert-butyldimethylsilyloxyethyl] -2-oxo-azetidinyl] -2-hydroxyacetate used in the next step;

Vmax (CH2CI2) 3681, 3518, 1758, 1676, 1448, 1376, 1326, 1209, 1148, 1092, 954 a 836 cm·1, ô(CDCI3) inter alia 0,035(s), 0,061 (s) (spolu 6H,), 0,858 (s), 0,865(s) (spolu 9H), 1,21 (d, J6,2 Hz), 1,24 (d, J6,2 Hz), (spolu 3H), 1,44 (3H, t, J7,2 Hz), 2,31 (3H, s), 2,95-3,00 (1H, m), 3,25-3,64 (2H, m), 6,53 (s), 6,56(s) ppm.Ν max (CH 2 Cl 2 ) 3681, 3518, 1758, 1676, 1448, 1376, 1326, 1209, 1148, 1092, 954 and 836 cm -1 , δ (CDCl 3 ) inter alia 0.035 (s), 0.061 (s) (total 6H,), 0.858 (s), 0.865 (s) (total 9H), 1.21 (d, J6.2 Hz), 1.24 (d, J6.2 Hz), (total 3H), 1 44 (3H, t, J 7.2 Hz), 2.31 (3H, s), 2.95-3.00 (1H, m), 3.25-3.64 (2H, m), 6, 53 (s), 6.56 (s) ppm.

(g) Alyl 2-{(3S,4R)-4-[(1 -etyl-5-metylpyrazol-3-yl)karbonylmetyl]-3-[(R)-1 -terc-butyldimetylsilyloxyetyl]-2-oxoazetidinyl)}-2-(tri-n-butylfosforanylidén)acetát(g) Allyl 2 - {(3S, 4R) -4 - [(1-ethyl-5-methylpyrazol-3-yl) carbonylmethyl] -3 - [(R) -1-tert-butyldimethylsilyloxyethyl] -2-oxoazetidinyl) } -2- (tri-n -butylphosphoranylidene) acetate

- 14 Alyl (2R a 2S)-2-{(3S,4R)-4-[(1-etyl-5-metylpyrazol-3yl)-karbonylmetyl]-3[(R)-1-terc-butyldimetylsilyloxyetyl]-2-oxo-azetidinyl}-2-hydroxyacetát (surový vyššie pripravený) v suchom THF (125 ml) v atmosfére argónu bol ochladený na -20 °C a spracovaný s 2,6-lutidínom (1,98 ml), následne bol pridaný tionylchlorid (1,24 ml). Zmes bola miešaná pri -20 °C počas 30 minút a potom zahriata na izbovú teplotu a prefiltrovaná, zvyšok bol praný THF (20 ml). Filtrát bol odparený vo vákuu, bol dodaný toluén (70 ml) a oddelený vákuovo. Olejové zvyšky boli vysušené vo vákuu. Olej bol potom vložený do 1,4-dioxánu (40 ml) v atmosfére argónu a spracovaný s tri-n-butylfosfínom (3,11 ml). Zmes bola miešaná 1 hodinu. Následne bol pridaný 2,6-lutidín (1,59 ml) a zmes bola miešaná ďalších 30 minút. Zmes bola zriedená etylacetátom, vypratá vodou, potom soľným roztokom a sušená (MgSOJ. Po odstránení etylacetátu surový produkt bol chromatograficky delený na silikagéli, eluovaný zmesou etylacetát/hexán s cieľom získať fosforan, ktorý bol použitý v ďalšom stupni.14 Allyl (2R and 2S) -2 - {(3S, 4R) -4 - [(1-ethyl-5-methylpyrazol-3yl) carbonylmethyl] -3 - [(R) -1-tert-butyldimethylsilyloxyethyl] -2 -oxo-azetidinyl} -2-hydroxyacetate (crude prepared above) in dry THF (125 mL) under an argon atmosphere was cooled to -20 ° C and treated with 2,6-lutidine (1.98 mL), followed by addition of thionyl chloride (1.24 mL). The mixture was stirred at -20 ° C for 30 minutes and then warmed to room temperature and filtered, washed with THF (20 mL). The filtrate was evaporated in vacuo, toluene (70 mL) was added and collected in vacuo. The oily residue was dried under vacuum. The oil was then taken up in 1,4-dioxane (40 mL) under argon and treated with tri-n-butylphosphine (3.11 mL). The mixture was stirred for 1 hour. 2,6-Lutidine (1.59 mL) was then added and the mixture was stirred for an additional 30 minutes. The mixture was diluted with ethyl acetate, washed with water, then brine and dried (MgSO4. After removal of ethyl acetate, the crude product was chromatographed on silica gel, eluting with ethyl acetate / hexane to give the phosphorane which was used in the next step.

(h) Alyl 2-{(3S,4R)-4-[(1-etyl-5-metylpýrazolr3-yl)karbonylmetyl]-3-[(R)-1-hydroxyetyl]-2-oxoazetidinyl}-2-(tri-n-butylfosforanylidén)acetát(h) Allyl 2 - {(3S, 4R) -4 - [(1-ethyl-5-methylpyrazol-3-yl) carbonylmethyl] -3 - [(R) -1-hydroxyethyl] -2-oxoazetidinyl} -2- ( tri-n-butylphosphoranylidene) acetate

Fosforan pripravený vyššie bol zmiešaný s 1,4-dioxánom (60 ml) a spracovaný 5M HCL (20 ml). Po 1 hodine miešania bolo opatrne pridané cca 40 ml nasýteného vodného NaHCO3, následne tuhý NaHCO3až pH bolo ľahko alkalické. Bol pridaný nasýtený soľný roztok a zmes bola extrahovaná dvakrát etylacetátom. Spojené extrakty boli vysušené (MgSOJ a odparené. Zbytok bol chromatograficky delený na silikagéli, eluovaný zmesou etylacetát/hexán. s cieľom získať hydroxy zlúčeninu (2,60g), vmax (CH2CI2) 3454, 1741, 1667, 1606, 1448, 1403, 1379, 1155, 1087, 953 a 811 cm'1.The phosphorane prepared above was mixed with 1,4-dioxane (60 mL) and treated with 5M HCl (20 mL). After stirring for 1 hour, about 40 mL of saturated aqueous NaHCO 3 was carefully added, followed by solid NaHCO 3 until the pH was slightly alkaline. Saturated brine was added and the mixture was extracted twice with ethyl acetate. The combined extracts were dried (MgSO 4 and evaporated. The residue was chromatographed on silica gel, eluting with ethyl acetate / hexane to give the hydroxy compound (2.60g), in max (CH 2 Cl 2 ) 3454, 1741, 1667, 1606, 1448 , 1403, 1379, 1155, 1087, 953 and 811 cm -1 .

(i) Alyl (5R,6S)-6-[(R)-1-hydroxyetyl]-2-(1-etyl-5-metylpyrazol-3-yl)karbapen-2ém-3-karboxylát(i) Allyl (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2- (1-ethyl-5-methylpyrazol-3-yl) carbapenem-3-carboxylate

- 15 Alyl 2-{(3S,4R)-4-[(1 -etyl-5-metylpyrazol-3-yl)karbonylmetyl]-3-[(R)-1 -hydroxyetyl]-2-oxoazetidinyl}-2-(tri-n-butylfosforanylidén)acetát (2,6 g) v toluéne (120 ml) s obsahom hydrochinónu (20 mg) bol ohrievaný pod refluxom v atmosfére argónu počas 4 hodín, následne státie počas 64 hodín a potom ohrievanie pod refluxom počas ďalších dvoch hodín. Zmes bola chladená a potom prepúšťaná kolónou (4,5 x 12 cm) so silikagélom (veľkosť častíc 0,04 až 0,063), eluovaná zmesou etylacetát/hexán; 1:1; 6:4; 7:3; 8:2; 9:1 (250 ml z každého pomeru) a následne etylacetátom. Získaný bol karbapeném (436 mg); vmax (CH2CI2) 3604, 2976, 1774, 1716, 1600, 1546, 1311, 1189 cm’1; ?,max (EtOH )/nm 321.5 (S/dm3moľ1cm-1 14,856), ô(CDCI3) 1,36 (d, J6,3 Hz), 1,39 (t, J7,3 Hz), (spolu 5H), 1,80 (1H, d, J5,0 Hz), 2,28 (3H, s), 3,19 (1H, dd, J2,7 & 6,7 Hz), 3,28 (1H, dd, J9,0 & 18,6 Hz), 3,60 (1H, dd, J9,9 & 18,5 Hz), 4,08 (2H, q, J7,3Hz), 4,16-4,30 (2H, m), 5,27 (1 H, m, approx d, J cca 17Hz), 5,46 (m, aprox d, J, cca 17Hz), 5,93-6,08 (1H, m), 7,00 (1H, s) ppm; [Zistené m/z 345.1693. C18H23N3O4žiadané m/z 345.1689] (j) (5R,6S)-6-[(R)-1 -hydroxýetyl]-2-(1 -etyl-5-metylpyrazol-3-yl)karbapen-2-ém-3karboxylát sodný15 Allyl 2 - {(3S, 4R) -4 - [(1-ethyl-5-methylpyrazol-3-yl) carbonylmethyl] -3 - [(R) -1-hydroxyethyl] -2-oxoazetidinyl} -2- (tri-n-butylphosphoranylidene) acetate (2.6 g) in toluene (120 mL) containing hydroquinone (20 mg) was heated under reflux under argon for 4 hours, then allowed to stand for 64 hours and then heated under reflux for further two hours. The mixture was cooled and then passed through a silica gel (4.5 x 12 cm) column (particle size 0.04-0.063), eluting with ethyl acetate / hexane; 1: 1; 6: 4; 7: 3; 8: 2; 9: 1 (250 mL of each ratio) followed by ethyl acetate. Carbapenem (436 mg) was obtained; ν max (CH 2 Cl 2 ) 3604, 2976, 1774, 1716, 1600, 1546, 1311, 1189 cm -1 ; λ max (EtOH) / nm 321.5 (S / dm 3 m 1 cm -1 14.856), δ (CDCl 3) 1.36 (d, J 6.3 Hz), 1.39 (t, J 7.3 Hz), (total 5H), 1.80 (1H, d, J5.0 Hz), 2.28 (3H, s), 3.19 (1H, dd, J2.7 & 6.7 Hz), 3.28 ( 1H, dd, J9.0 & 18.6 Hz), 3.60 (1H, dd, J9.9 & 18.5 Hz), 4.08 (2H, q, J7.3Hz), 4.16-4 30 (2H, m), 5.27 (1H, m, approx. D, J ca. 17Hz), 5.46 (m, aprox d, J, ca. 17Hz), 5.93-6.08 (1H, m), 7.00 (1H, s) ppm; [Found m / z 345.1693. C 18 H 23 N 3 O 4 desired m / z 345.1689] (j) (5 R, 6 S) -6 - [(R) -1-hydroxyethyl] -2- (1-ethyl-5-methyl-pyrazol-3-yl) sodium carbapen-2-em-3-carboxylate

Alyl (5R,6S)-6-[(R)-1 -hydroxyetyl]-2-(1 -etyl-5-metylpyrazol-3-yl)karbapen-2em-3-karboxylát (267 mg) v dichlórmetáne (3 ml) a etylacetát (3 ml) v atmosfére argónu bol spracovaný s 2-etylhexanoátom sodným (183 mg), následne bol pridaný trifenylfosfín (24 mg), a potom tetrakis(trifenylfosfín)paládia (0) (35 mg). Zmes bola miešaná počas 45 minút. Následne bol pridaný dietyléter (100 ml) a po 90 minútach miešania zmes bola odstredená. Tuhý zvyšok bol sušený prúdom argónu a následne v exikátore. Tuhá látka bola potom vložená do vody s obsahom chloridu sodného a podrobená chromatografií na DIAION HP20SS živici, eluovaná zmesou voda/THF; 1%, 2% a 3% THF. Frakcie boli monitorované HPCL. Tie, ktoré obsahovali produkt boli spojené, bol znížený objem a vymrazením boli vysušené s cieľom získať (5R,6S)-6-[(R)-1-hydroxyetyl]-2-(1-etyl-5-metylpyrazol-3-yl)karbapen-2-ém-3-karboxylát sodný ako tuhú látku (168 mg); vmax(KBr) 1761, 1608, 1577, 1381, 1225, cm·1, Xmax(H2O)/nrn 298 (s/dm3moľ1cm·1 8,531); Ô(D2O) 1,26 (d, J cca 6Allyl (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2- (1-ethyl-5-methylpyrazol-3-yl) carbapen-2em-3-carboxylate (267 mg) in dichloromethane (3 mL) ) and ethyl acetate (3 mL) under argon was treated with sodium 2-ethylhexanoate (183 mg) followed by addition of triphenylphosphine (24 mg) followed by tetrakis (triphenylphosphine) palladium (0) (35 mg). The mixture was stirred for 45 minutes. Diethyl ether (100 ml) was then added and after stirring for 90 minutes the mixture was centrifuged. The solid residue was dried with a stream of argon and then in a desiccator. The solid was then taken up in water containing sodium chloride and subjected to chromatography on a DIAION HP20SS resin, eluting with a water / THF mixture; 1%, 2% and 3% THF. Fractions were monitored by HPCL. Those containing the product were combined, reduced in volume and freeze dried to afford (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2- (1-ethyl-5-methylpyrazol-3-yl) ) sodium carbapen-2-em-3-carboxylate as a solid (168 mg); ν max (KBr) 1761, 1608, 1577, 1381, 1225, cm · 1 , λ max (H 2 O) / µm 298 (s / dm 3 m 1 cm · 1 8.531); Ô (D2O) 1.26 (d, J approx

-16Ηζ), 1,27 (d, J cca 7Hz) (spolu 5H), 2,23 (3H, s), 3,17 (2H, approx d, J cca 9Hz), 3,44 (1H, dd, J 2,9 & 6,0Hz, 4,04 (2H,q, J 7,3 Hz), 4,15 - 4,25 (2H, m), 6,41 (1 H, s) ppm.-16Ηζ), 1.27 (d, J ca. 7Hz) (together 5H), 2.23 (3H, s), 3.17 (2H, approx d, J ca. 9Hz), 3.44 (1H, dd, J 2.9 & 6.0 Hz, 4.04 (2H, q, J 7.3 Hz), 4.15-4.25 (2H, m), 6.41 (1H, s) ppm.

Claims (9)

PATENTOVÉ NÁROKYPATENT CLAIMS 1. Estery karbapenémov všeobecného vzorca (I) kde R je vybrané so skupiny obsahujúcej izobutyryloxymetyl, (5-metyl-2-oxo-1,3dioxolen-4-yl)metyl a benzoyloxymetyl.Carbapenem esters of general formula (I) wherein R is selected from isobutyryloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl and benzoyloxymethyl. 2. Ester karbapenému podľa nároku 1, ktorým je izobutyryloxymetyl (5R,6S)2-[1 -etyl-5-metylpyrazol-3-yl]-6-[(1 R)-1 -hydroxyetyl]-2-karbapeném-3-karboxylát.The carbapenem ester according to claim 1, which is isobutyryloxymethyl (5R, 6S) 2- [1-ethyl-5-methylpyrazol-3-yl] -6 - [(1R) -1-hydroxyethyl] -2-carbapenem-3 carboxylate. 3. Ester karbapenému podľa nároku 1, ktorým je (5-metyl-2-oxo-1,3-dioxolen4-yl)-metyl-(5R,6S)-2-[1 -etyl-5-metyl pyrazol-3-yl]-6-[( 1 R)-1 hydroxyetyl]-2-karbapeném-3-karboxylát.The carbapenem ester according to claim 1 which is (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl (5R, 6S) -2- [1-ethyl-5-methyl pyrazole-3- yl] -6 - [(1R) -1 hydroxyethyl] -2-carbapenene-3-carboxylate. 4. Ester karbapenému podľa nároku 1, ktorým je benzoyloxymetyl (5R,6S)-2[1-etyl-5-metylpyrazol-3-yl]-6-[(1R)-1-hydroxyetyl]-2-karbapeném-3-karboxylát.The carbapenem ester according to claim 1, which is benzoyloxymethyl (5R, 6S) -2 [1-ethyl-5-methylpyrazol-3-yl] -6 - [(1R) -1-hydroxyethyl] -2-carbapenem-3- carboxylate. 5. Farmaceutický prostriedok, vyznačujúci s a t ý m, že obsahuje zlúčeninu podľa ktoréhokoľvek z predchádzajúcich nárokov a farmaceutický prijateľný nosič alebo vehikulum.A pharmaceutical composition comprising a compound according to any one of the preceding claims and a pharmaceutically acceptable carrier or vehicle. 6. Spôsob liečenia bakteriálnych infekcií u ľudí a zvierat aplikáciou terapeuticky účinného množstva zlúčeniny podľa ktoréhokoľvek nároku 1 až 4.A method of treating bacterial infections in humans and animals by administering a therapeutically effective amount of a compound according to any one of claims 1 to 4. 7. Použitie zlúčeniny podľa ktoréhokoľvek nároku 1 až 4 na výrobu liečiv na liečenie bakteriálnych infekcií.Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment of bacterial infections. - 18- 18 8. Spôsob prípravy esterov karbapenémov podľa nároku 1, všeobecného vzorca (I), kde R je izobutyryloxymetyl alebo benzoyloxy metyl, vyznačujúci sa t ý m, že na príslušnú zlúčeninu podľa vzorca (I), kde R je alkalický kovový katión sa pôsobí zlúčeninou vzorca XCH2OCOCHMe2 alebo XCH2OCOC6H5, kde X je odštiepiteľná skupina.A process for the preparation of carbapenem esters according to claim 1, wherein R is isobutyryloxymethyl or benzoyloxy methyl, characterized in that the corresponding compound of formula (I) wherein R is an alkali metal cation is treated with a compound of formula XCH 2 OCOCHMe 2 or XCH 2 OCOC 6 H 5 , wherein X is a leaving group. 9. Spôsob prípravy esterov karbapenémov podľa nároku 1, všeobecného vzorca (I), kde R je (5-metyl-2-oxo-1,3-dioxolen-4-yl)metyl, vyznačujúci sa t ý m, že na príslušnú zlúčeninu vzorca (I), kde R je alkalický kovový katión sa pôsobí zlúčeninou vzorca:A process for the preparation of carbapenem esters according to claim 1, wherein R is (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl, characterized in that for the corresponding compound of formula (I) wherein R is an alkali metal cation is treated with a compound of formula: kde X je odštiepiteľná skupina.wherein X is a leaving group.
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