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Ep 0617036 A2 Europaisches Patentamt 19 European Patent Office Office europeen des brevets © Publication number: 0 617 036 A2 12 EUROPEAN PATENT APPLICATION (2j) Application number: 94102400.2 © int. ci.5: C07D 477/00, A61K 31/40 (22) Date of filing : 17.02.94 © Priority : 16.03.93 US 33684 Inventor : Bitha, Panayota 287 Treetop Circle @ Date of publication of application : Nanuet, New York 10954 (US) 28.09.94 Bulletin 94/39 Inventor : Sakya, Subas 7 Phyllis Drive Pomona, New York 10970 (US) States @ Designated Contracting : Inventor : Strohmeyer, Timothy W. AT BE CH DE DK ES FR GB GR IE IT LI LU NL 19 Lenox Avenue PT SE Demarest, New Jersey 07627 (US) Inventor : Bush, Karen (ft) Applicant : AMERICAN CYANAMID COMPANY 11 Brook Drive West One Cyanamid Plaza Princeton, New Jersey 08540 (US) Wayne New Jersey 07470 (US) (74) Representative : Wachtershauser, Giinter, (72) Inventor : Lin, Yang-I Prof. Dr. 35 Constitution Drive Patentanwalt Tappan, New York 10983 (US) Tal 29 D-80331 Miinchen (DE) (54) Novel 2-thiosubstituted carbapenems. (57) Carbapenem antibiotic compounds of the general formula : C00R. wherein the moiety CM < CO is a 4, 5 or 6 membered mono, di- or tri- substituted oxygen or sulfur containing ring ; wherein Z is CO oxygen, sulfur, sulfoxide and sulfone, pharmaceutical compositions thereof useful for the treatment of o bacterial infections, processes for preparing the compounds and new intermediates useful in the ro- process. te o Q_ LU Jouve, 18, rue Saint-Denis, 75001 PARIS EP 0 617 036 A2 FIELD OF THE INVENTION This invention relates to novel carbapenem antibiotics and non-toxic pharmaceutical^ acceptable salts thereof, which have antimicrobial activity. Therefore, the present carbapenem antibiotics and pharmaceutical compositions thereof are useful in the treatment of bacterial infections in humans and animal, either alone or in combination with other antibiotics. The present invention also provides processes for the preparation of the carbapenem antibiotics and of certain novel intermediates. SUMMARY OF THE INVENTION This invention is concerned with novel carbapenems, represented by formula I, which have antibacterial activity; with methods of treating infectious disease in humans and other animals when administering these new compounds; with pharmaceutical preparations containing these compounds; with novel intermediate com- pounds and stereoselective processes for the production of compounds of formula IV; and with the production of compounds of formulae I. i 5 — 1 7 C00I, wherein the moiety is a 4,5 or 6 membered mono-, di- or tri-substituted oxygen or sulfur containing ring. For example, the moiety may be a 5 membered ring of the formula In such an instance, the following isomers are included: EP 0 617 036 A2 C0^R3 (CH2)nR2 (CH2)nR2 C02R3 C02R3 and C02R3 (CH2)nR2 (CH2)nR2 and the stereochemical assignment of each residue and — (CH2)nR2 on the 4, 5 or 6-membered ring (containing the Z substituent) can be either R or S. DETAILED DESCRIPTION As stated, the invention relates to compounds of Formula I: coot, EP 0 617 036 A2 wherein the moiety: represents a 4,5 or 6 membered mono, di-or tri-substituted ring and (A) Z is selected from oxygen, sulfur, sulfoxide and sulfone; when Z is sulfoxide, the relative stereochem- istry between the substituent and the sulfoxide can be cis or trans; (B) Ro is hydrogen, (CVC^alkyl, CH2OR4, CH2NHR5, CH(OR4)CH3, CHFCH3 or CH(NHR5)CH3; wherein (i) R4 is selected from hydrogen, and moieties of the formulae: 0 0 0 0 0 II II II II II C -CHjOCR, -CHjOCOR, -C R t > -COR, ,-COCHjO R, , 0 0 0 0 II II II " -COCHjOCOR,, -S0R, and » '<! OR. (ii) R5 is selected from hydrogen, and moieties of the formulae: C0CH20CR, .COCHjOCOR, CR,, COR, , , 11 P OR . sor, and i • 11 OR 0 UK« (iii) R6 is selected from a straight, branched or substituted (CrC18)alkyl, (C2-C18) alkenyl, unsubstituted or substituted (C3-C7)monocyclo(C1-C10)alkyl, unsubstituted or substituted (C5-C10)bicyclo(C1-C10)al- kyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocy- clyl; the substitution for the alkyl, monocycloalkyl and bicycloalkyl moieties are selected from trifluor- omethyl, pentafluoroethyl, amino, mono(CrC6)-alkylamino, di(CrC6)alkylamino, hydroxy, (CrC6)al- koxy, (C3-C8)cycloalkoxy, carboxy, (C2-C10)carboalkoxy, cyano and (CrC10)carboxamido; the substi- tution for the aryl, heteroaryl and heterocyclyl moieties is selected from (CrC6)alkyl, (CrC6)mono-, di- or polyfluoroalkyl, hydroxy, (CrC6)alkoxy, (C3-C8)cycloalkoxy, amino, mono(CrC6)alkylamino, di(CrC6)alkylamino, carboxy, (C2-C10)carboalkoxy, cyano and (CrC10)carboxamido; (C) Ri is straight or branched (CVCaJalkyl, straight or branched (C2-C8)alkenyl, (C3-C8)cycloalkyl, or (CH2)n,R; wherein n' is an integer of from 1-6 and R is selected from CF3, C2F5, fluorine, chlorine, bromine, hydroxy, alkoxy, nitrile, azido, a quaternary ammonio group, amidino, formamidino, guanidino and NR'R"; wherein (i) R' and R" are independently selected from hydrogen, straight or branched (CrC6)alkyl, straight or EP 0 617 036 A2 branched (CVC^alkoxy, 2-hydroxyethyl, 2-azidoethyl and 2-aminoethyl; (ii) and when R' is hydrogen or straight or branched (CrC6)alkyl, R" may also be selected from amino, hydroxy, mono(CrC6)alkylamino, di(CrC6)alkylamino, acyl, benzoyl, dihydroxy benzoyl, an acyl resi- due of an amino acid or peptide, and straight or branched substituted (CVC^alkyl wherein said alkyl 5 substituent is selected from hydroxy, (CrC6)alkoxy, azido, amino, mono(CrC6)alkylamino, di(CrC6)al- kylamino, guanidino, nitrile, carboxy, formimidoyl and phenyl; or (iii) R' and R" taken together with the associated nitrogen may also be an unsubstituted or substituted monocyclic or bicyclic heterocyclic ring having up to four (4) heteroatoms in each ring independently selected from oxygen, nitrogen and sulfur, wherein said substituent is selected from straight or branch- 10 ed (CrC6)alkyl, straight or branched (CrC6)alkoxy, (C3-C8)cycloalkyl, (C3-C8)cycloalkoxy, trif luorome- thyl, hydroxy, halogen (selected from bromine, chlorine, fluorine and iodine), amino, nitrile, carboxy, carbamido, carbamoyl, straight or branched mono(CrC6)alkylamino, straight or branched di(CrC6)al- kylamino, and amino(C1-C6)alkyl. The term "acyl residue of an amino acid or peptide" as used herein means the acyl residue of a naturally 15 occurring amino acid, a racemic amino acid or a peptide derived therefrom. Suitable amino acids are those described herein and other known amino acids such as alanine, glycine, arginine, cysteine, iso- leucine, leucine, lysine, methionine, phenylalanine, proline, aminopimelic acid, threonine and the like. The substituent or substituents on the 25 ring are independently selected from moieties of the formula -(CH2)nR2 wherein: (D) n is an integer from 0-4 and (E) R2 is: (i) methyl, fluorine, or any suitable leaving group such as but not limited to chlorine, bromine, iodine, OCOCH3, OCOCF3, OS02CH3, OS02Ph, N02, cyano or azido; 30 (ii) R2 may also be a moiety of the formula: -S(0)n.Ra wherein n" is an integer from 0-2; and Ra is (a) hydrogen or (b) an organic group bonded via a carbon atom selected from (CrC6)alkyl, (C3-C7)cycloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, aryl^-C^alkyl, heteroaryl(CrC6)alkyl, (CrC6)alkanoyl, arylcarbonyl, heteroarylcarbonyl, heterocy- 35 clyl, heterocyclyl(CrC6)alkyl, heterocyclyl(CrC6)thioalkyl, any of such groups being optionally substi- tuted. Preferably, the heteroatom or heteroatoms in the above-named heterocyclyl and heteroaryl moi- eties are nitrogen atoms and may be quaternized and carry a positive charge and be associated with a physiologically acceptable counterion. As used herein, a physiologically acceptable counterion is se- lected from anions such as CI", OH", HC03", CH3C02", Br", I", H2P04", carboxylate and the like. 40 Optional substituents on the group Ra include (CrC6)alkyl, hydroxy, (CrC6)alkoxy, phenyl, heterocyclyl, amino, amidino, guanidino, carboxamido, carbamoyl, (CrC6)alkanoylamino, mono- and di(CrC6)alkylamino, an acyclic quaternary ammonio moiety of the formula: -NR7R8R9 45 wherein R7, R8 and R9 are the same or different and are selected from hydrogen, a straight or branched (Cr C6)alkyl, (C2-C6)alkenyl and substituted (CrC6)alkyl, wherein the substitution is selected from hydroxy, (Cr C6)alkoxy, azido, amino, (CrC6)alkylamino, di(CrC6)alkylamino, guanidino, nitrile, carboxy, formimidoyl, phe- nyl, an amidino or guanidino moiety of the formula: -N=CR10-NR11R12 so wherein R10 is hydrogen, straight o branched (C1-C6)alkyl, amino, (C1-C6)alkylamino or di(CrC6)alkylamino; and Rn and R12 are independently selected from hydrogen and straight or branched (CrC6)alkyl. Suitably, Ra is (C1-C6)alkyl for example methyl, ethyl or isopropyl, optionally substituted by amino, (Cr C6)alkanoylamino, carboxy, mono- and di(CrC6)alkylamino, hydroxy, amidino or (C1-C6)alkoxy. Preferably, Ra is ethyl substituted by (CrC6)alkanoylamino, for example Ra is acetamidoethyl. 55 Suitably, Ra is (C2-C6)alkenyl and, in particular, optionally substituted vinyl wherein the substituents are selected from those described hereinabove. Preference for substituents is given to (CrC6)alkanoylamino such as acetamido; carbamoyl groups including mono- and di(CrC6)alkylcarbamoyl, such as phenylcarbamoyl and NH2CO-; a carboxy group where the carboxy group is esterif ied with an alkyl ester such as methyl or as its 5 EP 0 617 036 A2 aralkyl ester such as 4-nitrobenzyl ester or the carboxy group is salif ied as its sodium or potassium salt. Suitably, Ra is aryl such as phenyl; aralkyl wherein the aryl moiety is phenyl and the alkyl moiety is 1 to 6 carbon atoms such as benzyl or phenethyl. In particular Ra may be optionally substituted aralkyl wherein the substituents for the (CrC6)alkyl portion is as hereinabove defined and optional substitution for the phenyl ring 5 consists of one or more of the following substituents: amino, (CrC6)alkanoylamino, monoand di(CrC6)alky- lamino, hydroxy, amidino, (CrC6)alkoxy, sulphanoyl, carbamoyl, nitro, chloro, fluoro, bromo, carboxy and salts and esters thereof.
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