HRP931189A2 - Antibiotic compounds - Google Patents

Description

Prikazani izum se odnosi na karbapeneme i posebno na takve spojeve koji sadrže karboksi supstituiranu tienil grupu. Ovaj izum se nadalje odnosi na postupak pripreme tih spojeva, na intermedijere u njihovoj pripremi, na njihovu upotrebu kao terapeutskih sredstava i na farmaceutske pripravke koji ih sadrže. Spojevi prema ovom izumu su antibiotici i mogu se upotrijebiti u liječenju bilo koje bolesti koja se uobičajeno tretira antibioticima, na primjer u liječenju bakterijskih infekcija kod sisavaca uključujući i ljude. The presented invention relates to carbapenems and especially to such compounds containing a carboxy substituted thienyl group. This invention further relates to the preparation process of these compounds, to intermediates in their preparation, to their use as therapeutic agents and to pharmaceutical preparations containing them. The compounds of the present invention are antibiotics and can be used in the treatment of any disease that is normally treated with antibiotics, for example in the treatment of bacterial infections in mammals including humans.

Karbapenemi su prvo, 1974. godine izolirani iz fermentacijskog medija i pronađeno je da imaju širokospektralnu antibakterijsku aktivnost. Od tog otkrića načinjena su značajna istraživanja u svezi novih derivata karbapenema i objavljene su stotice patenata i znanstvenih opisa. Carbapenems were first isolated from the fermentation medium in 1974 and were found to have broad-spectrum antibacterial activity. Since that discovery, significant research has been done on new carbapenem derivatives and hundreds of patents and scientific descriptions have been published.

Prvi i za sada jedini karbapenem koji je komercijaliziran je imipenem (N-formimidoil tienamicin). Ovaj spoj ima široki spektar antibakterijske aktivnosti. The first and so far the only carbapenem to be commercialized is imipenem (N-formimidoyl thienamycin). This compound has a broad spectrum of antibacterial activity.

Prikazani izum osigurava spojeve sa širokim spektrom antibakterijske aktivnosti, uključujući aktivnost prema Gram pozitivnim i negativnim, aerobnim i anaerobnim bakterijama. Oni pokazuju dobru stabilnost prema beta-laktamazama. Dodatne, tipični spojevi ovog izuma pokazuju poželjnu farmakokinetiku. The presented invention provides compounds with a wide spectrum of antibacterial activity, including activity against Gram positive and negative, aerobic and anaerobic bacteria. They show good stability towards beta-lactamases. Additional, typical compounds of this invention exhibit desirable pharmacokinetics.

Derivati karbapenema prikazani ovdje,su imenovani u skladu sa opće prihvaćenom semi-sistematičnom nomenklaturom: The carbapenem derivatives shown here are named according to the generally accepted semi-systematic nomenclature:

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U skladu s tim, prikazani izum osigurava spoj formule (I) Accordingly, the present invention provides a compound of formula (I)

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gdje je: where is:

R1 1-hidroksietil, 1-fluoroetil ili hidroksimetil; R1 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;

R2 vodik ili C1-4alkil; R 2 is hydrogen or C 1-4 alkyl;

R3 vodik ili C1-4alkil; R 3 is hydrogen or C 1-4 alkyl;

i tienil prsten je po izboru dalje supstituiran sa jedim ili dva supstituenta izabranih između halogena, cijano, C1-4alkil, nitro, hidroksi, karboksi, C1-4alkoksi, trifluorometil, C1-4alkoksikarbonil, amino, C1-4alkilamino, di-C1-4alkilamino, sulfonske kiseline, C1-4alkilS(O)n -gdje je n 0-2, C1-4alkanoilamino, C1-4alkanoil(N-C1-4alkil)amino, karbamoil, C1-4alkilkarbamoil, di-C1-4alkilkarbamoil i N-C1-4alkanesulfonamido; ili sa tetrametilen grupom koja prijanja na susjedni ugljikov atom u tienil prstenu; and the thienyl ring is optionally further substituted with one or two substituents selected from halogen, cyano, C1-4 alkyl, nitro, hydroxy, carboxy, C1-4 alkoxy, trifluoromethyl, C1-4 alkoxycarbonyl, amino, C1-4 alkylamino, di-C1-4 alkylamino , sulfonic acids, C1-4alkylS(O)n -where n is 0-2, C1-4alkanoylamino, C1-4alkanoyl(N-C1-4alkyl)amino, carbamoyl, C1-4alkylcarbamoyl, di-C1-4alkylcarbamoyl and N-C1 -4alkanesulfonamido; or with a tetramethylene group attached to an adjacent carbon atom in the thienyl ring;

ili njegovu farmaceutski prihvatljivu sol ili in vivo hidrolizirajući ester. or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof.

Termin alkil uključuje sve ravne ili razgranate strukture lanca, na primjer, C1-4alkil uključuje n-butil i 2-metilpropil. The term alkyl includes all straight or branched chain structures, for example, C1-4alkyl includes n-butyl and 2-methylpropyl.

Povoljno je da je It is favorable that it is

R1 1-hidroksietil. R1 1-hydroxyethyl.

R2 je vodik ili C1-4alkil na primjer metil, etil, n-propil, 1-metiletil i n-butil. R 2 is hydrogen or C 1-4 alkyl for example methyl, ethyl, n-propyl, 1-methylethyl and n-butyl.

Povoljno je da je R2 vodik ili metil. Posebno kada je R2 metil. Preferably, R 2 is hydrogen or methyl. Especially when R2 is methyl.

R3 je vodik ili C1-4alkil na primjer metil, etil, n-propil, 1-metiletil i n-butil. R 3 is hydrogen or C 1-4 alkyl for example methyl, ethyl, n-propyl, 1-methylethyl and n-butyl.

Povoljno je da je R3 vodik ili metil. Posebno kada je R3 vodik. Preferably, R 3 is hydrogen or methyl. Especially when R3 is hydrogen.

Prikladni supstituenti za tienil prsten uključuju, na primjer: Suitable substituents for the thienyl ring include, for example:

za halogen: fluoro, kloro, bromo i jodo; for halogen: fluoro, chloro, bromo and iodo;

za C1-4alkil: metil, etil, propil, 1-metil-etil, butil i 2-metilpropil; for C1-4alkyl: methyl, ethyl, propyl, 1-methyl-ethyl, butyl and 2-methylpropyl;

za C1-4alkoksi: metoksi, etoksi, propoksi, 1-metil-etoksi, butoksi i 2-metilpropoksi; for C1-4Alkoxy: methoxy, ethoxy, propoxy, 1-methyl-ethoxy, butoxy and 2-methylpropoxy;

za C1-4alkilkarbamoil: metilkarbamoil, etilkarbamoil i propilkarbamoil; for C1-4alkylcarbamoyl: methylcarbamoyl, ethylcarbamoyl and propylcarbamoyl;

za di-C1-4alkilkarbamoil: dimetilkarbamoil i dietilkarbamoil; for di-C1-4alkylcarbamoyl: dimethylcarbamoyl and diethylcarbamoyl;

za C1-4alkilamino: metilamino, etilamino i propilamino; for C1-4 alkylamino: methylamino, ethylamino and propylamino;

za di-C1-4alkilamino: dimetilamino, dietilamino i metil-etilamino; for di-C1-4alkylamino: dimethylamino, diethylamino and methyl-ethylamino;

za C1-4alkilS(O)n-: metiltio, metilsulfinil i metil-sulfonil; for C1-4alkylS(O)n-: methylthio, methylsulfinyl and methylsulfonyl;

za C1-4alkanoilamino: acetamido i propionamido; for C1-4alkanoylamino: acetamido and propionamido;

za C1-4alkoksikarbonil: metoksikarbonil, etoksikarbonil i propoksikarbonil; for C1-4 alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;

za C1-4alkanoil(N-C1-4alkil)amino: N-metilacetamido i N-etilacetamido; for C1-4alkanoyl(N-C1-4alkyl)amino: N-methylacetamido and N-ethylacetamido;

za N-C1-4alkanesulfonamid.o: N-metansulfonamido i N-etansulfonamido. for N-C1-4alkanesulfonamide.o: N-methanesulfonamido and N-ethanesulfonamido.

Povoljno je kada je tienil prsten po izboru supstituiran, a izborni supstituenti su izabrani između halogena, cijano, C1-4alkil, nitro, karboksi, hidroksi, C1-4alkoksi, karbamoil, amino, trifluorometil i tetrametilena. It is advantageous when the thienyl ring is optionally substituted, and the optional substituents are selected from halogen, cyano, C1-4alkyl, nitro, carboxy, hydroxy, C1-4alkoxy, carbamoyl, amino, trifluoromethyl and tetramethylene.

Najpovoljnije je kada je tienil prsten dalje ne-supstituiran ili je dalje supstituiran sa jednom hidroksi, metil ili tetrametilen grupom. It is most advantageous when the thienyl ring is further unsubstituted or further substituted with one hydroxy, methyl or tetramethylene group.

Prikazani izum pokriva sve epimere, dijastereoizomere i tautomere spoja formule (I) gdje je apsolutna stereokemija na položaju 5 prikazana u formuli (1). Kada je veza prikazana kao klin, to ukazuje da bi u trećoj dimenziji veza izlazila iz papira, te kada je veza prikazana crtkano, to ukazuje da bi u trećoj dimenziji veza išla natrag u papir. Spojevi formule (1) imaju brojne stereocentre, poimenično: unutar grupe R1 (kada je R1 1-hidroksi-etil ili 1-fluoroetil); na položaju 6; na položaju 1 (kada je R2 C1-4alkil); te na 2' i 4' u pirolidinskom prstenu: The presented invention covers all epimers, diastereoisomers and tautomers of the compound of formula (I) where the absolute stereochemistry at position 5 is shown in formula (1). When the bond is shown as a wedge, it indicates that in the third dimension the bond would exit the paper, and when the bond is shown as a dash, it indicates that in the third dimension the bond would go back into the paper. Compounds of formula (1) have numerous stereocenters, namely: within the group R1 (when R1 is 1-hydroxyethyl or 1-fluoroethyl); at position 6; at position 1 (when R 2 is C 1-4 alkyl); and at 2' and 4' in the pyrrolidine ring:

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Preferirani spojevi su oni u kojima su beta-laktamski protoni u trans konfiguraciji jedni prema drugima. Kada je R1 1-hidroksietil ili 1-fluoroetil, povoljno je da 8-supstituent ima R-konfiguraciju. Tako preferiran razred spojeva ima formulu (III): Preferred compounds are those in which the beta-lactam protons are in a trans configuration with respect to each other. When R 1 is 1-hydroxyethyl or 1-fluoroethyl, the 8-substituent preferably has the R-configuration. Thus, a preferred class of compounds has the formula (III):

[image] [image]

i njegove farmaceutski prihvatljive soli i in vivo hidrolizirajući esteri, gdje su R2, R3 i izborni supstituenti na tienil prstenu isti kao prethodno definirani. and pharmaceutically acceptable salts and in vivo hydrolyzable esters thereof, wherein R 2 , R 3 and optional substituents on the thienyl ring are as previously defined.

Kada je R2 C1-4alkil, na primjer metil, povoljno je da spoj ima oblik 1R konfiguracije. When R 2 is C 1-4 alkyl, for example methyl, it is advantageous for the compound to take the form of the 1R configuration.

Preferirani spojevi su oni u kojima pirolidinski prsten ima slijedeću apsolutnu stereokemiju na položajima 2'- i 4'-: Preferred compounds are those in which the pyrrolidine ring has the following absolute stereochemistry at the 2'- and 4'- positions:

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Prikladan razred spojeva prema prikazanom izumu je onaj formule (IV): A suitable class of compounds according to the presented invention is that of formula (IV):

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kao i njegove farmaceutski prihvatljive soli i in vivo hidrolizirajući esteri tog spoja; as well as its pharmaceutically acceptable salts and in vivo hydrolyzable esters of that compound;

gdje su R3 i izborni supstituenti pa tienil prstenu isti kao i oni prethodno definirani u formuli (1). where R3 and optional substituents on the thienyl ring are the same as those previously defined in formula (1).

Sa drugog aspekta, prikladni razred spojeva su oni spojevi formule (IV) u kojima je R3 vodik, metil ili etil; a izborni supstituenti na tienil prstenu su isti kao i oni definirani u formuli (I). In another aspect, a suitable class of compounds are those compounds of formula (IV) in which R 3 is hydrogen, methyl or ethyl; and the optional substituents on the thienyl ring are the same as those defined in formula (I).

U još jednom aspektu, prikladan razred spojeva su oni spojevi formule (IV) u kojima je tienil prsten po izboru dalje supstituiran sa jednim ili dva supstituenta izabranim između metil, etil, hidroksi, karboksi, cijano, fluoro, kloro, bromo, karbamoil, nitro, metoksi, etoksi i propoksi; ili sa tetrametilen grupom koja prijanja na susjedne ugljikove atome na tienil prstenu; i R3 je isti kao prethodno definiran u formuli (I). In yet another aspect, a suitable class of compounds are those compounds of formula (IV) in which the thienyl ring is optionally further substituted with one or two substituents selected from methyl, ethyl, hydroxy, carboxy, cyano, fluoro, chloro, bromo, carbamoyl, nitro , methoxy, ethoxy and propoxy; or with a tetramethylene group attached to adjacent carbon atoms on the thienyl ring; and R 3 is the same as previously defined in formula (I).

Poseban razred spojeva prema prikazanom izumu su oni formule (IV) u kojima: A special class of compounds according to the presented invention are those of formula (IV) in which:

R3 je vodik ili metil; R 3 is hydrogen or methyl;

i tienil prsten je po izboru dalje supstituiran sa jednim supstituentom izabranim između metil, etil, hidroksi, karboksi, cijano, kloro, bromo, nitro, metoksi, etoksi i tetrametilen. and the thienyl ring is optionally further substituted with one substituent selected from methyl, ethyl, hydroxy, carboxy, cyano, chloro, bromo, nitro, methoxy, ethoxy and tetramethylene.

Preferiran razred spojeva prema prikazanom izumu je onaj formule (IV) gdje: A preferred class of compounds according to the presented invention is that of formula (IV) where:

R3 je vodik; R 3 is hydrogen;

i tienil prsten je po izboru dalje supstituiran sa jednini supstituentom izabranim između metil, hidroksi, kloro, tetrametilen i karboksi. and the thienyl ring is optionally further substituted with a single substituent selected from methyl, hydroxy, chloro, tetramethylene and carboxy.

Još više preferiran razred spojeva prema izumu su spojevi formule (IV) gdje: An even more preferred class of compounds according to the invention are compounds of formula (IV) where:

R3 je vodik; R 3 is hydrogen;

i tienil prsten je ili dalje ne-supstituiran ili je supstituiran sa jednim supstituentom izabranim između metil ili hidroksi ili tetrametilen. and the thienyl ring is either further unsubstituted or substituted with one substituent selected from methyl or hydroxy or tetramethylene.

Pojedinačni spojevi prema prikazanom izumu su, na primjer, slijedeći spojevi formule (IV): Individual compounds according to the presented invention are, for example, the following compounds of formula (IV):

(1S,5S,6S,8R,2'S,4'S)-2-(2-(2-karboksi-4-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina; (1S,5S,6S,8R,2'S,4'S)-2-(2-(2-carboxy-4-thienylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid;

(1R,5S,6S,8R,2'S,4'S)-2-(2-(2-karboksi-3-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-metilkarbapenem-3-karboksilna kiselina; (1R,5S,6S,8R,2'S,4'S)-2-(2-(2-carboxy-3-thienylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-methylcarbapenem-3-carboxylic acid;

(1R,5S,6S,8R,2'S,4'S)-2-(2-(4-karboksi-2-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina; (1R,5S,6S,8R,2'S,4'S)-2-(2-(4-carboxy-2-thienylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid;

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-karboksi-2-(4,5,6,7)-tetrahidrobenzo[b]-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina; (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-2-(4,5,6,7)-tetrahydrobenzo[b]-thienylcarbamoyl)pyrrolidin-4-ylthio)- 6-(1-Hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid;

(1R,5S,6S,8R,2'S,4'3)-2-(2-(3-karboksi-4-metil-2-tienilkarbamoil)-pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina, (1R,5S,6S,8R,2'S,4'3)-2-(2-(3-carboxy-4-methyl-2-thienylcarbamoyl)-pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)- 1-methylcarbapenem-3-carboxylic acid,

(1R,5S,6S,8R,2'S,4"S)-2-(2-(2-karboksi-5-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina; (1R,5S,6S,8R,2'S,4"S)-2-(2-(2-carboxy-5-thienylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3 -carboxylic acid;

(1R,5S,6S,8R,2'3,4'S)-2-(2-(5-karboksi-3-hidroksi-2-tienilkarbamoil)-pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina; (1R,5S,6S,8R,2'3,4'S)-2-(2-(5-carboxy-3-hydroxy-2-thienylcarbamoyl)-pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)- 1-methylcarbapenem-3-carboxylic acid;

kao i njihove farmaceutski prihvatljive soli i in vivo hidrolizirajući esteri. as well as their pharmaceutically acceptable salts and in vivo hydrolyzable esters.

Prikladne farmaceutski prihvatljive soli uključuju kiselinske soli kao što su hidroklorid, hidrobromid, citrat, maleat, te soli formirane sa fosfornom i sumpornom kiselinom. Sa idućeg aspekta, prikladne soli su bazične soli kao što su soli alkalijskih metala, na primjer natrijeve ili kalijeve, soli alkalijskih metala zemlje, na primjer kalcijeve ili magnezijeve, soli organskih amina, na primjer trietilamin, morfolin, N-metilpiperidin, N-etilpiperidin, procain, dibenzilamin, N,N-dibenziletilamin ili aminokiseline, na primjer, lizin. Suitable pharmaceutically acceptable salts include acid salts such as the hydrochloride, hydrobromide, citrate, maleate, and salts formed with phosphoric and sulfuric acids. In a further aspect, suitable salts are basic salts such as alkali metal salts, for example sodium or potassium, alkaline earth metal salts, for example calcium or magnesium, salts of organic amines, for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine , procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids, for example, lysine.

Da bi se izbjegle nedoumice treba napomenuti da mogu biti jedan, dva, tri ili četiri kationa koja formiraju soli ovisno o broju funkcija karboksilne kiseline kao i o valenciji spomenutih kationa. In order to avoid confusion, it should be noted that there can be one, two, three or four cations that form salts depending on the number of carboxylic acid functions as well as the valence of the mentioned cations.

Preferirane farmaceutski prihvatljive soli su natrijeve i kalijeve, soli. Naravno, da bi se olakšalo izoliranje soli za vrijeme pripreme, mogu se preferirati soli koje su manje topive u izabranom otapalu, bile one farmaceutski prihvatljive ili ne. Preferred pharmaceutically acceptable salts are the sodium and potassium salts. Of course, to facilitate the isolation of the salt during preparation, salts that are less soluble in the chosen solvent, whether pharmaceutically acceptable or not, may be preferred.

In vivo hidrolizirajući esteri su oni farmaceutski prihvatljivi esteri koji hidroliziraju u ljudskom tijelu dajući osnovni hidroksi ili karboksi spoj. Takvi esteri se mogu identificirati primjenom, npr. intravenozno životinjama za testiranje, spoja koji se testira i nakon toga testiranjem tjelesnih tekućina životinje pod testom. Prikladne grupe koje formiraju in vivo hidrolizirajuće estere, za hidroksi, uključuju acetil, propionil, pivaloil, C1-4alkoksikarbonil na primjer etoksikarbonil i fenilacetil. Prikladni in vivo hidrolizirajući esteri za karboksi uključuju C1-6alkoksimetil estere na primjer metoksimetil; C1-6alkanoiloksimetil estere na primjer pivaloiloksimetil; C3-8cikloalkoksikarboniloksiC1-6alkil, na primjer 1-cikloheksil-oksikarboniloksietil, 1,3-dioksolen-2-onilmetil estere na primjer 5-metil-1,3-dioksolen-2-onimetil; ftalidil estere i C1-6alkoksikarboniloksietil estere na primjer 1-metoksikarboniloksi-etil i mogu biti formirani na bilo kojoj karboksi grupi u spoju prema ovom izumu. In vivo hydrolyzable esters are those pharmaceutically acceptable esters that hydrolyze in the human body to give the basic hydroxy or carboxy compound. Such esters can be identified by administering, eg, intravenously to test animals, the test compound and subsequently testing the body fluids of the test animal. Suitable groups which form in vivo hydrolyzable esters, for hydroxy, include acetyl, propionyl, pivaloyl, C1-4 alkoxycarbonyl for example ethoxycarbonyl and phenylacetyl. Suitable in vivo hydrolysable carboxy esters include C1-6 alkoxymethyl esters for example methoxymethyl; C1-6alkanoyloxymethyl esters for example pivaloyloxymethyl; C3-8cycloalkoxycarbonyloxyC1-6alkyl, for example 1-cyclohexyl-oxycarbonyloxyethyl, 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onemethyl; phthalidyl esters and C 1-6 alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxy-ethyl and may be formed on any carboxy group in the compound of this invention.

Da bi se koristio spoj prema izumu formule (I) ili njegova farmaceutski prihvatljiva sol ili in vivo hidrolizirajući ester u svrhu liječenja sisavaca uključujući i ljude, posebno za liječenje infekcija, on se uobičajeno formulira u skladu sa standardnom farmaceutskom praksom kao farmaceutski pripravak. In order to use a compound of the invention of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof for the treatment of mammals including humans, in particular for the treatment of infections, it is usually formulated in accordance with standard pharmaceutical practice as a pharmaceutical preparation.

Zbog toga sa idućeg aspekta prikazanog izuma, on osigurava farmaceutski pripravak koji sadrži spoj formule (I) ili njegovu farmaceutski prihvatljivu sol ili in vivo hidrolizirajući ester i farmaceutski prihvatljivu podlogu. Therefore, from the next aspect of the presented invention, it provides a pharmaceutical composition containing a compound of formula (I) or its pharmaceutically acceptable salt or in vivo hydrolyzable ester and a pharmaceutically acceptable base.

Farmaceutski pripravci prema izumu mogu se primjeniti na uobičajen način za bolesna stanja koja treba liječiti, na primjer oralno, rektalno ili parenteralno. Zbog toga, spojevi ovog izuma mogu biti formulirani na načine poznate u struci u obliku, na primjer, tableta, kapsula, vodenih ili uljnih otopina ili suspenzija, emulzija, disperzibilnih prašaka, supozitorija i sterilnih injektibilnih vodenih ili uljnih otopina ili suspenzija. The pharmaceutical preparations according to the invention can be administered in the usual way for the disease states to be treated, for example orally, rectally or parenterally. Therefore, the compounds of this invention may be formulated in ways known in the art in the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, emulsions, dispersible powders, suppositories and sterile injectable aqueous or oily solutions or suspensions.

Spojevi prikazanog izuma mogu biti formulirani kao suhi prašak napunjen u medicinske bočice koji može sadržavati spoj prikazanog izuma samog ili kao suhu pomiješanu smjesu. Na primjer kiselinski spoj prema prikazanom izumu može biti pomiješan sa karbonatom ili bikarbonatom alkalijskog metala. Zaleđivanjem osušene formulacije spojeva prema prikazanom izumu mogu se prirediti kao samostalne ili kao smjesa sa uobičajenim ekscipijensima. Standardni ekscipijensi uključuju sredstva za oblikovanje, krioprotektante i pH modifikatore, kao što su mannitol, sorbitol, laktoza, glukoza, natrijum klorid, dekstran, maltoza, želatina, albumin goveđeg seruma (BSA), glicin, manoza, riboza, polivinilpirolidon(PVP), derivati celuloze, glutamin, inositol, kalijum glutamat, eritritol, serin i ostale amino kiseline i puferi, npr. dinatrijum hidrogen, fosfat i kalijum citrat. The compounds of the presented invention can be formulated as a dry powder filled in medical vials which can contain the compound of the presented invention alone or as a dry mixed mixture. For example, the acid compound according to the presented invention can be mixed with an alkali metal carbonate or bicarbonate. The freeze-dried formulations of the compounds according to the presented invention can be prepared as stand-alone or as a mixture with common excipients. Standard excipients include molding agents, cryoprotectants and pH modifiers, such as mannitol, sorbitol, lactose, glucose, sodium chloride, dextran, maltose, gelatin, bovine serum albumin (BSA), glycine, mannose, ribose, polyvinylpyrrolidone (PVP), cellulose derivatives, glutamine, inositol, potassium glutamate, erythritol, serine and other amino acids and buffers, eg disodium hydrogen, phosphate and potassium citrate.

Kao dodatak spojevima prikazanog izuma, farmaceutski pripravak prema ovom izumu može također sadržavati, ili biti primjenjen sa, jednim ili više lijekova izabranih između ostalih klinički korisnih antibakterijskih sredstava (na primjer ostali beta-laktami ili aminoglikozidi), inhibitorima beta-laktamaze (na primjer klavulanska kiselina), renalno tubularnim blokatorima (na primjer probenecid) i inhibitorima metabolitičkih enzima (na primjer inhibitori dehidropeptidaza, na primjer Z-2-acilamino-3-supstituirani propenoati kao što je cilastin) i N-aciliranim amino kiselinama kao što je betamipron (vidi također EP-A-178911). In addition to the compounds of the present invention, the pharmaceutical preparation according to the present invention may also contain, or be administered with, one or more drugs selected from other clinically useful antibacterial agents (for example other beta-lactams or aminoglycosides), beta-lactamase inhibitors (for example clavulanic acid), renal tubular blockers (for example probenecid) and metabolic enzyme inhibitors (for example dehydropeptidase inhibitors, for example Z-2-acylamino-3-substituted propenoates such as cilastin) and N-acylated amino acids such as betamiprone (see also EP-A-178911).

Prikladan farmaceutski pripravak ovog izuma je onaj koji je prikladan za oralnu primjenu u jediničnom dozirnom obliku, na primjer u tableti ili kapsuli koje sadrže između 100 mg i 1 g spoja prema ovom izumu. A suitable pharmaceutical composition of the present invention is one which is suitable for oral administration in a unit dosage form, for example in a tablet or capsule containing between 100 mg and 1 g of a compound of the present invention.

Preferirani farmaceutski pripravak ovog izuma je onaj prikladan za intravenozno, subkutano ili intramuskularno injiciranje, na primjer sterilni injektibilni pripravak koji sadrži između 1 i 50% tež./tež. spoja prema izumu. A preferred pharmaceutical composition of the present invention is one suitable for intravenous, subcutaneous or intramuscular injection, for example a sterile injectable composition containing between 1 and 50% w/w. compound according to the invention.

Specifični primjeri pripravaka, koji su načinjeni kao 1%-tna otopina u vodi, osušeni zaleđivanjem i mogu se prirediti dodavanjem 0.9%-tne vodene otopine natrijum klorida da bi se postigla željena koncentracija, povoljna je 1 mg-10 mg/ml, su slijedeći: Specific examples of preparations, which are formulated as a 1% solution in water, freeze-dried and can be prepared by adding 0.9% aqueous sodium chloride to achieve the desired concentration, preferably 1 mg-10 mg/ml, are as follows :

Pripravak 1 Preparation 1

Spoj iz Primjera 1 50 mg Compound from Example 1 50 mg

Pripravak 2 Preparation 2

Spoj iz Primjera 1 50 mg Compound from Example 1 50 mg

Glicin 31 mg Glycine 31 mg

Daljnji specifični primjeri pripravaka su isti kao i prethodni, ali je u njima spoj iz primjera 1 zamijenjen jednim iz primjera od 2 do 7. Further specific examples of preparations are the same as the previous ones, but in them the compound from example 1 is replaced by one from examples 2 to 7.

Farmaceutski pripravci prema izumu će biti uobičajeno primjenjeni ljudima da bi se suzbila infekcija uzrokovana bakterijama, na isti način kao što se upotrebljava imipenem, ali sa promjenama u odnosu prema kliničkoj upotrebi imipenema koje ovise o farmakokinetici spoja prema prikazanom izumu. Tako će svaki pacijent primiti dnevno intravenozno, subkutano ili intra-muskularno dozu od 0.05 do 5 g, te je povoljnije od 0.1 do 2.5 g, spoja prema izumu, a pripravak se primjenjuje 1 do 4 puta dnevno, povoljnije je 1 do 2 puta dnevno. Intravenozne, subkutane i intramuskularne doze se mogu davati pomoću velikih injekcija. Alternativno, intravenozne doze se mogu davati kontinuiranom infuzijom tokom određenog vremena. Alternativno,svaki pacijent će primiti dnevnu oralnu dozu koja je aproksimativno ekvivalentna dnevnoj parenteralnoj dozi. Tako je prikladna dnevna oralna doza od 0.05 do 5 g spoja prema izumu, a pripravak se primjenjuje od 1 do 4 puta dnevno. Pharmaceutical compositions according to the invention will be commonly administered to humans to control infection caused by bacteria, in the same way as imipenem is used, but with changes in relation to the clinical use of imipenem that depend on the pharmacokinetics of the compound according to the present invention. Thus, each patient will receive a daily intravenous, subcutaneous or intramuscular dose of 0.05 to 5 g, and preferably 0.1 to 2.5 g, of the compound according to the invention, and the preparation is applied 1 to 4 times a day, preferably 1 to 2 times a day . Intravenous, subcutaneous and intramuscular doses can be administered using large injections. Alternatively, intravenous doses can be given by continuous infusion over a period of time. Alternatively, each patient will receive a daily oral dose that is approximately equivalent to a daily parenteral dose. Thus, a daily oral dose of 0.05 to 5 g of the compound according to the invention is suitable, and the preparation is applied from 1 to 4 times a day.

Daljnji aspekt prikazanog izuma osigurava postupak pripreme spojeva formule (1) ili njihovih farmaceutski prihvatljivih soli ili in vivo hidrolizirajućih estera koji obuhvaća uklanjanje zaštitne grupe u spoju formule (V) gdje je tienil prsten po izboru dalje supstituiran kao u formuli (1): A further aspect of the presented invention provides a process for the preparation of compounds of formula (1) or their pharmaceutically acceptable salts or in vivo hydrolyzable esters, which includes the removal of the protecting group in the compound of formula (V) where the thienyl ring is optionally further substituted as in formula (1):

[image] [image]

gdje je R2 isti kao prethodno definiran; R10 je grupa R3 ili zaštitna amino grupa; R13 je grupa R1, zaštićeni hidroksimetil ili 1-(zaštićeni hidroksi)etil; R11 je vodik ili zaštitna karboksi grupa; R12 je vodik ili zaštitna amino grupa; R18 je karboksi ili zaštićena karboksi grupa i gdje je svaki od izbornih supstituenata na tienil prstenu po izboru zaštićen; te gdje je najmanje jedna zaštitna grupa prisutna; te kasnije ako je neophodno: where R 2 is the same as previously defined; R 10 is the group R 3 or a protective amino group; R13 is the group R1, protected hydroxymethyl or 1-(protected hydroxy)ethyl; R11 is hydrogen or a protective carboxy group; R 12 is hydrogen or an amino protecting group; R 18 is a carboxy or protected carboxy group and wherein each of the optional substituents on the thienyl ring is optionally protected; and where at least one protecting group is present; and later if necessary:

(i) formiranje farmaceutski prihvatljive soli, (i) formation of a pharmaceutically acceptable salt,

(ii) esterifikaciju da bi se formirali in vivo hidrolizirajući esteri. (ii) esterification to form in vivo hydrolyzable esters.

Zaštitne grupe mogu općenito biti izabrane iz bilo koje grupe opisane u literaturi ili poznate iskusnim kemičarima kao odgovarajuće zaštitne grupe, te se mogu uvesti uobičajenim postupcima. Protecting groups may generally be selected from any group described in the literature or known to skilled chemists as suitable protecting groups, and may be introduced by conventional procedures.

Zaštitne grupe se mogu ukloniti uobičajenim postupcima opisanim u literaturi ili poznatim iskusnim kemičarima kao odgovarajuće za uklanjanje zaštitnih grupa, te takvi postupci se mogu izabrati tako da se što je manje moguće uznemire grupe na drugim mjestima u molekuli. Protecting groups can be removed by conventional procedures described in the literature or known to skilled chemists as appropriate for removing protecting groups, and such procedures can be chosen to disturb groups elsewhere in the molecule as little as possible.

Spojevi formule (V) su novi i čine još jedan aspekt izuma. Zbog praktičnosti su u daljnjem tekstu prikazani specifični primjeri zaštitnih grupa, gdje "niži" označava da grupa kojoj je pridružen ima 1-4 ugljikova atoma. Jasno je da ti primjeri nisu iscrpni. Slično tome i tamo gdje su prikazani specifični primjeri za uklanjanje zaštitnih grupa i oni nisu iscrpni. Upotreba zaštitnih grupa i postupci uklanjanja nisu posebno spominjani, ali su naravno unutar dosega izuma. The compounds of formula (V) are novel and form another aspect of the invention. For convenience, specific examples of protecting groups are shown below, where "lower" means that the group to which it is attached has 1-4 carbon atoms. It is clear that these examples are not exhaustive. Similarly, where specific examples for deprotection are presented, they are not exhaustive. The use of protecting groups and removal procedures are not specifically mentioned, but are of course within the scope of the invention.

Karboksi zaštitna grupa može biti ostatak ester-formirajućeg alifatskog ili aralifatskog alkohola ili ester-formirajućeg silanola (spomenuti alkohol ili silanol sadrži 1-20 ugljikovih atoma). The carboxy protecting group can be the residue of an ester-forming aliphatic or araliphatic alcohol or an ester-forming silanol (said alcohol or silanol contains 1-20 carbon atoms).

Primjeri karboksi zaštitnih grupa uključuju ravni ili razgranati lanac (1-12C)alkil grupa (npr. izopropil, t-butil); niži alkoksi nižih alkil grupa (npr. metoksimetil, etoksimetil, izobutoksimetil); niži alifatski aciloksi nižih alkil grupa, (npr. acetoksimetil, propioniloksimetil, butiriloksimetil, pivaloiloksimetil); niži alkoksikarboniloksi nižih alkil grupa (npr. 1-metoksikarboniloksietil, 1-etoksikarboniloksietil); aril nižih alkil grupa (npr. D-metoksibenzil, o-nitrobenzil, p-nitrobenzil, benzhidril i ftalidil); tri(niži alkil)silil grupe (npr. trimetilsilil i t-butildimetilsilil); tri(niži alkil)silil nižih alkil grupa (npr. trimetilsililetil); diaril(niži alkil)silil grupe (npr. t-butildifenilsilil); i (2-6C)alkenil grupe (npr. alil i viniletil). Examples of carboxy protecting groups include straight or branched chain (1-12C)alkyl groups (eg, isopropyl, t-butyl); lower alkoxy of lower alkyl groups (eg methoxymethyl, ethoxymethyl, isobutoxymethyl); lower aliphatic acyloxy of lower alkyl groups, (eg acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (eg 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (eg D-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (eg trimethylsilyl and t-butyldimethylsilyl); tri(lower alkyl)silyl of lower alkyl groups (eg trimethylsilylethyl); diaryl(lower alkyl)silyl groups (eg t-butyldiphenylsilyl); and (2-6C)alkenyl groups (eg allyl and vinylethyl).

Postupci posebno prikladni za uklanjanje karboksi zaštitnih grupa uključuju, na primjer kiselinom-, lužinom-, metalom- ili enzimatski- katalizirane hidrolize; za grupe poput p-nitrobenzil-oksikarbonil, hidriranje; za grupe poput o-nitrobenziloksikarbonil, fotolitički. Processes particularly suitable for the removal of carboxy protecting groups include, for example, acid-, alkali-, metal- or enzyme-catalyzed hydrolyses; for groups such as p-nitrobenzyloxycarbonyl, hydrogenation; for groups such as o-nitrobenzyloxycarbonyl, photolytically.

Primjeri hidroksi zaštitnih grupa uključuju niže alkenil grupe (npr. alil); niže alkanoil grupe (npr. acetil); niže alkoksi-karbonilgrupe (npr. t-butoksikarbonil); niže alkeniloksikarbonil grupe (npr. benzoiloksikarbonil, p-metoksibenziloksikarbonil, o-nitrobenziloksikarbonil, p-nitrobenziloksikarbonil); tri niži alkilsilil (npr. trimetilsilil, t-butildimetilsilil); diaril (niži alkil)silil (npr. t-butildifenilsilil) i aril niži alkil (npr. benzil). Examples of hydroxy protecting groups include lower alkenyl groups (eg, allyl); lower alkanoyl groups (eg acetyl); lower alkoxycarbonyl groups (eg t-butoxycarbonyl); lower alkenyloxycarbonyl groups (eg benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri-lower alkylsilyl (eg, trimethylsilyl, t-butyldimethylsilyl); diaryl(lower alkyl)silyl (eg t-butyldiphenylsilyl) and aryl lower alkyl (eg benzyl).

Primjeri amino zaštitnih grupa uključuju formil, aralkil grupe (npr. benzil i supstituirani benzil, npr. D-metoksibenzil, nitrobenzil i 2,4-dimetoksibenzil, te trifenilmetil); di-p-anisimetil i furilmetil grupe; niže alkoksikarbonil (npr. t-butoksikarbonil); niže alkeniloksikarbonil (npr. alkiloksikarbonil); aril nižih alkoksikarbonil grupa (npr. benziloksikarbonil, p-metoksibenziloksikarbonil, o-nitrobenziloksikarbonil, p-nitro-benziloksikarbonil; trialkilsilil (npr. trimetilsilil i t-butil-dimetilsilil); diaril(niži alkil)silil (npr. t-butildifenil-silil); alkildiene (npr. metildiene), benzildiene i supstituirane benzildiene grupe. Examples of amino protecting groups include formyl, aralkyl groups (eg, benzyl and substituted benzyl, eg, D-methoxybenzyl, nitrobenzyl, and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisimethyl and furylmethyl groups; lower alkoxycarbonyl (eg t-butoxycarbonyl); lower alkenyloxycarbonyl (eg alkyloxycarbonyl); aryl of lower alkoxycarbonyl groups (e.g. benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitro-benzyloxycarbonyl; trialkylsilyl (e.g. trimethylsilyl and t-butyl-dimethylsilyl); diaryl(lower alkyl)silyl (e.g. t-butyldiphenyl-silyl ); alkyldienes (eg methyldienes), benzyldienes and substituted benzyldiene groups.

Postupci odgovarajući za uklanjanje hidroksi i amino zaštitnih grupa uključuju, na primjer, kiselinom-, lužinom-, metalom- ili enzimatski- kataliziranu hidrolizu; za grupe poput p-nitro-benziloksikarbonil, hidriranje; te za grupe poput o-nitrobenziloksikarbonil, fotolitički. Methods suitable for removing hydroxy and amino protecting groups include, for example, acid-, alkali-, metal-, or enzyme-catalyzed hydrolysis; for groups such as p-nitro-benzyloxycarbonyl, hydrogenation; and for groups like o-nitrobenzyloxycarbonyl, photolytic.

Preferirane zaštitne grupe za karboksi i hidroksi grupe u spojevima formule (I) su grupe alil i p-nitrobenzil. Preferirani postupak za uklanjanje alil grupe je palladium kataliza uz upotrebu tetrakis(trifenilfosfin)palladiuma i Meldrumove kiseline, u DMF ili dipolarnom aprotičkom otapalu smjesi tetrahidrofurana, kao što je dimetilsulfoksid/tetrahidrofuran ili 1,3-dimetil-2-okso-tetrahidropirimidin/tetrahidrofuran, ili smjesa alkohol/tetrahidrofuran kao što je izopropanol/tetrahidrofuran, povoljno je pri sobnoj temperaturi. Alternativno, umjesto Meldrumove kiseline se može koristiti metilanilin u diklorometanu. Ovi uvjeti dozvoljavaju izoliranje produkta precipitacijom natrijeve soli kao što je natrijum 2-etilheksanoat. Preferred protecting groups for carboxy and hydroxy groups in compounds of formula (I) are allyl and p-nitrobenzyl groups. The preferred method for removal of the allyl group is palladium catalysis using tetrakis(triphenylphosphine)palladium and Meldrum's acid, in DMF or a dipolar aprotic tetrahydrofuran solvent mixture, such as dimethylsulfoxide/tetrahydrofuran or 1,3-dimethyl-2-oxo-tetrahydropyrimidine/tetrahydrofuran, or an alcohol/tetrahydrofuran mixture such as isopropanol/tetrahydrofuran, preferably at room temperature. Alternatively, methylaniline in dichloromethane can be used instead of Meldrum's acid. These conditions allow isolation of the product by precipitation of a sodium salt such as sodium 2-ethylhexanoate.

Preferirani postupak za uklanjanje p-nitrobenzil grupe je hidriranje uz upotrebu palladiuma kao katalizatora. The preferred procedure for removing the p-nitrobenzyl group is hydrogenation using palladium as a catalyst.

Sa idućeg aspekta prikazanog izuma, spojevi formule (I) i (V) mogu se prirediti: From the next aspect of the presented invention, compounds of formulas (I) and (V) can be prepared:

a) reakcijom spojeva formule (VI) i (VII): a) by reaction of compounds of formulas (VI) and (VII):

[image] [image]

gdje su R2, R10, R12, R13 i R18 i ti kao prethodno definirani, izborni supstituenti tienil prstena su isti kao prethodno definirani, a L je grupa koja se otpušta, ili wherein R 2 , R 10 , R 12 , R 13 and R 18 and ti are as previously defined, optional thienyl ring substituents are as previously defined, and L is a leaving group, or

b) ciklizacijom spoja formule (VIII): b) by cyclization of the compound of formula (VIII):

[image] [image]

gdje su R2, R10, R11, R12, R13 i R18 isti kao prethodno definirani, izborni supstituenti tienil prstena su isti kao prethodno definirani, a R14, R15 i R16 su svaki zasebno izabrani između C1-6alkoksi, ariloksi, di-C1-6alkilamino i diarilamino ili bilo koja dva od R14-R16 predstavlja o-fenilenedioksi ili jedan od R14-R16 predstavlja C1-4alkil, alil, benzil ili fenil, a preostale dvije vrijednosti su svaka zasebno izabrane između C1-4alkil, trifluorometil ili fenil, gdje je svaka fenil grupa po izboru supstituirana sa C1-3alkil ili C1-3alkoksi; te je svaka funkcionalna grupa po izboru zaštićena i kasnije ako je neophodno: wherein R 2 , R 10 , R 11 , R 12 , R 13 and R 18 are as defined above, optional thienyl ring substituents are as defined above, and R 14 , R 15 and R 16 are each independently selected from C 1-6 alkoxy, aryloxy, di-C 1-6 alkylamino and diarylamino or any two of R14-R16 represents o-phenylenedioxy or one of R14-R16 represents C1-4alkyl, allyl, benzyl or phenyl, and the remaining two values are each independently selected from C1-4alkyl, trifluoromethyl or phenyl, where each phenyl group optionally substituted with C 1-3 alkyl or C 1-3 alkoxy; and each functional group is optionally protected later if necessary:

(i) ukloni se zaštitna grupa; (i) the protecting group is removed;

(ii) formira se farmaceutski prihvatljiva sol; (ii) a pharmaceutically acceptable salt is formed;

(iii) provede se esterifikacija da bi se dobio in vivo hidrolizirajući ester. (iii) esterification is carried out to give an in vivo hydrolyzable ester.

Prikladno je da je spoju formule (VI), L reaktivni ester hidroksi grupe kao što je sulfonat (na primjer C1-6alkansulfonil-oksi, trifluorometansulfoniloksi, benzensulfoniloksi, toluen-sulfoniloksi), fosforni esteri ( na primjer diarilfosforni ester kao što je difenilfosforni ester) ili je L halid (na primjer klorid). Alternativno L je sulfoksid, na primjer -SOCH=CH-NHCOCH3 koji se može lako ukloniti. Povoljno je da je L difenilfosforni ester (-OP(O)(OPh)2). Suitably for the compound of formula (VI), L is a reactive ester of a hydroxy group such as a sulfonate (for example C1-6alkanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy), phosphoric esters (for example a diarylphosphoric ester such as diphenylphosphoric ester) or L is a halide (eg chloride). Alternatively L is a sulfoxide, for example -SOCH=CH-NHCOCH3 which can be easily removed. Advantageously, L is diphenylphosphoric ester (-OP(O)(OPh)2).

Spojevi formule (VI) i njihova priprema su dobro poznati u literaturi o karbapenemu, na primjer vidi EP-A126587, EP-A-160391, EP-A-243686 i EP-A-343499. Compounds of formula (VI) and their preparation are well known in the carbapenem literature, for example see EP-A-126587, EP-A-160391, EP-A-243686 and EP-A-343499.

Reakcija između spojeva formule (VI) i (VII) se obično provodi u prisutnosti lužine poput organskog amina, na primjer di-izopropiletilamina ili anorganske baze poput kalij karbonata. Reakcije se obično provodi pri temperaturi između -25ºC i sobne, prikladno je kod oko 4°C. Reakcija se obično provodi u organskom otapalu poput acetonitrila ili dimetilformamida. Reakcija se uobičajeno provodi na način sličan onome opisanome u literaturi za reakcije sličnog tipa. The reaction between compounds of formula (VI) and (VII) is usually carried out in the presence of a base such as an organic amine, for example di-isopropylethylamine, or an inorganic base such as potassium carbonate. Reactions are usually carried out at a temperature between -25ºC and room temperature, about 4°C is suitable. The reaction is usually carried out in an organic solvent such as acetonitrile or dimethylformamide. The reaction is usually carried out in a manner similar to that described in the literature for reactions of a similar type.

Spojevi formule (VII) su novost i čine još jedan aspekt prikazanog izuma. The compounds of formula (VII) are novel and form another aspect of the present invention.

Spojevi formule (VII) se mogu pripremiti uklanjanjem zaštitnih grupa sa spoja formule (IX): Compounds of formula (VII) can be prepared by deprotection of compounds of formula (IX):

[image] [image]

gdje su R10, R12 i R18 isti kao prethodno definirani, izborni supstituenti tienil prstena su isti kao prethodno definirani i R17 je zaštitna grupa, na primjer C1-6alkanoil, C1-6alkoksi-karbonil ili benzoil. Preferirane vrijednosti za R17 su acetil i t-butoksikarbonil. Spojevi formule (IX) se mogu lako prevesti u spojeve formule (VII) uobičajenim postupcima deprotekcije, na primjer acetil grupe se mogu ukloniti baznom hidrolizom u vodenom alkanolu, alkenolu, na primjer u alil alkoholu ili tetrahidrofuranu. where R 10 , R 12 and R 18 are the same as previously defined, the optional thienyl ring substituents are the same as previously defined and R 17 is a protecting group, for example C 1-6 alkanoyl, C 1-6 alkoxycarbonyl or benzoyl. Preferred values for R17 are acetyl and t-butoxycarbonyl. Compounds of formula (IX) can be easily converted to compounds of formula (VII) by conventional deprotection procedures, for example acetyl groups can be removed by base hydrolysis in aqueous alkanol, alkenol, for example in allyl alcohol or tetrahydrofuran.

Spojevi formule (IX) su novost i čine još jedan aspekt prikazanog izuma* The compounds of formula (IX) are novel and constitute another aspect of the present invention*

Spojevi formule (IX) se mogu prirediti reakcijom aktiviranih derivata spoja formule (X), koji se mogu prirediti in situ, sa spojem formule (XI): Compounds of formula (IX) can be prepared by reacting activated derivatives of compounds of formula (X), which can be prepared in situ, with compounds of formula (XI):

[image] [image]

gdje su R10, R12, R17 i R18 isti kao prethodno definirani i izborni supstituenti tienil prstena su isti kao prethodno definirani. Aktivirani derivati spoja formule (X) uključuju kiselinske halide, anhidride i " aktivirane" estere kao što je 1H-benzo[1,2,3]-triazol-1-il, pentafluorofenil i 2,4,5-trikloro-fenil esteri ili benzimidazol-2-il ester tiokarboksilne kiseline odgovarajući za (X). Reakcija spojeva formule (X) i (XI) se provodi uz uobičajene postupke, na primjer u prisutnosti sulfonil klorida pri sobnoj temperaturi. where R 10 , R 12 , R 17 and R 18 are as previously defined and optional thienyl ring substituents are as previously defined. Activated derivatives of the compound of formula (X) include acid halides, anhydrides and "activated" esters such as 1H-benzo[1,2,3]-triazol-1-yl, pentafluorophenyl and 2,4,5-trichloro-phenyl esters or thiocarboxylic acid benzimidazol-2-yl ester corresponding to (X). The reaction of the compounds of formula (X) and (XI) is carried out by conventional procedures, for example in the presence of sulfonyl chloride at room temperature.

Spojevi formule (X) i (XI) se priređuju uobičajenim postupcima poznatim iskusnim kemičarima poput postupaka opisanih u Primjerima u daljnjem tekstu,postupaka opisanih u EP-A-126587 ili pomoću postupaka koji su njima analogni ili slični. Compounds of formula (X) and (XI) are prepared by conventional procedures known to skilled chemists such as the procedures described in the Examples below, the procedures described in EP-A-126587 or by procedures analogous or similar to them.

Prikladno, spojevi formule (VIII) imaju za R14, R15 i R16 slobodni izbor između C1-6alkoksi, kao što su metoksi, etoksi, izopropoksi, n-propoksi ili n-butoksi; ariloksi, kao što je po izboru supstituiran fenoksi; di-C1-6alkilamino, kao što je dimetil-amino ili dietilamino; diarilamino, kao što je difenilamino ili bilo koji od R14-R16 predstavlja o-fenilenedioksi. Povoljno je da svaki od R14-R16 ima istu vrijednost i da je, na primjer metoksi, etoksi, izopropoksi ili n-butoksi ili fenoksi. Suitably, the compounds of formula (VIII) have for R 14 , R 15 and R 16 a free choice between C 1-6 alkoxy, such as methoxy, ethoxy, isopropoxy, n-propoxy or n-butoxy; aryloxy, such as optionally substituted phenoxy; di-C 1-6 alkylamino, such as dimethylamino or diethylamino; diarylamino, such as diphenylamino or any of R14-R16 represents o-phenylenedioxy. Advantageously, each of R14-R16 has the same value and is, for example, methoxy, ethoxy, isopropoxy or n-butoxy or phenoxy.

Spojevi formule (VIII) se cikliziraju uz uobičajene uvjete poznate u struci za formiranje spojeva formule (V). Tipični uvjeti su zagrijavanje u inertnom otapalu poput toluena, xilena ili etil acetata pri temperaturama u intervalu između 60-150°C. Uobičajeno se reakcija provodi u atmosferi dušika i provodi se u prisutnosti radikalnog sredstva za čišćenje, na primjer hidrokvinona. Compounds of formula (VIII) are cyclized under the usual conditions known in the art for the formation of compounds of formula (V). Typical conditions are heating in an inert solvent such as toluene, xylene or ethyl acetate at temperatures in the interval between 60-150°C. Typically, the reaction is carried out under a nitrogen atmosphere and is carried out in the presence of a radical scavenger, for example hydroquinone.

Spojevi formule (VIII) se mogu formirati i ciklizirati in situ. Spojevi formule (VIII) se mogu uobičajeno prirediti reakcijom spojeva formule (XII) i (XIII): Compounds of formula (VIII) can be formed and cyclized in situ. Compounds of formula (VIII) can be usually prepared by the reaction of compounds of formula (XII) and (XIII):

[image] [image]

gdje su R2, R10-R16 i R18 isti kao prethodno definirani i izborni supstituenti tienil prstena su isti kao prethodno definirani. Prikladno je da je spoj formule (XIII) fosfit ili funkcionalni ekvivalent takvog spoja. wherein R 2 , R 10 -R 16 and R 18 are as previously defined and optional thienyl ring substituents are as previously defined. Suitably, the compound of formula (XIII) is a phosphite or a functional equivalent of such a compound.

Reakcija između spojeva formule (XII) i (XIII) se uobičajeno provodi u organskom otapalu poput toluena, ksilena, etil acetata, kloroforma, diklorometana, acetonitrila ili dimetilformamida. Tipično se reakcija provodi pri povišenoj temperaturi, na primjer 60-150°C. The reaction between compounds of formula (XII) and (XIII) is usually carried out in an organic solvent such as toluene, xylene, ethyl acetate, chloroform, dichloromethane, acetonitrile or dimethylformamide. Typically, the reaction is carried out at an elevated temperature, for example 60-150°C.

Spojevi formule (XII) se mogu pripremiti brojnim postupcima dobro poznatima u stuci. Na primjer, spojevi formule (XII) se mogu prirediti aciliranjem spoja formule (XIV): Compounds of formula (XII) can be prepared by a number of procedures well known in the art. For example, compounds of formula (XII) can be prepared by acylating a compound of formula (XIV):

[image] [image]

gdje su R2, R10, R12, R13 i R18 isti kao prethodno definirani i izborni supstituenti tienil prstena su isti kao prethodno definirani, sa spojem formule (XV): where R 2 , R 10 , R 12 , R 13 and R 18 are the same as previously defined and the optional thienyl ring substituents are the same as previously defined, with the compound of formula (XV):

Cl-CO-COOR11 (XV) Cl-CO-COOR11 (XV)

gdje je R11 isti kao prethodno definiran. where R11 is the same as previously defined.

Spojevi formule (XIV) se mogu prirediti reakcijom spoja formule (XVI) i (VII): Compounds of formula (XIV) can be prepared by reacting compounds of formula (XVI) and (VII):

[image] [image]

gdje su R2 i R13 isti kao prethodno definirani. Spojevi formule (XVI) su poznati u struci i mogu se prirediti poznatim postupcima te reagiraju sa spojevima formule (VII) uz uobičajene uvjete aciliranja poznate u struci. where R2 and R13 are the same as previously defined. Compounds of formula (XVI) are known in the art and can be prepared by known procedures and react with compounds of formula (VII) under the usual acylation conditions known in the art.

Spojevi formula (VII), (XII) i (XIV) su novi i kao takvi čine još jedan aspekt prikazanog izuma. The compounds of formulas (VII), (XII) and (XIV) are new and as such constitute another aspect of the presented invention.

Slijedeći postupci biološkog testiranja, podaci i Primjeri služe ilustriranju prikazanog izuma. The following biological test procedures, data and Examples serve to illustrate the disclosed invention.

Antibakterijska Aktivnost Antibacterial Activity

Farmaceutski prihvatljivi spojevi karbapenema prema prikazanom izumu su korisna antibakterijska sredstva sa širokim spektrom aktivnosti in vitro protiv standardnih laboratorijskih mikroorganizama, Gram-negativnih i Gram-pozitivnih, koji se koriste za snimanje aktivnosti protiv patogenih bakterija. Antibakterijska aktivnost i moć pojedinačnih spojeva se može odrediti pomoću standardnog test sistema. Karbapenemi prema prikazanom izumu pokazuju dobru stabilnost prema beta-laktamazama i imaju posebno dobro vrijeme eliminacije polu života u sisavaca. Pharmaceutically acceptable carbapenem compounds according to the present invention are useful antibacterial agents with a wide spectrum of activity in vitro against standard laboratory microorganisms, Gram-negative and Gram-positive, which are used to record activity against pathogenic bacteria. The antibacterial activity and potency of individual compounds can be determined using a standard test system. Carbapenems according to the presented invention show good stability against beta-lactamases and have a particularly good elimination half-life in mammals.

Općenito, spojevi pokazuju značajno poboljšanje u odnosu na imipenem. Overall, the compounds show significant improvement over imipenem.

Antibakterijska aktivnost i svojstva spojeva prema izumu se također mogu demonstrirati in vivo uobičajenim testovima. The antibacterial activity and properties of the compounds according to the invention can also be demonstrated in vivo by conventional tests.

Za spojeve karbapenema je pronađeno da su relativno netoksični za toplokrvne životinje, te se to odnosi i na spojeve prema prikazanom izumu. Reprezentativni spojevi ovog izuma su primjenjeni miševima u dozama koje premašuju one potrebne za zaštitu od bakterijskih infekcija, ali nisu zabilježeni toksični simptomi niti nus-efekti koji bi se mogli pripisati primjenjenim spojevima. Carbapenem compounds have been found to be relatively non-toxic to warm-blooded animals, and this also applies to the compounds according to the present invention. Representative compounds of this invention were administered to mice in doses exceeding those necessary for protection against bacterial infections, but no toxic symptoms or side effects attributable to the administered compounds were recorded.

Slijedeći rezultati su dobiveni za reprezentativne spojeve korištenjem standardnog test sistema in vitro uz upotrebu Dijagnostičkog Testa Osjetljivosti. Antibakterijska aktivnost je opisana terminom minimalne koncentracije inhibicije (MIC) koja je određena agar-razrjeđenje tehnikom sa inokuliranom veličinom od 104 CFU/mrlja. The following results were obtained for representative compounds using a standard in vitro test system using the Diagnostic Susceptibility Test. Antibacterial activity is described by the term minimum inhibition concentration (MIC) determined by the agar-dilution technique with an inoculated size of 104 CFU/spot.

MIC(μg/ml) MIC(μg/ml)

ORGANIZAM PRIMJER 1 ORGANISM EXAMPLE 1

S.aureus 0.125 S. aureus 0.125

Oxford Oxford

E. coli 0.008 E. coli 0.008

DCO DCO

P.morganii 0.008 P. morganii 0.008

I+001 I+001

Enterobacter 0.008 Enterobacter 0.008

cloacae P99- cloacae P99-

B. fragilis 0.125 B. fragilis 0.125

AMP S AMP S

U slijedećim primjerima koji su reprezentativnog dosega: In the following examples, which are representative in scope:

(a) NMR spektri su snimani pri 200 MHz ili 400 MHz osim ako je drugačije naznačeno; (a) NMR spectra were recorded at 200 MHz or 400 MHz unless otherwise indicated;

(b) Mliloksi označava propen-1-iloksi grupu –OCH2CH=CH2; (b) Mlyloxy means the propen-1-yloxy group –OCH2CH=CH2;

(c) THF označava tetrahidrofuran; (c) THF means tetrahydrofuran;

(d) DMF označava dimetilformamid; (d) DMF means dimethylformamide;

(e) DMSO označava dimetilsulfoksid; (e) DMSO means dimethylsulfoxide;

(f) Evaporacija otapala se provodi pri smanjenom tlaku; (f) Solvent evaporation is carried out at reduced pressure;

(g) HPLC označava visoko tlačnu tekuću kromatografiju; (g) HPLC means high pressure liquid chromatography;

(h) Temperature su prikazane u stupnjevima Celzijusa; (h) Temperatures are shown in degrees Celsius;

(i) TFA označava trifluorooctenu kiselinu; te (i) TFA means trifluoroacetic acid; you

(j) tlc označava tankoslojnu kromatografiju. (j) tlc stands for thin layer chromatography.

Primjer 1 Example 1

(1R,5S,6S,8R,2'S,4'S)-2-(2-(2-Karboksi-4-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina (dikalijeva sol) (1R,5S,6S,8R,2'S,4'S)-2-(2-(2-Carboxy-4-thienylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid (dipotassium salt)

Otopina 4-nitrobenzil(1R,5S,6S,8R,2'S,4'3)-2-(1-(4-nitro-benziloksikarbonil)-2-(2-karboksi-4-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-metilkarbapenem-3-karboksilata (diisopropiletilamin sol) (ekvivalent 250 mg slobodne kiseline, 0.31 mM) u vodi (10 ml) i kalijum bikarbonata (65 mg, 0629 mM) se hidrira pri atmosferskom tlaku i u prisutnosti paladijum/ugljik (10%) (200mg). Reakcija se prati analitički pomoću HPLC. Na kraju reakcije, katalizator se ukloni filtriranjem i preostala tekućina se pročisti preparativnom HPLC (Nucleosil C-18, 10 uM, promjer 2.4 cm; dužina 25 cm). Upotrebljavajući vodu kao eluans, frakcije koje sadrže željeni spoj se koncentriraju i liofiliziraju da bi dale naslovni spoj (65 mg, 37%). Solution 4-nitrobenzyl(1R,5S,6S,8R,2'S,4'3)-2-(1-(4-nitro-benzyloxycarbonyl)-2-(2-carboxy-4-thienylcarbamoyl)pyrrolidin-4-ylthio) -6-(1-hydroxyethyl)-methylcarbapenem-3-carboxylate (diisopropylethylamine salt) (equivalent to 250 mg free acid, 0.31 mM) in water (10 ml) and potassium bicarbonate (65 mg, 0.629 mM) was hydrated at atmospheric pressure and in presence of palladium/carbon (10%) (200mg). The reaction is monitored analytically by HPLC. At the end of the reaction, the catalyst is removed by filtration and the remaining liquid is purified by preparative HPLC (Nucleosil C-18, 10 µM, diameter 2.4 cm; length 25 cm). Using water as eluent, fractions containing the desired compound were concentrated and lyophilized to give the title compound (65 mg, 37%).

NMR (DMSO-d6+AcOD-d4) δ: 1.15 (2d, 2H); 1.75 (R, 1H); 2.65 (3, 1H); 2.82 (m, 1H); 3.2 (dd, 1H); 3.3-3.5 (m, 2H); 3.65 (m, 1H); 3.85-4.05 (m, 2H); 4.15(dd, 1H); 7.72 (s, 1H); 7.78 (s, 1H). NMR (DMSO-d6+AcOD-d4) δ: 1.15 (2d, 2H); 1.75 (R, 1H); 2.65 (3, 1H); 2.82 (m, 1H); 3.2 (dd, 1H); 3.3-3.5 (m, 2H); 3.65 (m, 1H); 3.85-4.05 (m, 2H); 4.15(dd, 1H); 7.72 (s, 1H); 7.78 (s, 1H).

Polazni materijal je pripremljen na slijedeći način: The starting material was prepared in the following way:

4-Nitro-2-tiofenkarboksilna kiselina 4-Nitro-2-thiophenecarboxylic acid

2-Tiofenkarboksilna kiselina (6.4g, 50mH) se suspendira u octenom anhidridu (15 ml) i dimeća nitritna, kiselina (15 ml) u glacijalnoj octenoj kiselini (25 ml) se polagano dodaje tokom jednog sata uz miješanje, te se temperatura reakcije zadržava ispod 30°C. Reakcijska smjesa se miješa na sobnoj temperaturi tokom dva sata. Produkt se pročisti podvrgavanjem kromatografiji (470 ml) na HP20ss smoli uz upotrebu metanol/(voda+1%octena kiselina):0/100→ 50/50 kao eluansa. Dobije se čisti naslovni produkt (1.3 g) skupa sa smjesom 4- i 5-nitrotiofen-2-karboksilnom kiselinom (4.4 g). 2-Thiophenecarboxylic acid (6.4g, 50mH) is suspended in acetic anhydride (15 ml) and fuming nitric acid (15 ml) in glacial acetic acid (25 ml) is added slowly over one hour with stirring, and the reaction temperature is maintained below 30°C. The reaction mixture is stirred at room temperature for two hours. The product was purified by chromatography (470 ml) on HP20ss resin using methanol/(water+1%acetic acid):0/100→50/50 as eluent. The pure title product (1.3 g) is obtained together with a mixture of 4- and 5-nitrothiophene-2-carboxylic acid (4.4 g).

NMR(CDCl3): δ 8.35 (d, 1H); 8.5 (d, 1H). NMR(CDCl3): δ 8.35 (d, 1H); 8.5 (d, 1H).

4-Amino-2-tiofenkarboksilna kiselina 4-Amino-2-thiophenecarboxylic acid

4-Nitro-2-tiofenkarboksilna kiselina (1g, 5.7 mmol) se doda uz miješanje u otopinu SnCl2.2H2O (3.25 g, 14.4 mmol) u koncentriranoj HCl(10 ml). Smjesa se miješa tokom 6 sati pri sobnoj temperaturi i pročisti podvrgavanjem kromatografiji na HP2OSS smoli, upotrebljavajući vodu kao eluans, da bi se dobio naslovni spoj (0.59g, 71%). 4-Nitro-2-thiophenecarboxylic acid (1g, 5.7 mmol) was added with stirring to a solution of SnCl2.2H2O (3.25 g, 14.4 mmol) in concentrated HCl (10 ml). The mixture was stirred for 6 hours at room temperature and purified by chromatography on HP2OSS resin, using water as eluent, to give the title compound (0.59g, 71%).

NMR (DMSO-d6+AcOD-d4): δ 7.6 (s, 2H). NMR (DMSO-d6+AcOD-d4): δ 7.6 (s, 2H).

(2S,4S)-1-(4-Nitrobenzilkarbonil)-2-(2-karboksi-4-tienilkarbamoil)-pirolidin-4-iltioacetat (2S,4S)-1-(4-Nitrobenzylcarbonyl)-2-(2-carboxy-4-thienylcarbamoyl)-pyrrolidine-4-ylthioacetate

(2S,4S)-4-Acetiltio-2-karboksi-1-(4-nitrobenziloksikarbonil)-pirolidin (1.5 g, 4.08 mmol) se otopi pri sobnoj temperaturi u tionil kloridu (10 ml). Smjesa se miješa tokom 4 sata pri sobnoj temperaturi. Tionil klorid se evaporira, preostalo ulje se uzme u diklorometan/toluen (10 ml, 1:1) i otapalo se ukloni evaporacijom. Preostalo ulje se suši u vakuumu tokom jednog sata i otopi se u dikloromethanu (25 ml). Ova otopina se doda u smjesu 4-amino-2-tiofenkarboksilne kiseline (0.58g, 4.08mmol), trimetilsilil klorida (1 ml, 8.2 mmol) i diizo-propiletilamina (3 ml, 17-25 mmol) u diklorometanu (40 ml) pri 0ºC. Reakcijska smjesa se miješa tokom 12 sati na sobnoj temperaturi, otapalo se evaporira i ostatak se otopi u DHF-u i podvrgne kromatografiji na HP2OSS smoli, uz eluaciju sa smjesom acetonitril/voda/octena kiselina (40:60:1), nakon čega slijedi koncentriranje i liofilizacija da bi se dobio naslovni spoj, (0.84 g, 42%). (2S,4S)-4-Acetylthio-2-carboxy-1-(4-nitrobenzyloxycarbonyl)-pyrrolidine (1.5 g, 4.08 mmol) was dissolved at room temperature in thionyl chloride (10 ml). The mixture is stirred for 4 hours at room temperature. The thionyl chloride was evaporated, the remaining oil was taken up in dichloromethane/toluene (10 ml, 1:1) and the solvent was removed by evaporation. The remaining oil was dried under vacuum for one hour and dissolved in dichloromethane (25 ml). This solution was added to a mixture of 4-amino-2-thiophenecarboxylic acid (0.58g, 4.08mmol), trimethylsilyl chloride (1ml, 8.2mmol) and diisopropylethylamine (3ml, 17-25mmol) in dichloromethane (40ml). at 0ºC. The reaction mixture is stirred for 12 hours at room temperature, the solvent is evaporated and the residue is dissolved in DHF and subjected to chromatography on HP2OSS resin, eluting with a mixture of acetonitrile/water/acetic acid (40:60:1), followed by concentration and lyophilization to give the title compound, (0.84 g, 42%).

NMR (DMSO-d6+AcOD-d4): δ 1.92 (m, 1H), 2.32 (s, 3H), 2.76 (m, 1H), 3.35 (m, 1H); 3.9-4.2 (m, 2H); 4.42 (m, 1H); 5.0-5.35 (m, 2H); 7.45 (d, 1H); 7.65 (d, 1H); 7.76 (s, 2H); 7-96 (d, 1H); 8.22 (d, 1H). NMR (DMSO-d6+AcOD-d4): δ 1.92 (m, 1H), 2.32 (s, 3H), 2.76 (m, 1H), 3.35 (m, 1H); 3.9-4.2 (m, 2H); 4.42 (m, 1H); 5.0-5.35 (m, 2H); 7.45 (d, 1H); 7.65 (d, 1H); 7.76 (s, 2H); 7-96 (d, 1H); 8.22 (d, 1H).

(2S,4S)-1-(4-Nitrobenziloksikarbonil)-2-(2-karboksi-4-tienil-karbamoil)-pirolidin-4-iltiol (2S,4S)-1-(4-Nitrobenzyloxycarbonyl)-2-(2-carboxy-4-thienyl-carbamoyl)-pyrrolidine-4-ylthiol

(2S,4S)-1-(4-Nitrobenziloksikarbonil-2-(2-karboksi-4-tienil-karbamoil)pirolidin-4-iltioacetat (0.475 g, 0.963 mmol) se otopi u smjesi dioksan/voda (1:1) (20 ml) i tretira sa 1M vodenom otopinom NaOH (2.5 ml,2.4 mmol). Reakcija se prati pomoću HPLC. Nakon jednog sata, pH se namjesti na pH 3 pomoću 6M vodene otopine HCl, pri 0ºC. Reakcijska smjesa se zatim evaporira i suši u vakuumu tokom jednog sata. (2S,4S)-1-(4-Nitrobenzyloxycarbonyl-2-(2-carboxy-4-thienyl-carbamoyl)pyrrolidine-4-ylthioacetate (0.475 g, 0.963 mmol) was dissolved in a mixture of dioxane/water (1:1) (20 ml) and treated with 1M aqueous NaOH (2.5 ml, 2.4 mmol). The reaction was monitored by HPLC. After one hour, the pH was adjusted to pH 3 using 6M aqueous HCl at 0ºC. The reaction mixture was then evaporated and dry in a vacuum for one hour.

4-Nitrobenzil (1R,5R,6S,8R,2'S,4'S)-2-(1-(4-nitrobenziloksikarbonil)-2-(2-karboksi-4-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksi-etil)-1-metilkarbapenem-3-karboksilat (diizopropiletilamin sol) 4-Nitrobenzyl (1R,5R,6S,8R,2'S,4'S)-2-(1-(4-nitrobenzyloxycarbonyl)-2-(2-carboxy-4-thienylcarbamoyl)pyrrolidin-4-ylthio)-6-(1 -hydroxy-ethyl)-1-methylcarbapenem-3-carboxylate (diisopropylethylamine salt)

Otopina 4-nitrobenzil(1R,5R,68,8R)-6-(1-hidroksietil)-1-metil-2-difenilfosforiloksikarbapenem-3-karboksilata (0.575 g, 0.968 mmol) u DHF-u (5 ml) se doda u otopinu (2S,4S)-1(4-nitrobenzil-oksikarbonil)-2-(2-karboksi-4-tienilkarbamoil)pirolidin-4-il-tiol u DMF-u (5 ml). U reakcijsku smjesu se dodaju diizopropiletilamin (0.505 ml, 2.9 mmol), tri-n-butilfosfin (0.24 ml, 0.963 mmol) i voda (20 ul, 0.968 mmol), te se miješa tokom 14 sati na 4ºC. Naslovni spoj se pročisti podvrgavanjem kromatografiji na HP2OSS smoli (100 ml) uz upotrebu smjese acetonitril/voda (30:70) kao eluansa. Evaporacija i liofilizacija daju naslovni spoj (0.375 g, 49%). A solution of 4-nitrobenzyl(1R,5R,68,8R)-6-(1-hydroxyethyl)-1-methyl-2-diphenylphosphoryloxycarbapenem-3-carboxylate (0.575 g, 0.968 mmol) in DHF (5 mL) was added in a solution of (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(2-carboxy-4-thienylcarbamoyl)pyrrolidin-4-yl-thiol in DMF (5 ml). Diisopropylethylamine (0.505 ml, 2.9 mmol), tri-n-butylphosphine (0.24 ml, 0.963 mmol) and water (20 ul, 0.968 mmol) were added to the reaction mixture, and it was stirred for 14 hours at 4ºC. The title compound was purified by chromatography on HP2OSS resin (100 ml) using acetonitrile/water (30:70) as eluent. Evaporation and lyophilization gave the title compound (0.375 g, 49%).

NMR (DMSO-d6+AcOD-d4): δ 1.15 (t, 15H); 1.25 (2d, 6H); 1.95 (m, 1H); 2.81 (m, 1H); 3.15 (q, 2H); 3.3 (m, 1H); 3.42 (m, 1H); 3.5-3.7 (m, 3H); 3.9-4.2 (m, 3H); 4.2-4.35 (m, 1H); 4.35-4.55 (m, 1H); 5.15-5.45 (m, 4H); 7.35-8.05 (m, 8H); 8.15 (s, 1H); 8.18 (s, 1H). NMR (DMSO-d6+AcOD-d4): δ 1.15 (t, 15H); 1.25 (2d, 6H); 1.95 (m, 1H); 2.81 (m, 1H); 3.15 (q, 2H); 3.3 (m, 1H); 3.42 (m, 1H); 3.5-3.7 (m, 3H); 3.9-4.2 (m, 3H); 4.2-4.35 (m, 1H); 4.35-4.55 (m, 1H); 5.15-5.45 (m, 4H); 7.35-8.05 (m, 8H); 8.15 (s, 1H); 8.18 (s, 1H).

Primjer 2 Example 2

(1R,5S,6S,8R,2'S,4'S)-2-(2-(2-Karboksi-3-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina (dikalijeva sol) (1R,5S,6S,8R,2'S,4'S)-2-(2-(2-Carboxy-3-thienylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid (dipotassium salt)

Otopina alil(1R,5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenziloksi-karbonil)-2-(2-karboksi-3-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilat diizopropil-etilamin sol (ekvivalent 0.49 g slobodne kiseline, 0.7 mmol) u THF-u (25 ml) se tretira sa trifenilfosfinom (20 mg, 0.076 mmol), kalijum heksanoatom (0.46M otopina u etil acetatu, 3.2 ml, 1.47 mmol), heksanonskom kiselinom (0.235 ml, 1.47 mmol) i tetra-kis(trifenilfosfin)paladijumom (70 mg) tokom jednog sata pri sobnoj temperaturi. Zatim se doda etil acetat (25 ml) u reakcijsku smjesu i precipitat se sakupi filtriranjem. Precipitat se ispere sa etil acetatom i suši (0.45 g, 87%). Taj sirovi produkt se otopi u vodi (10 ml) i hidrira pri atmosferskom tlaku preko paladijum/ugljika (10%, 0.35 g). Deprotekcija se prati pomolu analitičke HPLC. Na kraju reakcije (obično 0.5 do 1 sat), katalizator se filtrira, a filtrat se koncentrira i pročisti podvrgavanjem preparativnoj kromatografiji (Nucleosil C-18), uz upotrebu vode kao eluansa, da bi se dobio naslovni spoj, nakon koncentracije i liofilizacije odgovarajućih frakcija,(0.13g, 38%). Solution allyl(1R,5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenzyloxy-carbonyl)-2-(2-carboxy-3-thienylcarbamoyl)pyrrolidine-4-ylthio)-6-( 1-Hydroxyethyl)-1-methylcarbapenem-3-carboxylate diisopropylethylamine salt (equivalent to 0.49 g free acid, 0.7 mmol) in THF (25 mL) was treated with triphenylphosphine (20 mg, 0.076 mmol), potassium hexanoate (0.46 M solution in ethyl acetate, 3.2 ml, 1.47 mmol), hexanoic acid (0.235 ml, 1.47 mmol) and tetrakis(triphenylphosphine)palladium (70 mg) for one hour at room temperature. Ethyl acetate (25 ml) was then added to the reaction mixture and the precipitate was collected by filtration. The precipitate is washed with ethyl acetate and dried (0.45 g, 87%). This crude product is dissolved in water (10 ml) and hydrated at atmospheric pressure over palladium/carbon (10%, 0.35 g). Deprotection is monitored using analytical HPLC. At the end of the reaction (usually 0.5 to 1 hour), the catalyst is filtered, and the filtrate is concentrated and purified by subjecting it to preparative chromatography (Nucleosil C-18), using water as eluent, to obtain the title compound, after concentration and lyophilization of the appropriate fractions , (0.13g, 38%).

NMR (DMSO-d6+AcOD-d4): δ 1.15 (2d, 6H); 1.75 (m, 1H); 2.5-2.7 (m, 2H); 3.18 (dd, 1H); 3.2-3.65 (m, 3H); 3.9-4.05 (m, 2H); 4.15 (dd, 1H); 7.55 (d, 1H); 7.98 (d, 1H). NMR (DMSO-d6+AcOD-d4): δ 1.15 (2d, 6H); 1.75 (m, 1H); 2.5-2.7 (m, 2H); 3.18 (dd, 1H); 3.2-3.65 (m, 3H); 3.9-4.05 (m, 2H); 4.15 (dd, 1H); 7.55 (d, 1H); 7.98 (d, 1H).

(2S,4S)-1-(4-Nitrobenziloksikarbonil)-2-(2-karboksi-3-tienil-karbamoil)-pirolidin-4-iltioacetat (2S,4S)-1-(4-Nitrobenzyloxycarbonyl)-2-(2-carboxy-3-thienyl-carbamoyl)-pyrrolidine-4-ylthioacetate

Naslovni spoj se pripremi iz 3-nitro-2-tiofenkarboksilne kiseline upotrebljavajući postupak sličan onome iz Primjera 1, osim što nije potrebno siliranje. Amino kiselina se solubilizira u diklorometanu sa diizopropiletilaminom. The title compound was prepared from 3-nitro-2-thiophenecarboxylic acid using a procedure similar to that of Example 1, except that ensiling was not required. The amino acid is solubilized in dichloromethane with diisopropylethylamine.

NMR(DMSO-d6+AcOD-d4,TFA-d): δ 2.15 (m, 1H); 2.27 (s, 3H); 2.85 (m, 1H); 3.4 (m, 1H); 3.85-4.3 (m, 2H); 4.53 (dd, 1H); 5.22 (d, 2H); 7.5 (d, 2H); 7.75 (d, 1H); 7.92 (d, 1H); 8.05 (d,2H). NMR(DMSO-d6+AcOD-d4,TFA-d): δ 2.15 (m, 1H); 2.27 (s, 3H); 2.85 (m, 1H); 3.4 (m, 1H); 3.85-4.3 (m, 2H); 4.53 (dd, 1H); 5.22 (d, 2H); 7.5 (d, 2H); 7.75 (d, 1H); 7.92 (d, 1H); 8.05 (d, 2H).

Alil (1R,5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenziloksikarbonil)-2-(2-karboksi-3-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilat(diizopropiletil-amin sol) Allyl (1R,5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenzyloxycarbonyl)-2-(2-carboxy-3-thienylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl )-1-methylcarbapenem-3-carboxylate (diisopropylethylamine salt)

Naslovni spoj se pripremi iz (2S,4S)-1-(4-nitro-benzilkarbonil)-2-(2-karboksi-3-tienilkarbamoil)pirolidin-4-iltiola i alil (1R,5S,6S,8R)-6-(1-hidroksietil)-1-metil-2-difenifosforiloksikarbapenem-3-karboksilata upotrebljavajući postupak sličan onome iz primjera 1. The title compound was prepared from (2S,4S)-1-(4-nitro-benzylcarbonyl)-2-(2-carboxy-3-thienylcarbamoyl)pyrrolidine-4-ylthiol and allyl (1R,5S,6S,8R)-6 -(1-hydroxyethyl)-1-methyl-2-diphenyphosphoryloxycarbapenem-3-carboxylate using a procedure similar to that of Example 1.

NMR (DMSO-d6+AcOD-d4): δ 1.15 (s, 15H); 1.3 (2d, 6H); 2.05 (m, 1H); 3.88 (m, 1H); 3.15 (q,2H); 3.25 (dd, 1H); 3.32-3.58 (m, 2H); 3.62 (qi, 2H); 3.9-4.05 (m, 2H); 4.05-4.3 (m, 2H); 4.4-4.65 (m, 3H); 5.0-5.4 (m, 4H); 5.85 (m, 1H); 7.45 (d, 1H); 7.54 (d, 1H); 7.7 (d, 1H); 7.85-8.02 (m, 2H); 8.25 (d, 1H); NMR (DMSO-d6+AcOD-d4): δ 1.15 (s, 15H); 1.3 (2d, 6H); 2.05 (m, 1H); 3.88 (m, 1H); 3.15 (q, 2H); 3.25 (dd, 1H); 3.32-3.58 (m, 2H); 3.62 (q, 2H); 3.9-4.05 (m, 2H); 4.05-4.3 (m, 2H); 4.4-4.65 (m, 3H); 5.0-5.4 (m, 4H); 5.85 (m, 1H); 7.45 (d, 1H); 7.54 (d, 1H); 7.7 (d, 1H); 7.85-8.02 (m, 2H); 8.25 (d, 1H);

Primjer 3 Example 3

(1R,5S,6S,8R,2'S,4'S)-2-(2-(4-Karboksi-2-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina (dikalijeva sol) (1R,5S,6S,8R,2'S,4'S)-2-(2-(4-Carboxy-2-thienylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid (dipotassium salt)

Naslovni spoj se priredi iz alil(1R,5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenziloksikarbonil)-2-(4-aliloksikarbonil-2-tienil-karbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilat diizopropiletilamin soli upotrebljavajući postupak sličan onome iz primjera 2. The title compound was prepared from allyl(1R,5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenzyloxycarbonyl)-2-(4-allyloxycarbonyl-2-thienyl-carbamoyl)pyrrolidine-4-ylthio) -6-(1-Hydroxyethyl)-1-methylcarbapenem-3-carboxylate diisopropylethylamine salt using a procedure similar to that of Example 2.

NMR (DMSO-d6+AcOD-d4): δ 1.16 (2xd, 6H); 1.67 (m, 1H); 2.55 (m, 1H); 2.64 (m, 1H); 3.2 (dd, 1H); 3.39-3.43 (m, 2H); 3.60 (m, 1H); 3.93-3.97 (m, 2H); 4.15 (dd, 1H); 7.15 (s, 1H); 7.67 (s, 1H). NMR (DMSO-d6+AcOD-d4): δ 1.16 (2xd, 6H); 1.67 (m, 1H); 2.55 (m, 1H); 2.64 (m, 1H); 3.2 (dd, 1H); 3.39-3.43 (m, 2H); 3.60 (m, 1H); 3.93-3.97 (m, 2H); 4.15 (dd, 1H); 7.15 (s, 1H); 7.67 (s, 1H).

Alil 2-nitro-4-tiofenkarboksilat Allyl 2-nitro-4-thiophenecarboxylate

2-Nitro-4-tiofenkarboksilna kiselina (2.5g, 14.45 mmol) se suspendira u DMF-u (25 ml) u prisutnosti kalijum karbonata (4g, 28.9 mmol) pri sobnoj temperaturi. Alil bromid (5ml, 57.8 mmol) se doda u ovu otopinu i smjesa se miješa na sobnoj temperaturi preko noći. Smjesa se razrijedi vodom i ekstrahira sa etil acetatom. Nakon koncentriranja, ostatak se pročisti kromatogr-firanjem na silika gelu upotrebljavajući smjesu etil acetat/petrolej eter kao eluans (10:30) da bi se dobio naslovni spoj (2.4 5g, 77%). 2-Nitro-4-thiophenecarboxylic acid (2.5g, 14.45 mmol) was suspended in DMF (25 ml) in the presence of potassium carbonate (4g, 28.9 mmol) at room temperature. Allyl bromide (5ml, 57.8 mmol) was added to this solution and the mixture was stirred at room temperature overnight. The mixture is diluted with water and extracted with ethyl acetate. After concentration, the residue was purified by chromatography on silica gel using ethyl acetate/petroleum ether as eluent (10:30) to give the title compound (2.45g, 77%).

NMR (CDCl3): δ 4.78 (m, 1H); 4.80 (m, 1H); 5.25 (m, 1H); 5.45 (d, 1H); 6.0 (m, 1H); 8.25 (d, 1H); 8.75 (d, 1H). NMR (CDCl3): δ 4.78 (m, 1H); 4.80 (m, 1H); 5.25 (m, 1H); 5.45 (d, 1H); 6.0 (m, 1H); 8.25 (d, 1H); 8.75 (d, 1H).

Alil 2-amino-4-tiofenkarboksilat Allyl 2-amino-4-thiophenecarboxylate

Alil 2-nitro-4-tiofenkarboksilat se suspendira u koncentriranoj HCl (25 ml), pri 0°C. Doda se SnCl2.2H2O (7.44 g, 32.36 mmol) i nakon miješanja tokom četiri sata na sobnoj temperaturi, pH se namjesti na 10 pomoću NaOH. Ekstrakcija sa etil acetatom i pročišćavanje pomoću svjetlosne kromatografije na silika gelu uz upotrebu smjese etil acetata/petrolej etera kao eluansa (25: 75), daju naslovni spoj (1.15 g, 55%). Allyl 2-nitro-4-thiophenecarboxylate is suspended in concentrated HCl (25 ml), at 0°C. SnCl2.2H2O (7.44 g, 32.36 mmol) was added and after stirring for four hours at room temperature, the pH was adjusted to 10 with NaOH. Extraction with ethyl acetate and purification by light chromatography on silica gel using a mixture of ethyl acetate/petroleum ether as eluent (25:75) gave the title compound (1.15 g, 55%).

NMR (CDCl3): δ 3.75 (m, 2H); 4.65 (m, 1H); 4.72 (m, 1H); 5.2 (m, 1H); 5.35 (d, 1H); 6. (m, 1H); 6.57 (d, 1H); 7.35 (d, 1H). NMR (CDCl3): δ 3.75 (m, 2H); 4.65 (m, 1H); 4.72 (m, 1H); 5.2 (m, 1H); 5.35 (d, 1H); 6. (m, 1H); 6.57 (d, 1H); 7.35 (d, 1H).

(2S,4S)-1-(4-Nitrobenziloksikarbonil)-2-(4-aliloksikarbonil-2-tienilkarbamoil)pirolidin-4-iltioacetat(diizopropiletil-amin) sol (2S,4S)-1-(4-Nitrobenzyloxycarbonyl)-2-(4-allyloxycarbonyl-2-thienylcarbamoyl)pyrrolidine-4-ylthioacetate(diisopropylethylamine) salt

Naslovni spoj se priredi iz alil 2-amino-4-tiofenkarboksilata upotrebljavajući postupak sličan onome iz primjera 1, osim što je alil 2-amino-4-tiofenkarboksilat solubiliziran u diklorometanu sa diizopropiletilaminom kao što je to opisano u primjeru 2. The title compound was prepared from allyl 2-amino-4-thiophenecarboxylate using a procedure similar to that of Example 1, except that the allyl 2-amino-4-thiophenecarboxylate was solubilized in dichloromethane with diisopropylethylamine as described in Example 2.

NMR(DMSO-d6): δ 1.9 (m, 1H); 2.35 (s, 3H); 2.75 (m, 1H); 3.25 (m, 1H); 3.85-4.25 (m, 2H); 4.5 (m, 1H); 4.65-4.85 (m,2H); 5.05-5.5 (m, 4H); 6.0 (m, 1H); 6.9-8.4 (m,6H). NMR(DMSO-d6): δ 1.9 (m, 1H); 2.35 (s, 3H); 2.75 (m, 1H); 3.25 (m, 1H); 3.85-4.25 (m, 2H); 4.5 (m, 1H); 4.65-4.85 (m, 2H); 5.05-5.5 (m, 4H); 6.0 (m, 1H); 6.9-8.4 (m, 6H).

Alil (1R,5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenziloksikarbonil)--2-(4-aliloksikarbonil-2-tienilkarbamoil)pirolidin-4-iltio-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilat Allyl (1R,5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenzyloxycarbonyl)--2-(4-allyloxycarbonyl-2-thienylcarbamoyl)pyrrolidin-4-ylthio-6-(1-hydroxyethyl) )-1-methylcarbapenem-3-carboxylate

Naslovni spoj se pripremi iz (2S,4S)-1-(4-nitro-benziloksikarbonil)-2-(4-aliloksikarbonil-2-tienilkarbamoil)pirolidin-4-iltio acetata upotrebljavajući postupak sličan onome iz primjera 2. The title compound was prepared from (2S,4S)-1-(4-nitro-benzyloxycarbonyl)-2-(4-allyloxycarbonyl-2-thienylcarbamoyl)pyrrolidine-4-ylthio acetate using a procedure similar to that of Example 2.

NMR (DMSO-d6+AcOD-d4): δ 1.15 (2d, 6H); 1.9 (m, 1H); 2.8 (m, 1H); 3.25 (dd, 1H); 3.35 (m, 1H); 3.55 (m, 1H); 3.9-4.05 (m,2H); 4.2 (m, 1H); 4.4-4.75 (m, 5H); 5.0-5.4 (m,6H); 5.8-6.1 (m, 1H); 7.4-8.3 (m, 6H). NMR (DMSO-d6+AcOD-d4): δ 1.15 (2d, 6H); 1.9 (m, 1H); 2.8 (m, 1H); 3.25 (dd, 1H); 3.35 (m, 1H); 3.55 (m, 1H); 3.9-4.05 (m, 2H); 4.2 (m, 1H); 4.4-4.75 (m, 5H); 5.0-5.4 (m, 6H); 5.8-6.1 (m, 1H); 7.4-8.3 (m, 6H).

Primjer 4 Example 4

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-Karboksi-2-(4,5,6,7)-tetrahidro-benzo(b)-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina (dikalijeva sol). (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxy-2-(4,5,6,7)-tetrahydro-benzo(b)-thienylcarbamoyl)pyrrolidine-4-ylthio )-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid (dipotassium salt).

Naslovni spoj se priredi iz alil (1R,5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenziloksikarbonil)-2-(3-karboksi-2-(4,5,6,7)-tetrahidrobenzo(b)tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksi-etil)-1-metilkarbapenem-3-karboksilat diizopropiletilamin soli upotrebljavajući postupak sličan onome iz primjera 2. The title compound was prepared from allyl (1R,5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenzyloxycarbonyl)-2-(3-carboxy-2-(4,5,6,7)- tetrahydrobenzo(b)thienylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxy-ethyl)-1-methylcarbapenem-3-carboxylate diisopropylethylamine salt using a procedure similar to that of Example 2.

NMR (DMSO-d6+AcOD-d4): δ 1.15 (2d, 6H); 1.60-1.85 (m, 4H); 2.4-2.85 (m, 6H); 3.18 (dd, 1H); 3.3-3.65 (m, 3H); 3.88-4.1 (m, 2H); 4.15 (dd, 1H). NMR (DMSO-d6+AcOD-d4): δ 1.15 (2d, 6H); 1.60-1.85 (m, 4H); 2.4-2.85 (m, 6H); 3.18 (dd, 1H); 3.3-3.65 (m, 3H); 3.88-4.1 (m, 2H); 4.15 (dd, 1H).

(2S,4S)-1-(4-Nitrobenziloksikarbonil)-2-(3-karboksi-2-(4,5,6,7)-tetrahidrobenzo(b)tienilkarbamoil)pirolidin-4-iltioacetat (2S,4S)-1-(4-Nitrobenzyloxycarbonyl)-2-(3-carboxy-2-(4,5,6,7)-tetrahydrobenzo(b)thienylcarbamoyl)pyrrolidine-4-ylthioacetate

Naslovni spoj se priredi iz 2-amino-3-karboksi-4,5,6,7-tetrahidrobenzo(b)tiofena upotrebljavajući postupak sličan onome iz primjera 2. The title compound was prepared from 2-amino-3-carboxy-4,5,6,7-tetrahydrobenzo(b)thiophene using a procedure similar to that of Example 2.

NHR (DMSO-d6+AcOD-d4): δ 1.62-1.82 (m, 4H); 2.15 (m, 1H); 2.5-2.9 (m, 5H); 3.45 (m, 1H); 3.95-4.25 (m, 2H); 4.6 (dd, 1H); 5.15(d, 1H); 5.37 (d, 1H); 7.5 (d, 2H); 8.05 (d, 2H). NHR (DMSO-d6+AcOD-d4): δ 1.62-1.82 (m, 4H); 2.15 (m, 1H); 2.5-2.9 (m, 5H); 3.45 (m, 1H); 3.95-4.25 (m, 2H); 4.6 (dd, 1H); 5.15(d, 1H); 5.37 (d, 1H); 7.5 (d, 2H); 8.05 (d, 2H).

Alil (1R,5S,6S,8R,2'3,4'S)-2-(1-(4-nitrobenziloksikarbonil)-2-(3-karboksi-2-(4,5,6,7)-tetrahidrobenzo(b)tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilat (diizopropiletilamin sol) Allyl (1R,5S,6S,8R,2'3,4'S)-2-(1-(4-nitrobenzyloxycarbonyl)-2-(3-carboxy-2-(4,5,6,7)-tetrahydrobenzo(b )thienylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylate (diisopropylethylamine salt)

Naslovni spoj se pripremi iz alil (1R,5R,6S,8R)-6-(1-hidroksietil)-1-metil-2-difenilfosforiloksikarbapenem-3-karboksilata i (2S,4S)-1-(4-nitrobenziloksikarbonil)-2-(3-karboksi-2-(4,5,6,7)-tetrahidrooenzo(b)tienilkarbamoil)pirolidin-4-iltiola upotrebljavajući postupak sličan onome opisanome u primjeru 1. The title compound was prepared from allyl (1R,5R,6S,8R)-6-(1-hydroxyethyl)-1-methyl-2-diphenylphosphoryloxycarbapenem-3-carboxylate and (2S,4S)-1-(4-nitrobenzyloxycarbonyl)- 2-(3-carboxy-2-(4,5,6,7)-tetrahydrooenzo(b)thienylcarbamoyl)pyrrolidine-4-ylthiol using a procedure similar to that described in Example 1.

NMR (DMSO-d6+AcOD-d4): δ 1.15 (2d, 6H); 1.7 (s, 4H); 2.05 (m, 1H); 2.65 (s, 4H); 3.25 (dd, 1H); 3.3-4.75 (m, 10H); 4.9-5.45 (m, 4H); 5-75 (m, 1H); 7.1-8.35 (m, 4H). NMR (DMSO-d6+AcOD-d4): δ 1.15 (2d, 6H); 1.7 (s, 4H); 2.05 (m, 1H); 2.65 (s, 4H); 3.25 (dd, 1H); 3.3-4.75 (m, 10H); 4.9-5.45 (m, 4H); 5-75 (m, 1H); 7.1-8.35 (m, 4H).

Primjer 5 Example 5

(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-Karboksi-4-metil-2-tienilkarbamoil)-pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina (dikalijeva sol) (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxy-4-methyl-2-thienylcarbamoyl)-pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1- methylcarbapenem-3-carboxylic acid (dipotassium salt)

Naslovni spoj se pripremi iz alil(1R,5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenziloksikarbonil)-(2-(3-karboksi-4-metil-2-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metil-karbapenem karboksilat diisopropiletilamln soli upotrebljavajući postupak sličan onome iz primjera 2. The title compound was prepared from allyl(1R,5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenzyloxycarbonyl)-(2-(3-carboxy-4-methyl-2-thienylcarbamoyl)pyrrolidine-4 -ylthio)-6-(1-hydroxyethyl)-1-methyl-carbapenem carboxylate diisopropylethylamine salt using a procedure similar to that of Example 2.

NMR (DMSO-d6+AcOD d4): δ 1.15 (2d, 6H); 1.7 (m, 1H); 2.32 (s, 3H); 2.52 (m, 1H); 2.67 (m, 1H); 3.18 (dd, 1H); 3.19 (m, 1H); 3.50 (m, 2H); 3.95 (m, 1H); 4.02 (m, 1H); 4.15 (dd, 1H); 6.5 5(s, 1H). NMR (DMSO-d6+AcOD d4): δ 1.15 (2d, 6H); 1.7 (m, 1H); 2.32 (s, 3H); 2.52 (m, 1H); 2.67 (m, 1H); 3.18 (dd, 1H); 3.19 (m, 1H); 3.50 (m, 2H); 3.95 (m, 1H); 4.02 (m, 1H); 4.15 (dd, 1H); 6.5 5(s, 1H).

(2S,4S)-1-(4-Nitrobenziloksikarbonil)-2-(3-etoksikarbonil-4-metil-2-tienilkarbamoil)pirolidin-4-iltioacetat (2S,4S)-1-(4-Nitrobenzyloxycarbonyl)-2-(3-ethoxycarbonyl-4-methyl-2-thienylcarbamoyl)pyrrolidine-4-ylthioacetate

Naslovni spoj se priredi iz etil 2-amino-4-metil-3-tiofenkarboksilata upotrebljavajući postupak sličan onome iz primjera 2 osim što je etil 2-amino-4-metil-3-tiofenkarboksilat otopljen u diklorometanu u prisutnosti diizopropiletil-amina. The title compound was prepared from ethyl 2-amino-4-methyl-3-thiophenecarboxylate using a procedure similar to that of Example 2 except that the ethyl 2-amino-4-methyl-3-thiophenecarboxylate was dissolved in dichloromethane in the presence of diisopropylethylamine.

NMR (CDCl3): δ 1.35 (m, 3H); 2.2 (m, 1H); 2.35 (2s, 6H); 2.82 (m, 1H); 3.52 (m, 1H); 4.0 (m, 1H); 4.12-4.4 (m,3H); 4.4-4,7 (m, 1H); 4.9-5.5 (m, 2H); 6.42 (s, 1H); 7.2-8.3 (m, 4H). NMR (CDCl3): δ 1.35 (m, 3H); 2.2 (m, 1H); 2.35 (2s, 6H); 2.82 (m, 1H); 3.52 (m, 1H); 4.0 (m, 1H); 4.12-4.4 (m, 3H); 4.4-4.7 (m, 1H); 4.9-5.5 (m, 2H); 6.42 (s, 1H); 7.2-8.3 (m, 4H).

(2S,4S)-1-(4-Nitrobenziloksikarbonil)-2-(3-karboksi-4-metil-2-tienilkarbamoil)pirolidin-4-iltiol (2S,4S)-1-(4-Nitrobenzyloxycarbonyl)-2-(3-carboxy-4-methyl-2-thienylcarbamoyl)pyrrolidine-4-ylthiol

(2S,4S)-1-(4-Nitrobenziloksikarbonil)-2-(3-etoksikarbonil-4-metil-2-tienilkarbamoil)pirolidin-4-iltioacetat (0.86g, 1.8 mmol) u dioksanu (10 ml) i vodi (5 ml) se tretira sa 1M NaOH (5 ml, 4.8 mmol) tokom 3 sata na 60°C. Reakcijska smjesa se neutralizira sa 6M HCl do pH 6, na 0°C. Precipitirana bijela krutina se ukloni filtriranjem, ispere se vodom i suši uz vakuum. (2S,4S)-1-(4-Nitrobenzyloxycarbonyl)-2-(3-ethoxycarbonyl-4-methyl-2-thienylcarbamoyl)pyrrolidine-4-ylthioacetate (0.86g, 1.8 mmol) in dioxane (10 ml) and water ( 5 ml) is treated with 1M NaOH (5 ml, 4.8 mmol) for 3 hours at 60°C. The reaction mixture is neutralized with 6M HCl to pH 6, at 0°C. The precipitated white solid is removed by filtration, washed with water and dried under vacuum.

Alil(1R,5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenziloksikarbonil)-2-(3-karboksi-4-metil-2-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilat(diisopropiletilamin sol Allyl(1R,5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenzyloxycarbonyl)-2-(3-carboxy-4-methyl-2-thienylcarbamoyl)pyrrolidin-4-ylthio)-6- (1-hydroxyethyl)-1-methylcarbapenem-3-carboxylate (diisopropylethylamine sol

Naslovni spoj se pripremi iz alil (1R,5R,6S,8R)-6-(1-hidroksetil-1-metil-2-difenilfosforiloksikarbapenem-3-karboksilata i (2S,4S)-1-(4-nitrobenziloksikarbonil)-2-(3-karboksi-4-metil-2-tienilkarbamoil)pirolidin-4-iltiola upotrebljavajući postupak sličan onome iz primjera 1. The title compound was prepared from allyl (1R,5R,6S,8R)-6-(1-hydroxyethyl-1-methyl-2-diphenylphosphoryloxycarbapenem-3-carboxylate and (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2 -(3-carboxy-4-methyl-2-thienylcarbamoyl)pyrrolidine-4-ylthiol using a procedure similar to that of Example 1.

NMR (DMSO-d6+AcOD-d4) 1.15 (m, 6H); 2.05 (m, 1H); 2.15 (m, 3H); 2.9 (m, 1H); 3.12 (dd, 1H); 3.4-3.6 (m, 2H); 3.9-4.15 (m, 2H); 4.42 (m, 2H); 4.6 (m, 3H); 5.0-5.4 (m,4H); 5.6-6.05 (m, 1H); 6.62 (m, 1H); 7.2-8.3 (m, 4H). NMR (DMSO-d6+AcOD-d4) 1.15 (m, 6H); 2.05 (m, 1H); 2.15 (m, 3H); 2.9 (m, 1H); 3.12 (dd, 1H); 3.4-3.6 (m, 2H); 3.9-4.15 (m, 2H); 4.42 (m, 2H); 4.6 (m, 3H); 5.0-5.4 (m, 4H); 5.6-6.05 (m, 1H); 6.62 (m, 1H); 7.2-8.3 (m, 4H).

Primjer 6 Example 6

(1R,5S,6S,8R,2'S,4'S)-2-(2-(2-Karboksi-5-tienilkarbamoil)pirolidin--4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina, dikalijeva sol (1R,5S,6S,8R,2'S,4'S)-2-(2-(2-Carboxy-5-thienylcarbamoyl)pyrrolidine--4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3- carboxylic acid, dipotassium salt

U otopinu 4-nitrobenzil (1R,5S,6S,8R,2'S,4'S)-2-(1-(4-nitro-benziloksikarbonil)-2-(2-alliloksikarbonil-5-tienil-karbamoil)-pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilata (lg,1.2 mmol) u smjesi metilen klorida (5 ml) i etil acetata (3 ml) doda se trifenilfosfin (32 ng, C.12 mmol), tetrakis trifenilfosfin paladij (48 mg,0.04 mmol) i 0.4M otopina kalij 2-etil heksanoata u etil acetatu (3.5 ml, 1-38 mmol). Reakcijska smjesa se miješa na sobnoj temperaturi tokom jednog sata, razrijedi sa etil acetatom i precipitat se ukloni filtriranjem, ispere eterom i suši u vakuumu. Sirova kiselina se otopi u otopini vode (30 ml) koja sadrži kalij hidrogen karbonat (132 mg, 1.32 mmol) i pomiješa sa 10%-tnim paladijem na drvenom ugljenu(o.5g). Smjesa se miješa uz atmosferu vodika tokom dva sata. Katalizator se ukloni filtriranjem, organska se odbaci,vodena faza se djelomično koncentrira i pročisti obrnutom fazom kromatografije (Nucleosil C18 10 µ, 3.5×20 cm) uz vodu kao eluans , da bi nakon sušenja zamrzavanjem dala naslovni spoj (183 mg, 27%). In solution 4-nitrobenzyl (1R,5S,6S,8R,2'S,4'S)-2-(1-(4-nitro-benzyloxycarbonyl)-2-(2-allyloxycarbonyl-5-thienyl-carbamoyl)-pyrrolidine-4- ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylate (1g, 1.2 mmol) in a mixture of methylene chloride (5 ml) and ethyl acetate (3 ml) was added triphenylphosphine (32 ng, C.12 mmol ), tetrakis triphenylphosphine palladium (48 mg, 0.04 mmol) and a 0.4 M solution of potassium 2-ethyl hexanoate in ethyl acetate (3.5 ml, 1-38 mmol). The reaction mixture is stirred at room temperature for one hour, diluted with ethyl acetate and the precipitate is removed by filtration, washed with ether and dried under vacuum. The crude acid is dissolved in a water solution (30 ml) containing potassium hydrogen carbonate (132 mg, 1.32 mmol) and mixed with 10% palladium on charcoal (o.5g). The mixture is stirred under a hydrogen atmosphere for two hours. The catalyst is removed by filtration, the organic is discarded, the aqueous phase is partially concentrated and purified by reverse phase chromatography (Nucleosil C18 10 µ, 3.5×20 cm) with water as eluent, to give the title compound after freeze-drying (183 mg, 27%) .

NMR (DMSO-d6, AcOD-d4): δ 1.15 (d, 3H); 1.17 (d, 3H); 1.75 (m, 1H); 2.63 (m, 1H); 2.76 (m, 1H); 3.20 (dd, 1H); 3.34-3.43 (m, 2H); 3.64 (m, 1H); 3.94-4.02 (m, 2H); 4.15 (dd, 1H); 6.87 (d, 1H); 7.49 (d, 1H); MS (FAB+ve): 482 (M+H)+ ; 520(M+K)+. NMR (DMSO-d6, AcOD-d4): δ 1.15 (d, 3H); 1.17 (d, 3H); 1.75 (m, 1H); 2.63 (m, 1H); 2.76 (m, 1H); 3.20 (dd, 1H); 3.34-3.43 (m, 2H); 3.64 (m, 1H); 3.94-4.02 (m, 2H); 4.15 (dd, 1H); 6.87 (d, 1H); 7.49 (d, 1H); MS (FAB+ve): 482 (M+H)+ ; 520(M+K)+.

Polazni materijali su pripremljeni na slijedeći način: The starting materials were prepared in the following way:

5-Nitro-P-tiofenkarboksilna kiselina 5-Nitro-P-thiophenecarboxylic acid

Naslovni spoj se dobije polazeći od 2-tiofenkarboksilne kiseline,simultano sa 4-nitro-2-tiofenkarboksilnom kiselinom kako je prethodno opisano u primjeru 1. The title compound is obtained starting from 2-thiophenecarboxylic acid, simultaneously with 4-nitro-2-thiophenecarboxylic acid as previously described in example 1.

NMR (CDCl3):δ 7.65 (d, 1H); 7.88 (d, 1H). NMR (CDCl3): δ 7.65 (d, 1H); 7.88 (d, 1H).

Alil 5-Nitro-2-tiofenkarboksilat Allyl 5-Nitro-2-thiophenecarboxylate

U otopinu 5-nitro-2-tiofenkarboksilne kiseline (20g, 0.11 mol) u DMF-u(140 ml) se doda jedno za drugim, alil bromid (40 ml, 0.46 mol) i trietilamin (64 ml, 0.46 mol) uz hlađenje da bi se zadržala temperatura reakcijske smjese ispod 30°C. Nakon dodavanja reagenata, reakcijska smjesa se miješa tokom tri sata na sobnoj temperaturi i zatim se razrijedi sa etil acetaton. Precipitirana krutina se ukloni filtriranjem, filtrat se ispere vodom, zatim sa zasićenom vodenom otopinom natrij klorida, suši se iznad MgSO4 i koncentrira. Ostatak se pročisti kromatografijom na silika gelu uz upotrebu smjese CH2Cl2-petrolej eter (3:7) kao eluansa da bi se dobio naslovni spoj kao bijela krutina (8.8 g, 38%). Allyl bromide (40 ml, 0.46 mol) and triethylamine (64 ml, 0.46 mol) were added one after the other to a solution of 5-nitro-2-thiophenecarboxylic acid (20g, 0.11 mol) in DMF (140 ml) with cooling. to keep the temperature of the reaction mixture below 30°C. After adding the reagents, the reaction mixture was stirred for three hours at room temperature and then diluted with ethyl acetate. The precipitated solid is removed by filtration, the filtrate is washed with water, then with saturated aqueous sodium chloride solution, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography using CH 2 Cl 2 -petroleum ether (3:7) as eluent to give the title compound as a white solid (8.8 g, 38%).

NMR(CDCl3): δ 4.84 (d, 2H); 5.36-5.45 (m,2H); 6.0 (6m, 1H); 7.71 (d, 1H); 7.88 (d, 1H). NMR(CDCl3): δ 4.84 (d, 2H); 5.36-5.45 (m, 2H); 6.0 (6m, 1H); 7.71 (d, 1H); 7.88 (d, 1H).

Alil 5-amino-2-tiofenkarboksilat Allyl 5-amino-2-thiophenecarboxylate

U otopinu alil 5-nitro-2-tiofenkarboksilata (3.2 g, 15 mmol) u koncentriranom hidrogen kloridu (35 ml) doda se uz hlađenje SnCl2.H2O (10.1 g, 45 mmol). Smjesa se miješa tokom 3.5 sati na sočnoj temperaturi, razrijedi se sa etil acetatom i učini bazičnom pomoću 5N NaOH do pH 10. Organski sloj se ispere vodom i zasićenom vodenom otopinom natrij klorida, suši se iznad MgSO4 i koncentrira. Ostatak se pročisti kromatografijom na silika gelu uz upotrebu smjese etil acetata i petrolej etera (3:7) da bi se dobio naslovni spoj kao žuto ulje (1.94 g, 72%). SnCl2.H2O (10.1 g, 45 mmol) was added to a solution of allyl 5-nitro-2-thiophenecarboxylate (3.2 g, 15 mmol) in concentrated hydrogen chloride (35 ml) with cooling. The mixture is stirred for 3.5 hours at brine temperature, diluted with ethyl acetate and made basic with 5N NaOH to pH 10. The organic layer is washed with water and saturated aqueous sodium chloride solution, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (3:7) to give the title compound as a yellow oil (1.94 g, 72%).

NMR (CDCl3): δ 4.34 (br s, 2H); 4.73 (d, 2H); 5.23 (d, 1H); 5.36 (d, 1H); 5.99 (m, 1H); 5.09 (d, 1H); 7.48(d, 1H). NMR (CDCl3): δ 4.34 (br s, 2H); 4.73 (d, 2H); 5.23 (d, 1H); 5.36 (d, 1H); 5.99 (m, 1H); 5.09 (d, 1H); 7.48(d, 1H).

(2S,4S)-1-(4-Nitrobenziloksikarbonil)-2-(2-aliloksikarbonil-5-tienil-karbamoil)pirolidin-4-iltioacetat (2S,4S)-1-(4-Nitrobenzyloxycarbonyl)-2-(2-allyloxycarbonyl-5-thienyl-carbamoyl)pyrrolidine-4-ylthioacetate

U otopinu (2S,4S)-4-acetiltio-2-karboksi-1-(4-nitrobenziloksi-karbonil)pirolidina (3.79 g, 10.3 mmol) u CH2Cl2 (12 ml), doda se tionil klorid (3.75 ml, 51.5 mmol) i DMF (0.055 ml). Smjesa se miješa tokom 16 sati na sobnoj temperaturi, koncentrira i preostalo ulje se uzme u CH2Cl2-toluen i reevaporira. Ostatak se suši u vakuumu i solubilizira u CH2Cl2 (25 ml). U ovu otopinu ohlađenu na 0°C doda se N-diizopropiletilamin (2.05 ml, 11.8 mmol) i otopina alil 5-amino-2-tiofenkarboksilata (1.9 g, 10.3 mmol). Nakon 15 minuta na sobnoj temperaturi, otapalo se evaporira i ostatak se uzme u smjesu vode i etil acetata. Organski sloj se suši iznad MgSO4 i evaporira do suhoga. Ostatak se pročisti kromatografijom na silika gelu uz upotrebu smjese CH2Cl2-eter (9:1) da bi se dobio naslovni spoj kao žuta pjena (4.68g, 85%). To a solution of (2S,4S)-4-acetylthio-2-carboxy-1-(4-nitrobenzyloxy-carbonyl)pyrrolidine (3.79 g, 10.3 mmol) in CH2Cl2 (12 ml), was added thionyl chloride (3.75 ml, 51.5 mmol ) and DMF (0.055 ml). The mixture was stirred for 16 hours at room temperature, concentrated and the remaining oil was taken up in CH2Cl2-toluene and reevaporated. The residue is dried in vacuo and solubilized in CH2Cl2 (25 ml). N-diisopropylethylamine (2.05 ml, 11.8 mmol) and a solution of allyl 5-amino-2-thiophenecarboxylate (1.9 g, 10.3 mmol) were added to this solution cooled to 0°C. After 15 minutes at room temperature, the solvent is evaporated and the residue is taken up in a mixture of water and ethyl acetate. The organic layer is dried over MgSO4 and evaporated to dryness. The residue was purified by silica gel chromatography using CH2Cl2-ether (9:1) to give the title compound as a yellow foam (4.68g, 85%).

NHR (DHSO-d6+AcCD-d4): δ 2.33 (s,3H); 2.80 (m, 1H); 3.38 (m, 1H); 4.00-4.15 (m, 2H); 4.52 (m, 2H); 4.77 (d, 2H); 5.02-5.42 (m, 4H); 6.00 (m, 1H); 6.77 (n, 1H); 7.45 (m, 1H); 7-60-7.68 (m, 2H); 7.95 (m, 1H); 1.23 (m, 1H). NHR (DHSO-d6+AcCD-d4): δ 2.33 (s,3H); 2.80 (m, 1H); 3.38 (m, 1H); 4.00-4.15 (m, 2H); 4.52 (m, 2H); 4.77 (d, 2H); 5.02-5.42 (m, 4H); 6.00 (m, 1H); 6.77 (n, 1H); 7.45 (m, 1H); 7-60-7.68 (m, 2H); 7.95 (m, 1H); 1.23 (m, 1H).

(2S,4S)-1-(4-Nitrobenziloksikarbonil)-2-(2-aliloksikarbonil-tienil-karbamoil)pirolidin-4-iltiol (2S,4S)-1-(4-Nitrobenzyloxycarbonyl)-2-(2-allyloxycarbonyl-thienyl-carbamoyl)pyrrolidine-4-ylthiol

U otopinu (2S,4S)-1-(4-nitrobenziloksikarbonil)-2-(2-alil-oksikarbonil-5-tienilkarbamoil)pirolidin-4-iltioacetata (1.06 g, 2 mmol) u diklorometanu(2 ml) doda se na 0°C etanol (4 ml) i zatim 5N otopina metilamina u etanolu (0.8 ml, 4 mmol). Reakcijska smjesa se miješa na sobnoj temperaturi tokom 1.5 sati i zatim se acidifira ponoću 6N HCl do pH 4. U otopinu se doda etil acetat, organski sloj se ispere vodom i vodenom otopinom natrij klorida, suši se iznad MgSO4 i evaporira da bi se dobio naslovni spoj kao žuta pjena (0.96 g, 97%). In a solution of (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(2-allyl-oxycarbonyl-5-thienylcarbamoyl)pyrrolidine-4-ylthioacetate (1.06 g, 2 mmol) in dichloromethane (2 ml) was added to 0°C ethanol (4 ml) and then a 5N solution of methylamine in ethanol (0.8 ml, 4 mmol). The reaction mixture was stirred at room temperature for 1.5 hours and then acidified at midnight with 6N HCl to pH 4. Ethyl acetate was added to the solution, the organic layer was washed with water and aqueous sodium chloride, dried over MgSO4 and evaporated to give the title product. compound as a yellow foam (0.96 g, 97%).

NMR (DMSO-d6-TFA): δ 1.87 (m, 1H); 2.73 (m, 1H); 3.29 (m, 1H); 3.44 (m, 1H); 4.01 (m, 1H); 4.42 (m, 1H); 4.72 (br s, 2H); 5.02-5.40 (m, 4H); 6.01 (m, 1H); 7.76 (n, 1H); 7.43 (d, 1H); 7.61-7.68 (m, 2H); 7.93 (d, 1H); 8.25 (d, 1H). NMR (DMSO-d6-TFA): δ 1.87 (m, 1H); 2.73 (m, 1H); 3.29 (m, 1H); 3.44 (m, 1H); 4.01 (m, 1H); 4.42 (m, 1H); 4.72 (number s, 2H); 5.02-5.40 (m, 4H); 6.01 (m, 1H); 7.76 (n, 1H); 7.43 (d, 1H); 7.61-7.68 (m, 2H); 7.93 (d, 1H); 8.25 (d, 1H).

4-Nitrobenzil(1R,5S,6S,3R,2'S,4'S)-2-(1-(4-nitrobenziloksikarbonil)-2-(2-aliloksikarbonil-5-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilat 4-Nitrobenzyl(1R,5S,6S,3R,2'S,4'S)-2-(1-(4-nitrobenzyloxycarbonyl)-2-(2-allyloxycarbonyl-5-thienylcarbamoyl)pyrrolidin-4-ylthio)-6-(1 -hydroxyethyl)-1-methylcarbapenem-3-carboxylate

U otopinu 4-nitrobenzil (1R,5S,6S,8R)-6-(1-hidroksietil)-1-metil-2-difenilfosforiloksikarbapenem-3-karboksilata (940 mg, 1.9 mmol) u acetonitrilu (10 ml) doda se jedno iza drugoga N-diizopropiletilamin (0.33 ml, 1.9 mmol), (2S,4S)-1-(4-nitrobenzil-oksikarbonil)-2-(2-aliloksikarbonil-5-tienilkarbamoil)pirolidin-4-iltio (1 g, 1.9 mmol), u tri-n-butilfosfinu (0.095 ml, 0.38 mmol) i vodi (0.03 ml). Reakcijska smjesa se drži na 4°C preko noći, zatim se evaporira do suhoga i ostatak se podvrgne kromatografiji na silika gelu uz upotrebu smjese CH2Cl2-CH3CN (7:3) da bi se dobio naslovni spoj kao žuta pjena (1.03 g, 72%). To a solution of 4-nitrobenzyl (1R,5S,6S,8R)-6-(1-hydroxyethyl)-1-methyl-2-diphenylphosphoryloxycarbapenem-3-carboxylate (940 mg, 1.9 mmol) in acetonitrile (10 ml) was added one followed by N-diisopropylethylamine (0.33 ml, 1.9 mmol), (2S,4S)-1-(4-nitrobenzyl-oxycarbonyl)-2-(2-allyloxycarbonyl-5-thienylcarbamoyl)pyrrolidine-4-ylthio (1 g, 1.9 mmol), in tri-n-butylphosphine (0.095 ml, 0.38 mmol) and water (0.03 ml). The reaction mixture was kept at 4°C overnight, then evaporated to dryness and the residue chromatographed on silica gel using CH2Cl2-CH3CN (7:3) to afford the title compound as a yellow foam (1.03 g, 72% ).

NMR (DMSO-d6-AcOD-d4): δ 1.17 (d, 3H); 1.19 (d, 3H); 1.95 (d, 3H); 2.83 (n, 1H); 3.30-3.62 (m, 3H); 3.96-4.30 (m, 4H); 4.47-4.60 (dt, 1H); 4.73 (br s, 2H); 5.03-5.44 (m, 6H); 6.00 (m, 1H); 6.77 (dd, 1H); 7.44 (d, 1H); 7.61 (dd, 1H); 7.67 (d, 1H); 7.7 (d, 2H); 7.94 (d, 1H); 8.21 (d, 1H); 8.24 (d, 2H). NMR (DMSO-d6-AcOD-d4): δ 1.17 (d, 3H); 1.19 (d, 3H); 1.95 (d, 3H); 2.83 (n, 1H); 3.30-3.62 (m, 3H); 3.96-4.30 (m, 4H); 4.47-4.60 (dt, 1H); 4.73 (no. s, 2H); 5.03-5.44 (m, 6H); 6.00 (m, 1H); 6.77 (dd, 1H); 7.44 (d, 1H); 7.61 (dd, 1H); 7.67 (d, 1H); 7.7 (d, 2H); 7.94 (d, 1H); 8.21 (d, 1H); 8.24 (d, 2H).

Primjer 7 Example 7

(1R,5S,6S,8R,2'S,4'S)-2-(5-Karboksi-3-hidroksi-2-tienilkarbamoil)-pirolidin-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina (1R,5S,6S,8R,2'S,4'S)-2-(5-Carboxy-3-hydroxy-2-thienylcarbamoyl)-pyrrolidine-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid

Otopina natrij (1R,5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenzil-oksikarbonil)-2-(-5-karboksi-3-hidroksi-2-tienilkarbamoil)-pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilata (92 mg,0.13 mmol) u vodi (5 ml) i natrij biklarbonatu (pH namješten na 7.5) se hidrira pri atmosferskon tlaku u prisutnosti Pd/C (10%) (45 mg). Reakcija se prati analitički pomoću HPLC i traje oko 45 minuta. Katalizator se ukloni filtriranjem i vodena otopina se koncentrira, te pročisti preparativnom EPLC (Nucleosil C-18), uz eluaciju vodom. Sušenje zamrzavanjem odgovarajuće frakcije daje naslovni spoj (30 mg, 42%). Sodium solution (1R,5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenzyl-oxycarbonyl)-2-(-5-carboxy-3-hydroxy-2-thienylcarbamoyl)-pyrrolidine-4- ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylate (92 mg, 0.13 mmol) in water (5 ml) and sodium bicarbonate (pH adjusted to 7.5) was hydrogenated at atmospheric pressure in the presence of Pd/C (10%) (45 mg). The reaction is monitored analytically by HPLC and lasts about 45 minutes. The catalyst is removed by filtration and the aqueous solution is concentrated and purified by preparative EPLC (Nucleosil C-18), eluting with water. Freeze drying of the appropriate fraction afforded the title compound (30 mg, 42%).

NMR (DMSO-d6+AcOD-d4): δ 1.15 (m, 6H); 1.7 (m, 1H); 2.65 (m, 2H); 3.2 (dd, 1H); 3.45 (m, 2H); 3.6 (m, 1H); 3.95 (dq, 1H); 4.05 (t, 1H); 4.15 (dd, 1H); 7.18 (s, 1H). NMR (DMSO-d6+AcOD-d4): δ 1.15 (m, 6H); 1.7 (m, 1H); 2.65 (m, 2H); 3.2 (dd, 1H); 3.45 (m, 2H); 3.6 (m, 1H); 3.95 (dq, 1H); 4.05 (t, 1H); 4.15 (dd, 1H); 7.18 (s, 1H).

Polazni materijali su pripremljeni na slijedeći način: The starting materials were prepared in the following way:

tert-Butil 3-tert-butoksi-2-etiloksikarbonil-5-tiofenkarboksilat tert-Butyl 3-tert-butoxy-2-ethyloxycarbonyl-5-thiophenecarboxylate

Otopina etil-3-hidroksi-5-karboksi-2-tiofenkarboksilata (25g, 0.115 mmol) u suhom CH2Cl2 (200 ml) se tretira pri sobnoj temperaturi sa diizopropil-tert-butilizoureom (175 ml) koja se dodaje kapajući. Ta reakcija je egzotermna što zagrijava smjesu do refluksa. Reakcijska smjesa se zatim miješa tokom 12 sati, krutina se ukloni filtriranjem i CH2Cl2 se evaporira. Preostalo ulje se pročisti pomoću kromatografije na silika gelu uz eluaciju sa smjesom petrolej eter:eter (90:10) da bi se dobila smjesa dva produkta (28.5g). Ta dva produkta se odijele pomoću svjetlosne kromatografije uz eluaciju sa smjesom CH2Cl2:petrolej eter (1:1) da bi se dobio naslovni spoj (12.6 g, 33%). A solution of ethyl 3-hydroxy-5-carboxy-2-thiophenecarboxylate (25g, 0.115 mmol) in dry CH2Cl2 (200 ml) was treated at room temperature with diisopropyl-tert-butylisourea (175 ml), which was added dropwise. This reaction is exothermic, which heats the mixture to reflux. The reaction mixture was then stirred for 12 h, the solid was removed by filtration and the CH 2 Cl 2 was evaporated. The remaining oil was purified by silica gel chromatography eluting with petroleum ether:ether (90:10) to give a mixture of two products (28.5g). The two products were separated by light chromatography eluting with CH2Cl2:petroleum ether (1:1) to give the title compound (12.6 g, 33%).

NHR:(DMSO-d6): δ 1.29 (t, 3H); 1.36 (s, 9H); 1.53 (s, 9H); 4.25 (q, 2H); 7.41 (s, 1H). NHR:(DMSO-d6): δ 1.29 (t, 3H); 1.36 (s, 9H); 1.53 (s, 9H); 4.25 (q, 2H); 7.41 (s, 1H).

tert-Butil-3-tert-butoksi-2-karboksi-5-tiofenkarboksilat tert-Butyl-3-tert-butoxy-2-carboxy-5-thiophenecarboxylate

Otopina tert-butil-3-tert-butoksi-2-etilkarbonil-5-tiofen-karboksilata (11.5g, 35 mmol) u dioksanu sa NaOH(2N) (34.5 ml, 70 mmol) se zagrijava tokom 1.45 sati pri 50°C. Smjesa se ohladi na 0°C, neutralizira sa HCl (2N) i otapalo se evaporira. Ostatak se triturira sa koncentriranom vodenom otopinom Na2CO3 (400 ml) i eterom (200 ml). Ponovno se uzme vodena faza i ohladi na 0°C te acidifira pomoću HCl (5N) i ekstrahira sa eterom. Nakon sušenja, koncentriranja faze etera i pročišćavanja pomoću kromatografije na silika gelu uz svjetlost, dobiva se naslovni spoj (3.45g). A solution of tert-butyl-3-tert-butoxy-2-ethylcarbonyl-5-thiophene-carboxylate (11.5g, 35 mmol) in dioxane with NaOH(2N) (34.5 ml, 70 mmol) is heated for 1.45 hours at 50°C. . The mixture is cooled to 0°C, neutralized with HCl (2N) and the solvent is evaporated. The residue was triturated with concentrated aqueous Na2CO3 (400 ml) and ether (200 ml). The aqueous phase is taken again and cooled to 0°C and acidified with HCl (5N) and extracted with ether. After drying, concentration of the ether phase and purification by chromatography on silica gel under light, the title compound is obtained (3.45g).

NMR:(CDCl3): δ 1.55 (s, 9H); 1.58 (s ,9H); 7.5 (s, 1H). NMR: (CDCl3): δ 1.55 (s, 9H); 1.58 (with .9H); 7.5 (s, 1H).

tert-Butil-2-azidokarbonil-3-tert-butoksi-5-tiofenkarboksilat tert-Butyl-2-azidocarbonyl-3-tert-butoxy-5-thiophenecarboxylate

Otopina tert-butil-2-karboksi-3-tert-butoksi-5-tiofenkarboksilata (3g,0.01 mmol) u suhom acetonu (100 ml) se tretira pri 0°C sa trietilaminom (1.7 ml, 0.012 mmol) koji se dodaje kapajući. Smjesa se miješa tokom 15 minuta i zatim se doda kapajući etil kloroformat (1.25 ml, 0.013 mmol) pri 0°C. Nakon 30 minuta, polagano se doda natrij azid (1.1 g, 0.017 mmol) u vodi (5 ml) pri 0 C. Nakon 4 sata miješanja na sobnoj temperaturi, reakcijska smjesa se filtrira i otapalo evaporira. Uljni ostatak se otopi u CH2Cl2, otopina se ispere (2×) vodom, suši iznad MgSO4, te se otapalo evaporira da bi se dobio naslovni produkt (3.25 g, 100%). A solution of tert-butyl-2-carboxy-3-tert-butoxy-5-thiophenecarboxylate (3g, 0.01 mmol) in dry acetone (100 ml) is treated at 0°C with triethylamine (1.7 ml, 0.012 mmol) which is added dropwise. . The mixture was stirred for 15 min and then ethyl chloroformate (1.25 ml, 0.013 mmol) was added dropwise at 0°C. After 30 minutes, sodium azide (1.1 g, 0.017 mmol) in water (5 ml) was slowly added at 0 C. After stirring for 4 hours at room temperature, the reaction mixture was filtered and the solvent was evaporated. The oily residue was dissolved in CH2Cl2, the solution was washed (2×) with water, dried over MgSO4, and the solvent was evaporated to give the title product (3.25 g, 100%).

NHR (DMSO-d6): δ 1.50 (s, 9H); 1.6 (s, 9H); 7.45 (s, 1H). NHR (DMSO-d6): δ 1.50 (s, 9H); 1.6 (s, 9H); 7.45 (s, 1H).

tert-butil-2-aliloksikarbonilamino-3-tert-butoksi-5-tiofene-karboksilat tert-butyl-2-allyloxycarbonylamino-3-tert-butoxy-5-thiophene-carboxylate

Otopina tert-butil-2-azidokarbonil-3-tert-butoksi-5-tiofen-karboksilata (1.5 g, 4.6 mmol) u alil alkoholu (0.5 ml, 7.3 mmol) i suhom toluenu (15 ml) se zagrijava na 100°C tokom 30 minuta, dok se ne zaustavi razvijanje dušika. Smjesa se evaporira i ostatak se podvrgne svjetlosnoj kromatografiji na silika gelu uz eluaciju sa smjesom petrolej eter:eter (4:1) da bi se dobio naslovni spoj (1.64 g, 100%). A solution of tert-butyl-2-azidocarbonyl-3-tert-butoxy-5-thiophene-carboxylate (1.5 g, 4.6 mmol) in allyl alcohol (0.5 ml, 7.3 mmol) and dry toluene (15 ml) is heated to 100°C. during 30 minutes, until the evolution of nitrogen stops. The mixture was evaporated and the residue subjected to silica gel light chromatography eluting with petroleum ether:ether (4:1) to give the title compound (1.64 g, 100%).

NMR:(CDCl3): δ 1.28 (s, 9H); 1.49 (s, 9H); 4.66 (m, 2H); 5.25-5.37 (m, 2H); 6.0 (m, 1H); 7.25 (m, 1H). NMR: (CDCl 3 ): δ 1.28 (s, 9H); 1.49 (s, 9H); 4.66 (m, 2H); 5.25-5.37 (m, 2H); 6.0 (m, 1H); 7.25 (m, 1H).

tert-Butil-2-amino-3-tert-butoksi-5-tiofenkarboksilat tert-Butyl-2-amino-3-tert-butoxy-5-thiophenecarboxylate

Otopina tert-butil-2-aliloksikarbonilamino-3-tert-butoksi-5-tiofenkarboksilata (1.64 g, 4.62 mmol) u anhidridnom THF (50 ml) se tretira sa PPh3 (240 mg, 0.923 mmol), dimedonom (1.3 g, 9.23 mmol) i Pd(PPh3)4 (300 mg, 0.277 mmol). Nakon 30 minuta, otapalo se evaporira i ostatak se podvrgne svjetlosnoj kromatografiji na silika gelu da bi se pročistio, uz eluaciju sa smjesom petrolej eter:eter (80:20) da bi se dobio naslovni spoj (975 mg, 98%). A solution of tert-butyl-2-allyloxycarbonylamino-3-tert-butoxy-5-thiophenecarboxylate (1.64 g, 4.62 mmol) in anhydrous THF (50 ml) was treated with PPh3 (240 mg, 0.923 mmol), dimedone (1.3 g, 9.23 mmol) and Pd(PPh3)4 (300 mg, 0.277 mmol). After 30 min, the solvent was evaporated and the residue was subjected to silica gel light chromatography for purification, eluting with petroleum ether:ether (80:20) to give the title compound (975 mg, 98%).

NMR:(DMSO-d6): δ 1.24 (s, 9H); 1.45 (s, 9H); 6.0 (s, 2H); 7.08 (s, 1H). NMR: (DMSO-d6): δ 1.24 (s, 9H); 1.45 (s, 9H); 6.0 (s, 2H); 7.08 (s, 1H).

(2S,4S)-1-(4-Nitrobenziloksikarbonil)-2-(3-tert-butoksi-5-tert-butiloksikarbonil-2-tienilkarbamoil)pirolidin-4-iltioacetat (2S,4S)-1-(4-Nitrobenzyloxycarbonyl)-2-(3-tert-butoxy-5-tert-butyloxycarbonyl-2-thienylcarbamoyl)pyrrolidine-4-ylthioacetate

(2S,4S)-1-(4-Nitrobenziloksikarbonil)-4-acetiltio-2-karboksi-pirolidin (1.5g, 4 mmol) se solubilizira u suhom CH2Cl2 (15 ml) i tretira sa tionilkloridom (1.5 ml, 20 mmol) i katalitičkim iznosom DMF-a (20 ml). Smjesa se miješa tokom 12 sati pri sobnoj temperaturi, otapalo se evaporira i preostalo ulje se suši u vakuumu tokom dva sata, solubilizira u CH2Cl2 (15 ml) i doda se otopini tert-butil-2-amino-3-tert-butoksi-5-tenoata (1.1 g, 4 mmol) u CH2Cl2 (15 ml) i diizopropiletilaminu (0.85 ml, 4.9 mmol) pri 0°C. Smjesa se miješa tokom 30 minuta, otapalo se evaporira, te se ostatak pročisti svjetlosnom kromatografijom na silika gelu uz eluaciju sa smjesom petrolej eter:eter (20:80) da bi se dobio naslovni spoj (2.17 g, 85%). (2S,4S)-1-(4-Nitrobenzyloxycarbonyl)-4-acetylthio-2-carboxy-pyrrolidine (1.5g, 4 mmol) was solubilized in dry CH2Cl2 (15 ml) and treated with thionyl chloride (1.5 ml, 20 mmol) and a catalytic amount of DMF (20 ml). The mixture is stirred for 12 hours at room temperature, the solvent is evaporated and the remaining oil is dried in vacuo for two hours, solubilized in CH2Cl2 (15 ml) and added to the solution of tert-butyl-2-amino-3-tert-butoxy-5 -thenoate (1.1 g, 4 mmol) in CH2Cl2 (15 ml) and diisopropylethylamine (0.85 ml, 4.9 mmol) at 0°C. The mixture is stirred for 30 minutes, the solvent is evaporated, and the residue is purified by light chromatography on silica gel eluting with petroleum ether:ether (20:80) to give the title compound (2.17 g, 85%).

NMR:(CDCl3): δ 1.56 (s, 9H); 1.58 (s, 9H); 2.32 (s, 3H); 2.55 (m, 1H); 2.74 (m, 1H); 3.38 (m, 1H); 4.01 (m, 1H); 4.15 (m, 1H); 4.63 (m, 1H); 5.3 (m, 2H); 7.39 (s, 1H); 7.52 (m, 2H); 8.22 (m, 2H). NMR: (CDCl 3 ): δ 1.56 (s, 9H); 1.58 (s, 9H); 2.32 (s, 3H); 2.55 (m, 1H); 2.74 (m, 1H); 3.38 (m, 1H); 4.01 (m, 1H); 4.15 (m, 1H); 4.63 (m, 1H); 5.3 (m, 2H); 7.39 (s, 1H); 7.52 (m, 2H); 8.22 (m, 2H).

(2S,4S)-1-(4-Nitrobenziloksikarbonil)-2-(3-hidroksi-5-karboksi-2-tienil-karbamoil)pirolidin-4-iltiol (2S,4S)-1-(4-Nitrobenzyloxycarbonyl)-2-(3-hydroxy-5-carboxy-2-thienyl-carbamoyl)pyrrolidine-4-ylthiol

(2S,4S)-1-(4-Nitrobenziloksikarbonil)-2-(3-tert-butoksi-5-tert-butiloksikarbonil-2-tienilkarbamoil)pirolidin-4-iltioacetat (1 g, 1.6 mmol) se solubilizira u CH2Cl2 (2 ml) i suhom etanolu (5ml) i tretira sa otopinom metilamina (4.24M) u etanolu (1.15 ml, 4.83 mmol). Razvijanje reakcije se prati pomoću tlc. Nakon 1.5 sati, smjesa se evaporira, ostatak se solubilizira u CH2Cl2 (5 ml) i tretira sa THF (5 ml) tokom 1.5 sati pri sobnoj temperaturi. Otapalo se evaporira i ostatak se triturira sa eterom dajući naslovni spoj (1.1 g, 100%). (2S,4S)-1-(4-Nitrobenzyloxycarbonyl)-2-(3-tert-butoxy-5-tert-butyloxycarbonyl-2-thienylcarbamoyl)pyrrolidine-4-ylthioacetate (1 g, 1.6 mmol) was solubilized in CH2Cl2 ( 2 ml) and dry ethanol (5 ml) and treated with a solution of methylamine (4.24 M) in ethanol (1.15 ml, 4.83 mmol). The development of the reaction is monitored by tlc. After 1.5 hours, the mixture is evaporated, the residue is solubilized in CH2Cl2 (5 ml) and treated with THF (5 ml) for 1.5 hours at room temperature. The solvent was evaporated and the residue was triturated with ether to give the title compound (1.1 g, 100%).

NMR:(DMSO-d6): 1.8 (m, 1H); 2.7 (m, 1H); 3.4 (m, 1H); 4.00 (m, 2H); 4.82 (m, 1H); 5.00-5.26 (m, 2H); 7.16 (m, 1H); 7.45 (m, 1H); 7.65 (m, 1H); 7.94 (m, 1H); 8.23 (m, 1H). NMR: (DMSO-d 6 ): 1.8 (m, 1H); 2.7 (m, 1H); 3.4 (m, 1H); 4.00 (m, 2H); 4.82 (m, 1H); 5.00-5.26 (m, 2H); 7.16 (m, 1H); 7.45 (m, 1H); 7.65 (m, 1H); 7.94 (m, 1H); 8.23 (m, 1H).

Alil (1R,5R,6S,8R,2'S,4'S)-2-(1-(4-nitrobenziloksikarbonil-2-(3-hidroksi-5-karboksi-2-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilat Allyl (1R,5R,6S,8R,2'S,4'S)-2-(1-(4-nitrobenzyloxycarbonyl-2-(3-hydroxy-5-carboxy-2-thienylcarbamoyl)pyrrolidine-4-ylthio)-6-( 1-hydroxyethyl)-1-methylcarbapenem-3-carboxylate

Otopina alil (1R,5R,6S,8R)-6-(1-hidroksietil)-1-metil-2-diohenilfosforiloksikarbapenem-3-karboksilata (800mg, 1.6 mmol) u DMF-u (8 ml) pod argonom se tretira sa (2S,4S)-1-(4-nitro-benziloksikarbonil)-2-(3-hidroksi-5-karboksi-2-tienilkarbamoil)-pirolidin-4-iltiol (752 mg, 1.6 mmol), diizopropiletilaninom (0.835 ml, 4.8 mmol), tributilfosfinom (200 ul, 0.8 mmol) i vodom (15 ml, 0.8 mmol), tokom 12 sati na sobnoj temperaturi. Smjesa se zatim pročisti podvrgavanjem kromatografiji na HP2OSS koloni uz eluaciju sa stupnjevanom smjesom acetonitril, voda da bi se dobio naslovni spoj (286 mg, 25%). A solution of allyl (1R,5R,6S,8R)-6-(1-hydroxyethyl)-1-methyl-2-diohenylphosphoryloxycarbapenem-3-carboxylate (800 mg, 1.6 mmol) in DMF (8 ml) under argon was treated with (2S,4S)-1-(4-nitro-benzyloxycarbonyl)-2-(3-hydroxy-5-carboxy-2-thienylcarbamoyl)-pyrrolidine-4-ylthiol (752 mg, 1.6 mmol), diisopropylethylene (0.835 ml, 4.8 mmol), with tributylphosphine (200 ul, 0.8 mmol) and water (15 ml, 0.8 mmol), during 12 hours at room temperature. The mixture was then purified by chromatography on an HP2OSS column eluting with a graded mixture of acetonitrile, water to afford the title compound (286 mg, 25%).

NMR:(DMSOd6+AcOD-d4): δ 1.1-1.3 (m, 6H); 1.85 (m, 1H); 2.75 (m, 1H); 3.25 (dd, 1H); 3.3 (m, 1H); 3.5-3.7 (m, 1H); 3.7-4.3 (m, 4H); 4.5-4.8 (m,3H); 4.9-5.5 (m, 4H); 5.9 (m, 1H); 7.17 (m, 1H); 7.46 (m, 1H); 7.66 (m, 1H); 7.96 (m, 1H); 8.73 (m, 1H). NMR: (DMSOd6+AcOD-d4): δ 1.1-1.3 (m, 6H); 1.85 (m, 1H); 2.75 (m, 1H); 3.25 (dd, 1H); 3.3 (m, 1H); 3.5-3.7 (m, 1H); 3.7-4.3 (m, 4H); 4.5-4.8 (m, 3H); 4.9-5.5 (m, 4H); 5.9 (m, 1H); 7.17 (m, 1H); 7.46 (m, 1H); 7.66 (m, 1H); 7.96 (m, 1H); 8.73 (m, 1H).

(1R,5R,6S,8R,2'S,4'S)-2-(1-(4-Nitrobenziloksikarbonil)-2-(3-hidroksi-5-karboksi-2-tienilkarbamoil)pirolidinr-4-iltio)-6-(1-hidroksi-etil)-1-metilkarbapenem-3-karboksilna kiselina (1R,5R,6S,8R,2'S,4'S)-2-(1-(4-Nitrobenzyloxycarbonyl)-2-(3-hydroxy-5-carboxy-2-thienylcarbamoyl)pyrrolidine-4-ylthio)-6-( 1-Hydroxy-ethyl)-1-methylcarbapenem-3-carboxylic acid

Otopina alil (1R,5R,6S,8R,2'S,4'S)-2-(1-(4-nitrobenziloksi-karbonil)-2-(3-hidroksi-5-karboksi-2-tienilkarbamoil)-pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilata (240 mg,0.335 mmol) u DMF-u (4 ml) uz argon se tretira sa Pd(PPh3)4 (30 mg,0.026 mmol) i Meldrum-ovom kiselinom (48 mg, 0.335 mmol). Smjesa se miješa tokom jednog sata pri sobnoj temperaturi. Otapalo se evaporira, ostatak se solubilizira u vodi, pH se namjesti na 7.5 pomoću NaHCO3 i otopina se pročisti pomoću C18 (Nucleosil) kromatografije uz eluaciju sa smjesom voda: CH3CN (stupnjevano) da bi se dobio naslovni spoj (92 mg, 39%). Solution Allyl (1R,5R,6S,8R,2'S,4'S)-2-(1-(4-nitrobenzyloxy-carbonyl)-2-(3-hydroxy-5-carboxy-2-thienylcarbamoyl)-pyrrolidin-4-ylthio )-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylate (240 mg, 0.335 mmol) in DMF (4 ml) under argon is treated with Pd(PPh3)4 (30 mg, 0.026 mmol) and Meldrum's acid (48 mg, 0.335 mmol). The mixture is stirred for one hour at room temperature. The solvent was evaporated, the residue was solubilized in water, the pH was adjusted to 7.5 with NaHCO3 and the solution was purified by C18 (Nucleosil) chromatography eluting with water: CH3CN (stepwise) to give the title compound (92 mg, 39%) .

NMR:(DMSO-d6+AcOD-d4): δ 1.15 (m, 6H); 1.85 (m, 1H); 2.5 (m, 1H) (uz DMSO); 2.77 (m, 1H); 3.19 (dd, 1H); 3.25-3.5 (m, 1H); 3.8-4.2 (m, 3H); 4.6 (m, 1H); 4.7 (m, 1H); 5.0-5.3 (m, 2H); 7.15 (s, 1H); 7.46 (m, 1H); 7.67 (m, 1H); 7.97 (m, 1H); 8.24 (m, 1H). NMR: (DMSO-d6+AcOD-d4): δ 1.15 (m, 6H); 1.85 (m, 1H); 2.5 (m, 1H) (with DMSO); 2.77 (m, 1H); 3.19 (dd, 1H); 3.25-3.5 (m, 1H); 3.8-4.2 (m, 3H); 4.6 (m, 1H); 4.7 (m, 1H); 5.0-5.3 (m, 2H); 7.15 (s, 1H); 7.46 (m, 1H); 7.67 (m, 1H); 7.97 (m, 1H); 8.24 (m, 1H).

Claims (17)

1. Spoj formule (1): [image] ili njegova farmaceutski prihvatljiva sol ili njegov in vivo hidrolizirajući ester, naznačen time, da je: R1 1-hidroksietil, 1-fluoroetil ili hidroksimetil; R2 vodik ili C1-4alkil; R3 vodik ili C1-4alkil; te je tienil prsten dalje po izboru supstituiran sa jednim ili dva supstituenta izabranih između halogena, cijano, C1-4alkil, nitro, hidroksi, karboksi, C1-4alkoksi, trifluorometil, C1-4alkoksi-karbonil, amino, C1-4alkilamino, di-C1-4alkilamino, sulfonske kiseline, C1-4alkilS(O)n- (gdje je n 0-2), C1-4alkanoilamino, C1-4alkanoil(N-C1-4alkil)amino, karbamoil, C1-4alkilcarbanoil, di-C1-4alkilkarbamoil i N-C1-4alkansulfonamido; ili sa tetrametilen grupom koja prijanja na susjedne ugljikove atome u tienil prstenu.1. Compound of formula (1): [image] or a pharmaceutically acceptable salt thereof or an in vivo hydrolyzable ester thereof, characterized in that: R1 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl; R 2 is hydrogen or C 1-4 alkyl; R 3 is hydrogen or C 1-4 alkyl; and the thienyl ring is further optionally substituted with one or two substituents selected from halogen, cyano, C1-4 alkyl, nitro, hydroxy, carboxy, C1-4 alkoxy, trifluoromethyl, C1-4 alkoxy-carbonyl, amino, C1-4 alkylamino, di-C1 -4alkylamino, sulfonic acids, C1-4alkylS(O)n- (where n is 0-2), C1-4alkanoylamino, C1-4alkanoyl(N-C1-4alkyl)amino, carbamoyl, C1-4alkylcarbanoyl, di-C1-4alkylcarbamoyl and N-C1-4alkanesulfonamido; or with a tetramethylene group attached to adjacent carbon atoms in the thienyl ring. 2. Spoj prema zahtjevu 1, naznačen time,da je R1 1-hidroksietil.2. Compound according to claim 1, characterized in that R1 is 1-hydroxyethyl. 3. Spoj prema zahtjevu 1 ili prema zahtjevu 2, naznačen time, da je R2 vodik ili metil.3. Compound according to claim 1 or according to claim 2, characterized in that R2 is hydrogen or methyl. 4. Spoj prema zahtjevu 1 ili prema zahtjevu 2, naznačen time da je R2 metil.4. The compound according to claim 1 or according to claim 2, characterized in that R2 is methyl. 5. Spoj prema bilo kojem zahtjevu od 1 do 4, naznačen time,da je R3 vodik.5. A compound according to any one of claims 1 to 4, characterized in that R3 is hydrogen. 6. Spoj prema bilo kojem zahtjevu od 1 do 4, formule (IV): [image] naznačen time, da su R3 i izborni supstituenti tienil prstena isti kao što su definirani u zahtjevu 1.6. Compound according to any claim from 1 to 4, formula (IV): [image] characterized in that R 3 and optional thienyl ring substituents are the same as defined in claim 1. 7. Spoj prema zahtjevu 6, naznačen time, da je tienil prsten po izboru supstituiran sa halogenim, cijano, C1-4alkil, nitro, karboksi, hidroksi, C1-4alkoksi, karbamoil, amino, trifluorometil ili tetrametilenom.7. Compound according to claim 6, characterized in that the thienyl ring is optionally substituted with halogen, cyano, C1-4 alkyl, nitro, carboxy, hydroxy, C1-4 alkoxy, carbamoyl, amino, trifluoromethyl or tetramethylene. 8. Spoj prema zahtjevu 6 ili prema zahtjevu 7, naznačen time, da je R3 vodik i da je tienil prsten ili dalje nesupstituiran ili je supstituiran sa jednim supstituentom izabranim između metil ili hidroksi ili sa tetrametilenom.8. A compound according to claim 6 or according to claim 7, characterized in that R3 is hydrogen and that the thienyl ring is either further unsubstituted or is substituted with one substituent selected from methyl or hydroxy or with tetramethylene. 9. Spoj prema zahtjevu 1, naznačen time, da je (1R,5S,6S,8R,2'S,4'S)-2-(2-(2-karboksi-4-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina; (1R,5S,6S,8R,2'S,4'S)-2-(2-(2-karboksi-3-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina; (1R,5S,6S,8R,2'S,4'S)-2-(2-(4-karboksi-2-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina; (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-karboksi-2-(4,5,8,7)-tetrahidro-benzo(b)tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina; (1R,5S,6S3,8R,2'S,4'-S)-2-(2-(3-karboksi-4-metil-2-tienilkarbamoil)-pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina; (1R,5S,6S,8R,2'S,4'S)-2-(2-(2-karboksi-5-tienilkarbamoil)pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina; (1R,5S,6S,8R,2'S,4'S)-2-(2-(5-karboksi-3-hidroksi-2-tienilkarbamoil)-pirolidin-4-iltio)-6-(1-hidroksietil)-1-metilkarbapenem-3-karboksilna kiselina; ili njihove farmaceutski prihvatljive soli.9. Compound according to claim 1, characterized in that (1R,5S,6S,8R,2'S,4'S)-2-(2-(2-carboxy-4-thienylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid; (1R,5S,6S,8R,2'S,4'S)-2-(2-(2-carboxy-3-thienylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid; (1R,5S,6S,8R,2'S,4'S)-2-(2-(4-carboxy-2-thienylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid; (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-2-(4,5,8,7)-tetrahydro-benzo(b)thienylcarbamoyl)pyrrolidin-4-ylthio) -6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid; (1R,5S,6S3,8R,2'S,4'-S)-2-(2-(3-carboxy-4-methyl-2-thienylcarbamoyl)-pyrrolidin-4-ylthio)-6-(1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid; (1R,5S,6S,8R,2'S,4'S)-2-(2-(2-carboxy-5-thienylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid; (1R,5S,6S,8R,2'S,4'S)-2-(2-(5-carboxy-3-hydroxy-2-thienylcarbamoyl)-pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1- methylcarbapenem-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 10. Farmaceutski pripravak, naznačen time, da sadrži spoj prema bilo kojem zahtjevu od 1 do 9 i farmaceutski prihvatljivu podlogu.10. Pharmaceutical preparation, characterized in that it contains a compound according to any of claims 1 to 9 and a pharmaceutically acceptable base. 11. Postupak liječenja infekcije, naznačen time, da se pacijentu kojem je to potrebno primjenjuje antibakterijski efikasan iznos spoja formule (I).11. A method of treating an infection, characterized in that an antibacterially effective amount of the compound of formula (I) is administered to the patient who needs it. 12. Postupak pripreme spoja prema zahtjevu 1, naznačen time, da obuhvaća deprotekciju spoja formule (V): [image] gdje je R2 isti kao što je definiran u zahtjevu 1; R10 je grupa R3 (kao što je definirano u zahtjevu 1) ili amino zaštitna grupa; R13 je grupa R1 (kao što je definirano u zahtjevu 1), zaštićeni hidroksimetil ili 1-(zaštićeni hidroksi)etil; R11 je vodik ili karboksi zaštitna grupa; R12 je vodik ili amino zaštitna grupa, R18 je karboksi ili zaštićeni karboksi, te gdje je izborni supstituent na tienil prstenu definiran u zahtjevu 1 i po izboru je zaštićen; te gdje je prisutna najmanje jedna zaštitna grupa; te kasnije ako je neophodno; (i) formiranje farmaceutski prihvatljive soli, (ii) esterifikaciju da bi se formirao in vivo hidrolizirajući ester.12. The process for preparing the compound according to claim 1, characterized in that it includes the deprotection of the compound of formula (V): [image] where R2 is as defined in claim 1; R 10 is the group R 3 (as defined in claim 1) or an amino protecting group; R13 is the group R1 (as defined in claim 1), protected hydroxymethyl or 1-(protected hydroxy)ethyl; R11 is hydrogen or a carboxy protecting group; R12 is hydrogen or an amino protecting group, R18 is carboxy or protected carboxy, and where the optional substituent on the thienyl ring is defined in claim 1 and is optionally protected; and where at least one protecting group is present; and later if necessary; (i) formation of a pharmaceutically acceptable salt, (ii) esterification to form an in vivo hydrolyzable ester. 13. Spoj, naznačen time, da ima formulu (V) kao što je definirana u zahtjevu 12.13. A compound of formula (V) as defined in claim 12. 14. Postupak pripreme spoja prema zahtjevu 1 ili spoja formule (V) kao što je definirana u zahtjevu 12, naznačen time, da obuhvaća: a) reakciju spojeva formule (VI) i (VII): [image] gdje su R2, R10, R11, R12, R13 i R18 isti kao što su definirani u zahtjevu 12, izborni supstituenti tienil prstena su isti kao definirani u zahtjevu 12 i L je napuštajuča grupa, ili b) ciklizaciju spoja formule (VIII): [image] gdje su R2, R10, R11, R12, R13 i R18 isti kao što su definirani u zahtjevu 12, izborni supstituenti na tienil prstenu su isti kao što su definirani u zahtjevu 12, te su R14, R15 i R16 nezavisno izabrani između C1-6alkoksi, ariloksi, di-C1-6alkilamino i diarilamino i bilo koja dva od R14-R16 predstavljaju o-fenilenedioksi ili jedan od R14-R16 je C1-4alkil, alil, benzil ili fenil, a preostale dvije vrijednosti su nezavisno izabrane između C1-4alkil, trifluorometil ili fenil, gdje je svaka fenil grupa po izboru supstituirana sa C1-4alkil ili C1-4alkoksi; te gdje je svaka funkcionalna grupa po izboru zaštićena i kasnije ako je neophodno: (i) uklanjaju se zaštitne grupe; (ii) formiraju se farmaceutski prihvatljive soli; (iii) provede se esterifikacija da bi se dobili in vivo hidrolizirajući esteri.14. The procedure for preparing the compound according to claim 1 or the compound of formula (V) as defined in claim 12, characterized in that it includes: a) reaction of compounds of formulas (VI) and (VII): [image] wherein R 2 , R 10 , R 11 , R 12 , R 13 and R 18 are as defined in claim 12, optional thienyl ring substituents are as defined in claim 12 and L is a leaving group, or b) cyclization of the compound of formula (VIII): [image] where R 2 , R 10 , R 11 , R 12 , R 13 and R 18 are as defined in claim 12, the optional substituents on the thienyl ring are as defined in claim 12, and R 14 , R 15 and R 16 are independently selected from C 1-6 alkoxy , aryloxy, di-C1-6alkylamino and diarylamino and any two of R14-R16 represent o-phenylenedioxy or one of R14-R16 is C1-4alkyl, allyl, benzyl or phenyl, and the remaining two values are independently selected from C1-4alkyl , trifluoromethyl or phenyl, where each phenyl group is optionally substituted with C 1-4 alkyl or C 1-4 alkoxy; and where each functional group is optionally protected and later if necessary: (i) protective groups are removed; (ii) pharmaceutically acceptable salts are formed; (iii) esterification is carried out to obtain in vivo hydrolyzable esters. 15. Spoj formule (I), kao što je definiran u zahtjevu 1, naznačen time, da je u obliku farmaceutski neprihvatljive soli.15. The compound of formula (I), as defined in claim 1, characterized in that it is in the form of a pharmaceutically unacceptable salt. 16. Spoj, naznačen time, da ima formulu (VII) ili (VIII) kao što je definirano u zahtjevu 14.16. A compound of formula (VII) or (VIII) as defined in claim 14. 17. Spoj, naznačen time, da ima formulu (IX), (XII) ili (XIV): [image] gdje su R2, R10-R13 i R18 isti kao što su definirani u zahtjevu 12 i R17 je zaštitna grupa.17. A compound characterized by having the formula (IX), (XII) or (XIV): [image] wherein R2, R10-R13 and R18 are as defined in claim 12 and R17 is a protecting group.