IE56647B1 - Cephalosporin derivatives - Google Patents

Cephalosporin derivatives

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Publication number
IE56647B1
IE56647B1 IE455/83A IE45583A IE56647B1 IE 56647 B1 IE56647 B1 IE 56647B1 IE 455/83 A IE455/83 A IE 455/83A IE 45583 A IE45583 A IE 45583A IE 56647 B1 IE56647 B1 IE 56647B1
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IE
Ireland
Prior art keywords
methyl
compound
pharmaceutically acceptable
carboxylate
cephem
Prior art date
Application number
IE455/83A
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IE830455L (en
Original Assignee
Bristol Myers Squibb Co
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Priority claimed from US06/354,851 external-priority patent/US4406899A/en
Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co
Publication of IE830455L publication Critical patent/IE830455L/en
Publication of IE56647B1 publication Critical patent/IE56647B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
    • C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Novel cephalosporin derivatives of the formula wherein R<1> is hydrogen or a conventional amino-protecting group, and R<2> is a straight or branched alkyl group containing from 1 to 4 carbon atoms, allyl, 2- butenyl or 3-butenyl, or is a group wherein R<3> and R<4> each are independently hydrogen, methyl or ethyl, or R<3> and R<4>, taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, and nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates thereof exhibit potent antibacterial activity and can be incorporated into pharmaceutical compositions.

Description

BRISTOL-MYERS SQUIBB COMPANY, A CORPORATION ORGANISED UNDER THE LAWS OF THE STATE OF DELAWARE, UNITED STATES OF AMERICA, OF 345 PARK AVENUE, NEW YORK 10154, UNITED STATES OF AMERICA. ft wherein K1 is hydrogen or a conventional amino-protecting group, and K2 is a straight or branched alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or is a group R3—C~R4 5 I COOH 4 wherein K and K each are independently hydrogen, methyl or 4 ethyl, or κ and K , taken together with the carbon atom to which 10 tney are attached, may be a cycloalkylidene ring containing from 3 to carbon atoms, and nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates thereof. Processes for their preparation are also described. to Patent Specification No. 38172 contains a generic disclosure encompassing a vast number of cephalosporins of the formula wherein K is hydrogen or an organic group, Ka is an etherifying monovalent organic group linked to the oxygen through a carbon atom, B is S or and P is an organic group. However, the 2-aminothiazol-4-y1 group is not identified as an R substituent and there is no suggestion that P may be N-methylpyrrolidiniummethyl (or any other fully saturated nitrogen-containing ring which is attached IO to the 3-methyl moiety via its nitrogen atom and which contains an additional substituent On its nitrogen atom), U.S. Patent 5,971,778 and its divisionals Nos. 4,024,133, 4,024,137, 4,064,346 4,033,950, 4,079,178, 4,091,209, 4,092,477 and 4,093,803 have similar disclosures U.S. 4,278,793 contains a generic disclosure encompassing a vast number of cephalosporin derivatives of the formula in which the variables Up Rp Rp X and A include generic definitions of the corresponding substituents of the compounds of Formula I claimed herein. However, in the 20 columns of definitions of the various substituent groups, the 78 page long table of S structural formulae and the 225 examples, there is no disclosure that A may be N-methylpyrrolidiniuminethyl (or any other fully saturated nitrogen-containing heterocyclic ring) which is attached to the 3-methyl moiety via its nitrogen atom and which contains an additional substituent on its nitrogen atom. United Kingdom Patent Specification No. 1,604,971 is concordant thereto and has a substantially identical disclosure. Published United Kingdom Patent Application No. 2,023,3ns A, although apparently not formally related, contains the same broad generic disclosure but exemplifies A only as hydrogen.
West German ULS 2,805,655 discloses 7-[2-(2-aminothiazol-4-ylJ -2-(synjmethoxyiminoacetamidoJcephalosporin acid derivatives of the formula 2 in which R NH is an optionally protected amino group, R is halogen or an optionally substituted hydroxyl, thiol or amino group, end COOK is an optionally esterified carboxyl group. It is also 2 disclosed that, when R . is an amino group, it may be disubstituted and the suostituents, taken together with the N atom, may form inter alia a pyrrolidino group. However, there is no disclosure of an N-methyl-pyrrolidiniuinmethyl group (or of any other quaternary ammonium group) and substituent R^ cannot be connected to the 3-position via a methylene group.
U.S. Patent No. 4,278,071 discloses 7-[2-(2-aminothiazol-1-4-yl) -2-1 syn)-nicthoxyiminoacetainido]cephalosporin derivatives of the formula in which K^NH is an optionally protected amino group and R^ is hydrogen or the residue of a nucleophilic compound. The term the residue of a nucleophilic compound is broadly defined and it is then stated that R3 may alternatively be a quaternary ammonium group.
Pyridinium, variously substituted pyridinium, quinolinium, picolinium and lutidinium are disclosed as quaternary ammonium groups. There is no suggestion that the quaternary ammonium group may consist of a fully saturated nitrogen-containing heterocyclic ring system which is bound via its nitrogen atom and which contains an additional substituent on its nitrogen atom. United Kingdom Patent Specification No. 1,581,854 is concordant thereto and has a substantially identical disclosure. Other patents to the same patentee, which are not formally related but which have similar disclosures, include U.S.
Patent 4,098,888 and its divisionals U.S. Patents 4,203,899, 4,205,180 and 4,298,606, and United Kingdom Patent Specification No. 1,536,281.
U.S. Patent No. 4,168,309 discloses cephalosporin derivatives of a b wherein R is phenyl, thienyl or furyl; R and K are independently hydrogen, alkyl, cycloalkyl, phenyl, naphthyl, thienyl, furyl, a b carboxy, alkoxyearbonyl or cyano, or R and R , taken together with the carbon atom to which they are attached, form a cycloalkylidene or cycloalkenylidene ring; m and n are each 0 οτ 1 such that the sum of ra and n is 0 or 1; and R1, together with the nitrogen atom to which it is attached, is broadly defined but may not inter alia be a saturated 5-membered ring. The compound having the formula is exemplified in bxample 5 thereof. United Kingdom Patent 15 Specification No. 1,591,459 is concordant thereto and has a substantially identical disclosure. There is no suggestion in this patent that the R substituent may be the 2-aminothia2ol-4-yl moiety ur that the imino substituent not contain a carboxyl group.
This invention relates to cephalosporin derivatives of the formula wherein k^ is hydrogen or a conventional amino-protecting group, ano k^ is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or is a group F3 COOH IO 4 wherein κ and k each are independently hydrogen, methyl or 3 4 ethyl, or k and k , taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, and nontoxic pharmaceutically acceptable salts and physiologically hydrolyzable esters thereof. Also included within the scope of this invention are the solvates (including hydrates) of the compounds of Formula 1, as well as the tautomeric forms of the compounds of Formula 1, e.g. the 2-iminothiazolin-4-yl form of the 2-aminothiazol-4-yl moiety.
As shown in the structural formula, the compounds of Formula 1 have the syn or Z configuration with respect to the alkoxyimino (or alkenyloxyimino) group or the carboxy-substituted alkoxyimino group. Because the compounds are geometric isomers, some of the anti isomer may also be present. This invention comprises compounds of Formula 1 containing at least 90% of the syn*1 isomer. Preferably the compounds of Formula 1 are syn isomers which are essentially free of the corresponding anti isomers.
The pharmaceutically acceptable salts of the compounds of Formula 1 include the inorganic base salts such as the alkali metal salts (e.g. the sodium and potassium salts) and the alkaline earth metal salts (e.g. the calcium salts), ammonium salts, organic base salts (e.g. with triethylamine, procaine, phenethylbenzylamine, dibenzylethylenediamine and other organic bases which have been used in the penicillin and cephalosporin art), and the acid addition salts (e.g. the salts with hydrochloric, hydrobromic, formic, nitric, sulfuric, methanesulfonic, phosphoric, acetic or trifluoroacetic acid) lo and other acids which have been used in the penicillin and cephalosporin art. The physiologically hydrolyzable esters include the acyloxyalkyl esters, e.g. (lower)alkanoyl(lowerjalkyl esters such as, for example, acetoxymethyl, acetoxyethyl and pivaloyloxymethyl. The base salts and the esters may be formed with either of the carboxyl groups of the compounds of Formula I.
The compounds of Formula 1 in which is hydrogen exhibit high antibacterial activity against various Gram positive and Gram negative bacteria, and are useful in the treatment of bacterial infections in animals, including man. The compounds of Formula I may be formulated for parenteral use in a conventional manner utilizing known pharmaceutical carriers and excipients, and may ,be presented in unit dosage form or in multi-disage containers. The compositions may be in the form of solutions, suspensions or emulsions in oily or aqueous vehicles, and may contain conventional dispersing, suspending or stabilizing agents. The compositions may also be in the form of a dry powder for reconstitution before use, e.g. with sterile, pyrogen-free water. The compounds of Formula 1 may also be formulated as suppositories utilizing conventional suppository bases such as cocoa butter or other glycerides. The compounds of this invention may, if desired, be administered in combination with other antibiotics such as penicillins or other cephalosporins.
When provided in unit dosage forms the compositions will preferably contain from about 50 to about 1500 mg of the active ingredient of Formula 1. The dosage for adult human treatment will » preferably be in the range of from about SOU to about 5000 ing per day, depending on the frequency and route of administration. When administered intramuscularly or intravenously to an adult human, a total dosage ot from about 750 to about 3000 mg per day, in divided doses, normally will be sufficient, although higher daily doses of some of the compounds may be desirable in the case of Pseudomonas infections.
The preferred compounds of Formula 1 are those in which R^ is 3 4 hydrogen and R is methyl or ethyl or R and R each are independently hydrogen or methyl. In the most preferred compounds, 3 4 R is methyl or R and R each are methyl. In the primary evaluation of the compounds of this invention, the Minimum Inhibitory Concentrations (MIC’s) of the compounds and two reference compounds (cefotaxime and ceftazidime) were determined by the two-fold serial agar dilution method in Mueller-Hinton agar against 32 strains of test organisms in six groups. The geometric means of the MIC's determined in this test are shown in Tables 1 and 4.
(Cefotaxime; Comparison Compound) (Ceftazidime; Comparison Compounds) (Test Compounds) Jt may be seen that all of the test compounds were more active than cefotaxime against the (G-)-Il and (G-)-III groups of test organisms, with the most preferred Compound Ia being markedly more active. All of the test compounds were more active than ceftazidime against the (G+J-lu and (G+)-lb groups of test organisms, with the most preferred Compound la being markedly more active than ceftazidime against all groups of test organisms except (G-J-III, which was somewhat more susceptible to ceftazidime.
The absorption of the most preferred Compound Ia and of reference compounds (cefotaxime and ceftazidime) were determined in mice following a single intramuscular injection of the test compound (dissolved in p.XM phosphate buffer; pH 7) at a dosage of 20 mg/kg. blood samples were collected from the orbital sinuses into heparinized capillary tubes and assayed in Mueller-Hinton medium using Morganella Morganii A9b95 as the test organism. The blood levels at various time intervals, the half-life values (^/2^ an<1 t^ie areas under the curve (aUCJ are shown in Table 2.
Tests to identify organisms resistant to the preferred compound of Formula Ia, cefotaxime and ceftazidime were also conducted. The MIC's of these three compounds against 240 strains of bnterobacteriaceae were determined in Mueller-Hinton medium, and an MIC of equal to or greater than 8 for at least one of the test compounds was arbitrarily taken as indicating a resistant organism.
Uf the 240 strains, 27 were found to be resistant to at least one of the test compounds. The results, showing 3 organisms resistant to Compound la, 15 organisms resistant to ceftazidime and 18 organisms resistant to cefotaxime, are given in Table 3.
Table 1 Geometric Mean of MIC (mcg/mL) ί H H H 1 VO 7 0 CO VO co BO O OS m rd m 03 rd d Η N H Η λ 1 in 1 2 m m © os *c? h vo e ο ο ο O 0 O rd Π 03 ST 03 O HI 1 VO 1 2 ΓΊ 03 m rd (0 H —. m o mo- mo oi co m n rd Γ- οο m m ο o 0 Θ 0 0 © Θ o o o o o o .Q Hi 1 ~ m + *— 2 rd rd VO u> oj O U 0 Θ B γί ο γϊ cn os oi rd »«»· « c •d (0 <0 Η b 1 «U -* 10 o in Ο) Φ CO O rd β β o o o o rd rd d d H Ift Compound rd >, r a —. rd Ο — κΓ >» rd M d fd £ k & >,*-* oi £ 0 rd mg G) «Ρ © ’rd g *d g © -d m -d ό ο n η η x ·*« CM 03 03 03 19 © oi οέ fa cd «Ρ «y 0 «U •3 JQ U Ό © © Μ Μ Μ M C.) CJ . © 3 © b 4J © *e r·» oa G © ·-* © G •ri © © G K b © •d O © w w b © m 0 to b © rd © g ** © •ri 0 © G b © 0 © •d cc G § 0 © *G E c G 9 a © © G 0 — &» rd © 2 G ° •d rd •G © & G b . © A> r*. e« © ¢0 n r, c ta © 03 •ri G G «u © wd d b b © © © b b © w U jj 4> 0 n © © m m 0 *«* 03 W o to (0 0 9 •d I «d 1 ° : & © rd rd u b 0 0 c 9 9 υ 1 U 1 w — © © © ® 1 03 1 e. G • • , K 1 G K 1 — •d 10 CO 1 •rl G m © © 4J •d b © > b C © > G •d «Μ © b © •d © W «Ρ 4> «> •d © 03 VO © •d « to 03 •ri ** 41 (0 •d £ © rd G G n © © «r © © © © © © b © E w . b 1 •id -d 0 •d 1 I G rd G •d c b G G •ri •id •d G •d © rl •d 5 JQ -G © tr rd rd © 4J C* 9 rd rd 0 b 0 b b © wd •d rd id •d 0 © 0 u © E © E © © id •»d £ . > g Ge 1 0!e 9 •d © © © b b © Ud £ Ck U fa 1 U a 1 e. 1 Ud 0 ea •0 M G © H © Λ © fi H W © w M H M w 1 1 I 1 8 4» «X» 1 1 1 1 2 0 2 2 0 0 © σ Αί X σ © CM Φ XI E* •M £ o JJ c o Ή JJ m k «Μ •k c •c < U <0 k JJ fZ JJ < Θ) i4 *o •k £Q k 9 υ o D JC < 0 D1 υ 6 me*» ooo l*> "5? <** •-I *"J r-1 *5 6) ra r* m r· rk r*4 r«i c 0 © © tt 03 » ooo Ο H ? o © *0 0 o *9 -. k 3 5 <Μ Ό < 0 0 W rM φ a Jf a c •Η m ra ik r* CO tt CD © ΓΊ *0 tt <*> r> rk rk .-3 © 03 KO ro «er O 0 Q tt tt CD rk rk H © ο» ra m Ο Γ* H 03 CM CM Ό fi a 0 a g θ u *s rk-* υ >ixa *-* •G— . φ JJ Φ E fi M d E ·* *0 II Κ ·Η 03 Φ EM « «y (3 o -y ·«. IM IM «6 C-) Φ w u o m JJ to fi) AJ to 4«) to 0) JJ 03 n *k 0 0 6) 0 tt JJ tt Φ CO m k ω k fi) jj fi) > <3 —j fi) Λ <9 3 IJ Ί» HI Table 3 Resistance (MIC = Mi vg/ml) to One or More Test Compounds Among 240 Strains of Enterobacteriaceae in Mueller-Hinton Medium Organism No o of Strains Geometric Mean MIC (pg/ml) la Ceftazidime Cefotaxime 5 Escherichia coli Escherichia 1 «5, 0.25 32 8 coli Klebsiella 1 4 0.5 8 10 pneumoniae 1 2 IS 0.13 Enterobacter aerogenes Enterobacter 3 0u25 32 13 15 aerogenes Enterobacter 1 4 0 32 cloacae Enterobacter Ί > 0.13 Λ 8 20 cloacae Enterobacter cloacae Enterobacter 3 3 0.5 1.6 40 >63 50 >63 cloacae Eitrobacter 1 >32 >63 >63 25 freundii Eitrobacter 2 0.35 45 32 species Proteus 1 0.03 >63 32 vulgaris iorganella 1 0 :oc 8 8 30 vnorganii Serratia 1 0.06 32 32 marcescens X X X X6 Serratia marcescens X I 2 8 16 Table 3 - conto Organism NOo of Strains Geometric Mean MIC (pg/ml) la Ceftazidime Cefotaxime Serratia marcescens 2 2.8 2 11 Serratia’ marcescens X 4 8 63 Serratia marcescens 1 8 16 8 Serratia marcescens 1 32 >63 >63 Total Number of Resistant Strains 27 3 15 18 »2M (Test Compound) Table 4 Geometric Mean of MIC (mcg/mt) Compound Test Organisms Compound Ie (a) Cefotaxime fa) Ceftazidime (G+J-Ia (5 strains) 14 1.0 5.1 10 (G+J-Ib (5J 33 2.2 12 (G-J-Ia (5J 0.066 0.015 0.070 (G-J-Ib (6J 0.79 0.35 1.7 (G-J-Il 15J 1.2 4.1 2.6 (G-J-III 16J 4.0 22 1.8 lG+)-ia : Penicillin-sensitive S. aureus (5 strains) (G+J-Ib : Penicillin-resistant S. aureus (5 strains) (G-J-Ia : Ceohalothin-sensitive £. coli (2 strains). Kl. pneumoniae (1 strain) and Pr. mirabilis (2 strains) (G-J-Ib : Cephalothin-resistant E. coli (3 strains) and Kl. 20 (G-J-II pneumoniae (3 strains) : Pr. morgani (1 strain)e £nt. cloacae (2 strains) and Ser. Marcescens (2 strains) (G-J-III : Ps. aeruginosa (6 strains) (a) Mean of five experiments A It may be seen that compound Je was taore active than cefotaxime against the (0-)-33 group o£ test organises and markedly more active than cefotaxime against the (6-)^333 group of test organisms (Ps, aeruginosa?- 3t was more active than eeftaxidiae against all groups ef Grfiim-negative test organisms except (¢-)-333 (Ps. gteruginosa?„ which was somewhat more susceptible to ceftatidime.
The following forms of medication are included within the present invention:(i) Medication comprising an antibacterially effective amount of at least one compound of this invention, for use in a method of combatting bacterial infection in a warm-blooded animal. (ii) Medication comprising an antibacterially effective amount of 7-f(Z)-2-methoxyimino-2-(2-aminothiazol-4-yl) acetamido]-3-((1-methyl-1-pyrrolidinium)methyl]-3-cephem4-carboxylate or a nontoxic pharmaceutically acceptable salt or solvate thereof, for use in a method of combatting bacterial infection in a warm-blooded animal. (iii) Medication comprising an antibacterially effective amount of at least one compound of this invention, wherein R^ is as hereinbefore defined and R^ and R each are independently hydrogen, methyl or ethyl, or 3 4 R and R , taken together with the carbon atom to which they are attached may be a cycloalkylidene ring containing from 3 to 5 carbon atoms or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, for use in a method of combatting Gramnegative bacterial infection in a warm-blooded animal. (iv) Medication comprising an antibacterially effective amount of 7-(2-{2-aminothiazol-4-yl)-(2)-2-(2carboxyprop-2-oxyimino)-acetamido]-3- £( 1-methyl-1pyrrolidinium)methyl]-3-cephem-4-carboxylate or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, for use in a method of combatting Gram-negative bacterial infection in a warmblooded animal. 1/ Also, the following antibacterial compositions are included within the scope of the present invention:(a) An antibacterial composition active against Gram-negative bacteria comprising an antlbacterially effective amount of at least one compound of this invention wherein R1 is as hereinbefore defined and R3 and R4 each are independently hydrogen, methyl or ethyl, or •a 4 R and R , taken together with the carbon atom to which they are attached may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, and an inert pharmaceutical carrier. (b) The composition of (a) above wherein the compound of this invention is 7-£2-(2-aminothiazol-4-yl)15 (2)-2-( 2-carboxyprop-2-oxyimino) ace tamidoj -3- £( 1 -me thy 1 3-X(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof. (c) An antibacterial composition active against Gram-negative bacteria in unit dosage form comprising from about 50 mg to about 1500 mg of at least one compound of this invention wherein R1 is as hereinbefore 3 4 defined and R and R each are independently hydrogen, 4 methyl or ethyl, or R and R , taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, and an inert pharmaceutical carrier. {d) The composition of (c) above wherein the compound of this invention is 7-[2-(2-aminothiazol-4-yl)(Z)-2-(2-carboxyprop-2-oxyimino)acetamido]-3- [(1-me thy 1-1pyrrolidiniumjmethylj-3-cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt, physiologically hydroly35 zable ester or solvate thereof. « la another aspect,, this invention relates to processes io? the preparation oi the compounds oi Formula 1. There are two basic procedures for converting a readily available starting cephalosporin to another cephalosporin having different substituents on the 7- and 3-positions. One may first remove the 7»substituent and replace it with the desired ^substituent0 and then insert the desired 3*substitueat. AlternativelyP one may first insert the desired ^substituent and subsequently exchange the V^substituent. The compounds oi Formula 1 may be prepared by either procedure and both Iq are included within the scope oi this invention, but it is preferred to insert the desired 7°substitueat first and then insert the desired 3*substitu@nt. The preferred procedure is shown below in Reaction Scheme 1 while the alternative procedure is shown in Reaction Scbeene 2. The abbreviation Ty represents the trityl (triphenylmethyl) group, which is a preferred amino-protecting group. The abbreviation.
Ph" represents the phenyl group. Thus, the -CH(Ph)2 moiety is the benxhydryl group, which is a preferred carbonyl-protecting group.
Reaction Schemes 3 and 4 show the preparation of Compound (le) in 1 3 4 which κ is hydrogen stnd 8 and 8 are each methyl.
I Reaction Scheme 1 R21C M/ IXX XV ΤχΗΝ VI vxxx PCX5 pyridine IX \/ Nal »3C-»0 XI XII IV CONH COOCH(Ph)2 XIII deblock XS 'OR2 Mz CONH I Reaction Scheme 3 (Note - in the conversion of compound Va into compound Via represented below, iodide salts broadly may be employed even though Nal has been specifically shown).
Nal NZ COOCH(Ph), Via Tr)’ Vila Ie Reaction Scheme 4 pci5 pyridine *> IX Nal \y \z H3C-N XI Although the above Reaction Schemes show preferred multi-step procedures for the preparation of the compounds of Formula I, it will be appreciated that other starting materials and procedures may be utilized to prepare the intermediates used in the key step of each Reaction Scheme. Thus, the key step in Reaction Scheme 1 is the reaction of Compound VII with N-methylpyrrolidine. Compound VII may itself be prepared by other procedures. Similarly, the key step in Reaction Scheme 2 is the acylation of Compound XII with Compound IV. Both compounds XII and IV may be prepared by other procedures.
The key step in Reaction Scheme 5 is the reaction of Compound Via with N-methylpyrrolidine. Compound Via may itself be prepared by other procedures- Similarly, the key step in reaction Scheme 4 is the acylation of Compound XII with Compound Ilia'. Both Compounds XII and Ilia'may be prepared by other procedures.
The present invention provides a process for the preparation of compounds of the formula wherein R^ is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or is a group r3_-c—oR*1 I COOH 4 wherein R and R each are independently hydrogen, methyl or 3 4 etnyl, or R and R , taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, and nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates thereof which process comprises reacting a compound of the formula in which R2 is as defined above, B1 is a conventional 2 carboxyl-protecting group and B is a conventional amino-protecting 10 group, with N-methylpyrrolidine to produce a compound of the formula and subsequently removing all protecting groups by conventional means or which comprises reacting a compound of the formula a in which and are as defined above, B^ and B** are conventional carboxyl-protecting groups and B^ is a conventional amino-protecting group, with N-methylpyrrolidine to produce a compound of the formula XVa and subsequently removing all protecting groups by conventional means.
The reaction is carried out in a non-aqueous organic solvent such as; for example, methylene chloride, chloroform, ethyl ether, hexane ethyl acetate, tetrahydrofuran and acetonitrile or mixtures of such solvents. The reaction is conveniently carried out at a temperature of from about -10°C to +50°C; we normally prefer to conduct the reaction at room temperature. At least one mole of N-methylpyrrolidine should be used per mole of Compound XIV or XlVa; we normally prefer to utilize from about 50ϊ to ΙΟΟϊ excess of N-methylpyrrolidine.
Carboxyl-protecting groups suitable for use as B^ and B^ in the above reaction are well-known to those skilled in the art and include aralkyl groups such as benzyl, p-methoxybenzyl, p-nitrobenzyl and dipehnylmethyl (benezhydryl); alkyl groups such as t-butyl; haloalkyl groups such as 2,2,2-trichloroethyl, and other carboxyl-protecting groups described in the literature, e.g. in Patent Specification No. 38172. We prefer to utilize carboxyl-protecting groups which are readily removed by treatment with acid. Particularly preferred carboxyl-protecting groups are the benzhydryl and t-butyl moities.
Amino-protecting groups suitable for use as B2 are also well-known in the art» and include the trityl group and acyl groups such as chloroacetyl* Amino-protecting groups which are readily removed by treatment with acid, e.g. the t The present invention also provides a of compounds of the formula ltyl group, are preferred. process for the preparation wherein R is a straight or branched chain from 1 to 4 carbon atoms, allyl, 2-butenyl r3—c— I COOH wherein k5 and R4 each are independently hydrogen, methyl or ethyl, or K5 and R4, taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, and nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates thereof, which process comprises acylating a compound of the formula alkyl group containing or 3-butenyl, or is a group or an N-silyl derivative thereof, in which B^ is hydrogen or a conventional carboxy1 - protecting group, with an acylating derivative of an acid of tlie formula B HN N--r-C-COOH XVII wherein B^ is a conventional amino-protecting group and is as defined above, to produce a compound of the formula and subsequently removing all protecting groups or acylating compound XVI or an N-Silyl derivative thereof with an acylating derivative of an acid of the formula XVI la 3 wherein B is a conventional amino-protecting group, B is a 4 conventional carboxyl-protecting group and R and R each are 3 4 independently hydrogen, methyl or ethyl, or R and R , taken together with the carbon atom to which they are attached, may be a cycloalkcnylidene ring containing from 3 to 5 carbon atoms, to produce a compound of the formula XVa and subsequently removing all protecting groups.
The acylating derivatives of the acid of Formula XVII or XVIIa include the acid halides (and particularly the acid chloride), mixed acid anhydrides (such as the acid anhydrides formed with pivalic aciB or a haloformate such as ethyl chloroformate), and activated esters (such as may be formed with N-hydroxybenztriazole in the presence of a condensing agent such as dicyclohexylcarbodiimide). The acylation may also be effected by use of the free acid of Formula XVII or XVIIa in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or an isoxazolium salt. As used herein, the term acylating derivative of the acid of Formula XVII or XVIIa includes tne free acid itself in the presence of a condensing agent such as described above. The preferred acylating derivative of the acid of Formula XVII or XVIIa is the acid chloride, preferably used in the presence ot an acid Binding agent (and particularly a tertiary amine acid binding agent such as triethylamine, dimethylani1ine or pyridine).
When the acylation is conducted with an acid halide it is possible to utilize an aqueous reaction medium, but a non-aqueous medium is preferred. When acid anhydrides, activated esters, or the free acid in the presence of a condensing agent, are used for the acylation, the reaction medium should be non-aqueous. Particularly preferred solvents for the acylation reaction are halogenated hydrocarbons such as methylene chloride and chloroform, but tertiary amides such as dimethylacetamide or dimethylformamide may be utilized, as well as other conventional solvents such as , for example, tetrahydrofuran and acetonitrile.
The acylation reaction may be conducted at a temperature of front about -50°C to+50°C. However, it is preferably conducted at or below room temperature and most preferably from about -30°C to 0°C. It is usually preferred to acylate the compound of Formula XVI with about a stoichiometric amount of the acylating agent of Formula XVII or XVIIa, although a small excess (e.g. 5-25Ϊ) of the acylating agent may be utilized.
It is preferable that the compound of Formula XVI by acylated in the form of its N-silyl derivative (when utilizing a non-aqueous reaction medium)· This is conveniently done in situ by simply adding a suitable silylating agent (e.g.N,O-bistrimethylsilylacetamide) to the solution of compound XVI prior to the addition of the acylating agent of Formula XVII or XVIIa. We prefer to utilize about 3 moles of silylating agent per mole of Compound XVI although this is not critical. The silyl compound is readily removed after acylation by the addition of water.
The acylating acids of Formula XVII or XVIIa including carboxyland amino protected derivatives thereof, are known in the art or may be prepared by known procedures. This, (Z)-2-(2-t-butoxycarbonylprop-2 -oxyimino)-2-(2-tritylamino-thiazol-4-yl)acetic acid (Ilia) was prepared by the general procedure described in U.S. Patent 4,258,041 and Patent Specification No. 49172. The melting point reported therein was 152-156°C (decomp.) but, in our hands this compound melted at 174-175°C decomp.) Preparation No. 1 XX? TrHN υκ Ethyl (Z)-2-Methoxyimino-2-(2-tritylaminothiazol-4-yl)acetate (11 la) A mixture of ethyl (Z)-2-hydroxyimino-2-(2-tritylamino-thiazol4-yl) acetate (IIJ (5.UU g, 10.9 mmoles), CH^I (2.04 mL, 32.8 mmoles) and K^CO^ (4.54 g, 32.8 mmoles) in dry dimethyl-sulfoxide (DM50) (100 mL) was stirred at room temperature overnight and then poured into water (250 mL). The precipitate which formed was collected by filtration, washed with water and dried to give the title compound (5.15 g, quantitative yield). Mp, 115*>C (dec.) NMR : fiCDCl5 ppm 1.32 (3H. t), 3.98 (3H, s), 4.30 (2H, q)t 6.42 (IH, s), 7.2 (IH, m) , 7.25 (15H, s).
Compounds Illb, IIIc and Illd were prepared by the general procedure set forth above, but replacing the methyl iodide with the appropriate iodide.
Literature Compound Yield (t) Mp (°C) Mp (°C) Ilia methyl 100 115° (dec.) ca. 120° (dec.) Illb ethyl 67 97-98° Pl IIIc i sopropyl 26 51-55° 15 Hid allyl ft w R The ester was hydrolyzed without isolation (1hetrahedrom, 34, 2233 (1978) Preparation No. 2 IV (2)-2-Methoxyimino-2-(2-tritylaminothiazol-4-ylJacetic acid (IVa) .35 The ethyl ester Ilia prepared in Preparation No. 1 (6.00 g, 12.7 mmoles) in ethanol (120 mL) was treated with 2N NaUH (12.7 mL) at room temperature overnight. The reaction mixture was adjusted to pH 8 by the addition of powdered dry ice and the solvent was evaporated under reduced pressure. The residue was dissolved in water (100 mL) and the solution was acidified with IN HCl to pH 2 and then extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with a saturated aqueous NaCl solution, dried and evaporated. The residue was crystallized from ethyl acetate-hexane to afford 5.56 g (yield 98s) of the title product. Mp. 138-143°C (dec.). ΛΜΚ : δCUC13 ppm 3.89 (3H, s), 6.52 (IH, s), 7.2 (15H, sJ.
Compounds IVb, IVc and IVd were prepared by the general procedure set forth above.
Literature Compound R2 Yield (»J Mp (°C,dec.) Mp (°C dec. 15 IVa methyl 98 138-143 ca. 140 IVb ethyl 85 140-145 not reported IVc isopropyl 85 166-169 ca. 170 Hid allyl 66 170-178 ca. 170 (1J Tetrahedron), 34, 2233 (1978J Preparation No. 3 Benzhydryl 3-Hydroxymethyl-7-phenylacetamido-3-cephem-4-carboxylate (VI11 J To a stirred suspension of phosphate buffer (pH 7, 162.5 mb) and wheat bran (20 g, dry) at room temperature was added 7-phenylacetamidocephalosporanic acid sodium salt (5 gm, 12.1 mmoles) in one portion. The progress of the reaction was monitored by HPLC until the hydrolysis was complete (5 hours). The suspension was filtered to remove the wheat bran and the filtrate was cooled to 5-10°C for extractive esterification. To the cooled solution was added methylene chloride (32 mL) followed by a O.SM solution of diphenyldiazomethane in methylene chloride (24 mL). The pH was then adjusted to 3.0 with 28% phosphoric acid. After 1 hour the reaction mixture was allowed to rise to 20°C. Heptane (56 mL) was slowly auded and the resulting crystalline title product was recovered by filtration. Yield of the title product was 3.0 gm (50%).
Preparation No. 4 Benzhydryl 7-Amino-5-chloromethyl-5-cephem-4-carboxylate (V) To a slurry of PCI,. (8.3 g, 40 mmoles) in CH^Cl^ (100 mL) was added pyridine (3.2 g, 40 mmoles) and the mixture was stirred for 20 minutes at 20°C. To the mixture was added benzhydryl 3-hydroxymethyl-7-phenylacetamido-3-cephem-4-carboxylate prepared in Preparation No. 3 (5.1 g, 10 mmoles) with stirring at -40eC, in one portion. The mixture was stirred at -10°C for 15 minutes and allowed to stand at -10°C to -15°C for 7 hours. To the cooled solution (-20*0 was added propane-1,3-diol (10 mL) and the mixture was allowed to stand at -20°C for 16 hours and then at room temperature for 20 minutes with stirring. The resulting solution was washed with ice-water (2 x 20 mL) and saturated aqueous NaCl (10 mL), dried over MgSU4 and concentrated in vacuo. The gummy residue (12 g) was dissolved in a mixture of CHCl^ and n-hexane (2:1), and subjected to chromatography using a silica gel column (200 g) and the same solvent as eluant. Fractions containing the title compound were evaporated in vacuo and the residue triturated with n-hexane to give the title product (2.1 g, 51%), melting at >110°C (dec.).
IK : vKBr 3400, 2800, 1785, 1725 cm'1.
UV : λttUH 265 nm (E1* 1601. max 1cm NMR : Λ DMSU-d6 + COClj J69 (2H> sJ> 4.4J (2Hi St09 (1Η> d>Pl>m J = 4.5HzJ, 5.24 (IH, d, J = 4.5Hzl, 6.87 (IH, si, 7.3 (10, ml.
Example 1 7-(( 2)-2-Methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(l-methyi-1pyrrolidiniuinjmethyl)-3-cephem-4-carboxylate (la) A. Benz hyd ryl 3-Chloroniethyl-7 - [ ( 2)-2-methoxyiniino-2-(2-tritylaminothiazol-4-yljacetamidol-3-cephem-4-carboxylate (Via') Benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate prepared in Preparation No. 4 (2.29 g, 5.52 mmoles) in CH^CN (57 mL) was treated with bis(trimethylsilyl)acetamide (BSA, 4.09 mL, 16.6 mmoles) at room temperature for 50 minutes to give a clear solution.
To the solution was added an acid chloride solution, which was prepared from (Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IVa) (2.04 g, 4.60 mmoles) and PC1& (1.15 g, 5.52 mmoles) in methylene chloride (20 mL). The mixture was stirred at room temperature for 30 minutes, poured into cold water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with aqueous NaCl, dried and evaporated. The residual syrup (4 g) was chromatographed on a silica gel (150 g) column by eluting with 10:1 and 3:1 mixtures of toluene and ethyl acetate successively. The fractions containing the desired compound were combined and evaporated to afford 2.61 g (68¾) of Via' as an amorphous powder.
I NMK : 6CDC13 3.50 (2H, s), 4.02 (3H, S), 4.33 (2H, s). 4.98 (IH, d), 5.87 UH, q)> 6.65 UH. s), 6.90 11H, s), 7.3 (25H, mJ.
B. Benzhydryl 3-lodomethyl-7-[(2)-2-methoxyimino-2-(2-tritylamino5 thiazol-4-yljacetamido]-3-cephem-4-carboxylate (Vila*) A mixture of the 3-chloroinethyl derivative (Via') (1-50 g, 1.79 mmoles) and Nal (1.34 g, 8.93 mmoles) in methyl ethyl ketone (30 mL) was stirred at room temperature for 1 hour. After evaporation of the solvent the residue was dissolved in ethyl acetate (100 mL) and washed with water, aqueous Ν&2$2θ3 an(^ aQueous NaCl, dried and evaporated to give the title compound Vila* (1.47 g, 89%) as an amorphous powder.
NMR : δ Cl)C13 ppm 3.55 (2H, ABq), 4.00 (3H, s), 4.25 (2H, s). 4.97 (IH, d), 5.80 UH, q), 6.65 (IH, s), 6.90 (IH, s), 7.3 (25H, m).
C. 7-((2)-2-Methoxyimi no-2-(2-aininothiazol-4-y 1 j acetamido] - 3-[timet ny 1- 1-pyrrolidiniumJmethyl)-3-cephem-4-carboxylate (la) A mixture of Vila* (4.5 g, 4.83 mmoles) and N-methylpyrrolidinc (0.65 mL, 6.28 mmoles) in Ci^Cl? (45 mL) was stirred at room temperature for 20 minutes. Ether (300 mL) was added to the mixture to separate the quaternary salt of the blocked cephalosporin, which was collected by filtration and treated with 90% trifluoroacetic acid (TEA) (40 mL) at room temperature for 1 hour. The mixture was then evaporated under reduced pressure below 20°C. The residue was triturated with ether to give the TFA salt of Ia (2.40 g), which was dissolved in methanol (5 mL) and treated with IM solution of sodium-2ethylhexoate (SEH) in ethyl acetate (8 mL) at room temperature for 30 minutes. After the addition of ethyl acetate (100 mL), the precipitate (1.94 g) formed was collected by filtration. HPLC analysis showed that the Crude product was 7% pure with a 1:8 ratio cf 3 2 the Δ isomer to the δ isomer· Purification of the product by HPLC was repeated three times (Lichrosorb RP-18, 8 x 300mm, eluted with 5% aqueous or 0.01M ammonium phosphate buffer (pH 7.2) containing 5% CH^OH to give 35 mg (1.5%) of the title product as a colorless powder. Estimated purity (by HPLC) 90%. Mp. 150°C (dec.).
IK : vKBr cm'1 1770, 1660, 1620. max UV .^phosphate buffer, pH 7 nm(c , 1 235 (16200), 258 (15400). max NMR :«U2U ppm 2.31 (4H, m), 3.08 (3H, s), 3.63 (4H, m), 4.09 (3H, s), 5.43 (IH, d, J » 4.8 Hz) , 5.93 (IH, d), 7.08 (IH, s).
Example 2 7-((ZJ-2-Methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(1-methyl1-pyrrolidiniuinjinethyl J-5-cephem-4-carboxylate (Ia) To a stirred solution of 20.4 g (21.9 mmoles) of Vila' in 150 mL of dry methylene chloride was added 2.42 g (28.5 mmoles) of 1-methylpyrrolidine in one portion at room temperature. The mixture was stirred for 5 minutes and poured into 1000 mL of ether with vigorous stirring to form a precipitate, which was filtered, washed with ether (5 x 30 mL) and dried in vacuo to give 19.3 g of the blocked product as a pale yellow powder.
IK : vKBr cm'1 3400, 1780 (s), 1740, 1675, 1530. max TLC : solvent ethanol-CHCl^ (1:3), Rf=0.30 (Rf=0.95 for Vila'). 4ϋ The solid was dissolved in 185 mt of trifluroacetic acid-water (99:1), stirred for 1 hour at room temperature and concentrated to ca. 30 mL below 10°C. The concentrate was poured into 1000 mt of ether with vigorous stirring to form a precipitate, which was filtered, washed with ether (5 x 40 mt) and dried under vacuum to yield 10.6 g of pale yellow powder. The powder was dissolved in 20 mt of methanol and the solution was filtered. To the filtrate was added 45 mL of 0.8M SEH in ethyl acetate. The resultant suspension was poured to 400 mt of ethyl acetate and filtered to give 8.08 g of a solid which was a mixture of the title compound and the corresponding Δ3 isomer (Δ3/δ^ = 1:8) as shown by HPLC analysis (tichrosorb KP-18, 10-15% methanol in 0.01M phosphate buffer, pH 7). A second run from 28.9 g (31.0 minoles) of Vila* gave 16.0 g of the crude product (Δ 3/δ = 1:8). Isolation of the desired Δ3 isomer from the combined crude product (24.08 g) by using preparative HPLC (System 500, (waters Associates, PrepPAK SOO/C^g, 5-10% CH^OH) afforded 769 mg of Compound la.
Example 3 7-|(2)-2-Methoxyimino-2-(2-(2-aminothiazol-4-yljacetamidoj-3-[time thyl- 1-pyrrolidini uinjme thyl ] -3- cephem-4- car boxy late (la) A series of experiments were conducted to determine the effect or solvent, amount of solvent and reaction time on the yield of Compound 3 2 la and the δ /δ ratio in tne reaction product. The general procedure was as follows: To a suspension of the 3-iodomethyl derivative Vila' (45 mg, 0.048 mmole) in the indicated amount of the indicated solvent was added a solution of N-methylpyrrolidine (0.01 int, 0.097 mmole) in ether (0.1 mL) and the mixture was stirred at room temperature for the indicated period. The reaction mixture was diluted with ether (5 inL) and the resulting precipitate was collected by filtration and mixed with 90Ϊ TFA. The mixture was stirred for one hour and evaporated to dryness under reduced pressure below 20°C to give the product. The ratio of δ \δ in the product was determined by HPLC (Lichrosorb RP-18; mobile phase, 0.01 M ammonium phosphate buffer (pH 7.2) 2 containing 15% CH^OH;,retention time, Δ 6.60 minutes, 5.56 3 2 minutes). Yield of the product and the ratio of Δ /Δ isomers for each experiment are given below.
Ratio of Vila* ( in gms.) Experiment No Solvent to Solvent (in mL) Reaction Time (Min.) Yield (*) Rar io Δ J4 2 1 Cri2cl2 1:20 15 73 1/8 15 2 CH2C12-Ether 11 /10 J 1:100 15 25 4/1 3 tthyl acetate Ether (1/10) 1:100 15 27 4/1 4 Ethyl acetate-Ether (1/10) 1:100 60 64 2/1 5 Ether 1:100 15 31 6/1 6 Ether 1:100 60 62 3/1 20 7 Ether 1:60 15 55 3.5/1 8 Ether 1:60 60 82 1/1 Example 4 - [ ( 2 J - 2-Ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]- 3-K1-methyl-1pyrrolidiniumjmethyl]-3-cephem-4-carboxylate (lb) A. Benzhydryl 3-Chloromethyl-7-[(ZJ-2-ethoxyimino-2-(2-tritylaminothiazul-4-yl) acetamido]-3-cephem-4-carboxylate (VIb) To a solution of (Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl1 acetic acid (IVb) (1.095 g* 2.4 mmoles) in dichloromcthane (20 mL) was added phosphorus pentachloride (500 mg). After stirring for 1 hour at room temperature, the mixture was added in one portion to an ice-cooled solution of Compound V (1.083 g, 2.4 mmoles) and BSA (1 mL) in dichloromethane (20 mL). After stirring for 0.5 hour the reaction mixture was poured into 10% aqueous NaHCO^ (200 mL) and extracted with CHCl^ (100 mL). The extract was washed with water, dried over MgSO^, and evaporated under reduced pressure.
The residue was chromatographed on a silica gel column. Elution with CHCl^ gave VIb as an amorphous powder, 1.76 g (86%).
NMR : δ CUC13 ppm 1.40 (3H, t, CH^Hj), 3.53 (2H, ABq, 2-CHp, 4.37 (2H, 5, -CH2C1), 4.60 (2H, q, -CH2CH3), 4.90 (IH, d, 6-H), 5.89 (IH, d, 7-H), 6.88 (IH, s), thiazole-H), 6.91 (IH, s, benzhydrylCH.) B. Uiphenylmethyl 7-[(2)-2-Ethoxyimino-2-(2-tritylaminothiazo1-4-ylJ acetamido]-3-iodomethyl-3-cepftem-4-carboxylate (VIlb) A mixture of VIb (1.07 g, 1.25 mmoles) and Nal (562 mg, 2.75 20 mmoles) in acetone (20 mL) was stirred for 1 hour. The mixture was filtered and the filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous water and saturated aqueous NaCl, dried over MgSU^ and evaporated to give 1.04 g (89%) of Compound Vllb.
NMR : δ CDC13 ppm 3.55 (2H, q, 2-CH2), 4.27 (2H, s, CH,-I), .02 (IH, d, 6-H), 5.87 (IH, d, 7-H), 6.68 (IH, s, thiazole ring H), 6.93 (IH, s, benzhydryl-CH).
A C. 7-[(Z)-2-Ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(lmethyl-1-pyrrolidiniumJmethyl]-3-cephem-4-carboxylate (I b J A mixture Vllb (333 mg, 0.35 mmole) and N-mcthylpyrrolidine (60 mg, 0.7 mmole in CII^Cl^ (5 mL) was stirred for 0.5 hour at room temperature and then evaporated in vacuo. The residue was washed with ether and dissolved in y0% aqueous TFA. After standing for 0.5 hour at room temperature the mixture was concentrated under reduced pressure. Ether was added to the concentrate to separate the quaternized product, which was collected by filtration and dissolved lo in a small amount of methanol. The solution was chromatographed on an HP-2- column (40 mL). Elution with 30% aqueous CH-OH followed by ^2 3 lyophilization afforded 0.062 g of a mixture of theΔ and Δ isomer (δ^:δ^ » 5:1). The mixture was purified by HPLC (Lichrosorb KP-18, 8 x 300 mm, 15% methanol) and the desired δ^ isomer (lb) was isolated as pale yellow powder, 4.9 mg (2.7%).
UV . λphosphate buffer, Ph 7 nm(c} 235 (1S000), 258 (14000). max NMK δ°2U ppm 1.43 (3H, t), 2.33 (4H, m) , 3.10 (3H, s, 3.64 (4H, m), 4.36 (2H, q). 5.44 (IH, d), 5.95 (IH, d), 7.08 (IH, s).
Example 5 7-((2)-2-(2-PropoxyiminoJ -2-(2-aminothiazol-4-y1)acetamido]-5-[time thy 1 -1 -pyrrol id inium Jmethyl ] -3-cephem-4-carboxylate (Ic) A. Diphenylmethyl 3-Chloromethyl-7-[(Z)-2-(2-propoxyimino J - 2-(2tritylaminothiazol-4-yljacetamido)-3-cephem-4-carboxylate (Vic) A mixture of (2)-2-(2-propoxyimino)-2-(2-tritylamino-thiazol-4-yl) acetic acid (IVc) (707) mg, 1.5 mmoles) and phosphorus pentachloridc (344 mg, 1.65 mmoles) in dichlorornethane (14 mL) was stirred at room temperature for 1 hour and poured into a solution of Compound V (677 mg, 1.5 mmoles) and BSA (1.1 mt, 4.5 mmoles) in dichlorornethane (15 mL). The reaction mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate (200 mL), and water (3 x 100 mL), dried over sodium sulfate and evaporated to give 1.4 g (100%) of Compound Vic.
IK KBr -1 : v cm max 3360, 3020, 3060, 2960, 1785, 1725, 1500, 1450, 1375, 1300, 1250, 1160, 1010, 990, 840, 740, 700. 1680, 1090, 1520, 1060, UV : xEtUHn.n(c) max 240 (24600), 260 (20700). NMR CUC1, ηΛιη : δ 3 ppm 1.35 (6H, d, J=6Hz), 3.50 (2H, s), 4.35 2H, s), 4.58 (IH, m, J=6Hz), 5.00 (IH, d, J=4.5Hz), 5.91 (IH, d-d, J=4.5 8 9Hz; d by U,U, J«4.5riz), 6.68 (IH, s), 6.88 (IH, s), 7.25 (25H, s). B. Diphenylmethyl 3-Iodomethyl-7- [(2)-2-(2-propoxyimino)-2-(2 tritylaminothiazol-4 -y1acetamido]-3-cephem-4-carboxylate (VIIc) A mixture of Compound Vic (500 mg, 0.55 mmole) and sodium iodide (248 mg, 1.66 mmoles) in acetone (10 mL) was stirred at room temperature for 50 minutes. After evaporation, the residue was dissolved in ethyl acetate (15 mL), washed successively with 10% aqueous sodium thiosulfate (10 mL), water (10 mL) and aqueous NaCl (10 mL), dried over sodium sulfate and evaporated to yield 494 ing (90%) of the title compound (Vile).
IK vKBrcm max 3360, 3040. 3020, 2960, 1785, 1720, 1680, 1600, 1520, 1500, 1450, 1370, 1500, 1230, 1150, 1115, 1080, 990, 900, 840, 750, 700.
UV btUH nm(c) 240 (24900), 260 (19400). max NMR : sCUC13 ppm 1.30 (6H, d, J=6Hz), 3.37 $ 3.70 (IH each, d, J=16Hz), 4.22 (2H, s), 4.55 (IH, m, J-6Hz), 4.95 (IH, d, J=4.5Hz), 5.83 (IH, d-d, J-4.5 $ 9Hz; d by U2O), 6.66 (lH, s), 6.87 (IH, si, 7.25 (25H, s).
C. 7-((1)-2-(2-Propoxyimino)- 2-(2-aminothiazol-4-yl)acetamido] - 3((1-methy 1-1-pyrrolidinium)methylJ-3-cephem-4-carboxylate (Ic) A mixture of the Compound Vile (545 mg, 0.55 mmole) and 1-methylpyrrolidine (70 mg, 0,82 mmole) in dichloromethane (10 mL) was stirred at room temperature for 30 minutes and diluted with ether (100 mL). The resulting precipitate was collected by filtration. A solution of the precipitate in 90% TFA (4.5 mL) was stirred at room temperature for 30 minutes and evaporated in vacuo. The residue was triturated with ether to give 317 mg of the crude product, which was chromatographed on an HP-20 column (50 mL), eluted with water (500 mL) and 30% C1LOH (500 mL). The 30% CH,OH eluate was concentrated and 2 3 lyophilized to yield 109 mg ot a mixture of the Δ and Δ isomers (δ2/δ3 = 6/1), 100 mg of which was purified by HPLC (Lichrosorb KP-18, 15% MeOH) to give 5 mg (3%) of the desired title Compound Ic.
UV : xpH 7 buffer nm(c) 236 (15100), 252 (14600). max NMR : ί°2υρριη 1.42 (6H, d, J=6Hz), 2-33 (4H, s), 3.10 (5H, s), 3.65 (4H, s), 3.83 6 4.23 (IH each, d, J=17llz), 5.45 (IH, d, J-4.5Hz), 5.95 (IH, d, J=4.5Hz), 7.05 (IH, s).
Example 6 7-1(2 J-2-Allyloxyimino-2-(2-aminothiazol-4-yl)acctamido]-3-[(1-methyl l-pyrrolidiniumjmethyl]-3-cephem-4-carboxylate (IdJ A. Benzhydryl 7-[(2j-2-Allyloxyimino-2-(2-tritylaminothiazol«4-ylJ acetamido1-5-chioromethy1-S-cephem^A-carboxylate (Vid) To a suspension of Compound V (1.35 g, 3 mmoles) in methylene chloride (20 mt) was added BSA (l.l mL, 4.5 mmoles), and the mixture was stirred for 30 minutes at room temperature to become a clear solution. A mixture of lZ)-2-allyloxyimino-2-(2-tritylaminothiazol4-yl)acetic acid (IVd) (1.40 g, 3.0 mmoles) and phosphorus pentachloride (690 mg, 3.3 inmoles) in methylene chloride (20 mb) was stirred for 15 minutes at room temperature and poured in one portion into the solution of the triinethylsilylated Compound V. The mixture was stirred for 20 minutes at room temperature and diluted with ethyl acetate (200 mL), washed with aqueous sodium bicarbonate and water, dried and evaporated under reduced pressure. The oily residue was purified oy silica gel column chromatography (Wako-gel, C-200, 30 g). The column was eluted with chloroform and the fractions containing the desired product were combined. Evaporation under reduced pressure afforded the title compound (Vid) as an amorphous powder, yield 2.52 g (89t). Mp. 100-115°C (dec.).
Ik : vKBron'1 3990, 1790, 1730, 1680, 1530, 1380, 1250, max 1160, 1020.
NMR : aCUC13 ppm 3.50 (2H, 2-HJ, 4.32 (2H, s. 3-CH2J, 4.66.1 (7H, m, CH2CH=CH2 and 6,7-H}, 6.70 (IH, s, thiazole-H}, 6.90 (IH, s, Ph2CH), 7.1-7.6 (3UH, m, phenyl protons)· Λ Anal. Calc'd. for C48H4oNsO5S2Cl. 1/3CHC13: C, 64.05; H, 4.45; N, 7.75; S, 7.08; Cl, 7.82.
Found: C, 64.15, 65.99; H, 4.61, 4.64; N, 7.50, 7.30; S, 6.85, 6.85; A Cl, 7.55, 7.46 B. Benzhydryl 7-[(X)-2-Allyloxyimino-2-(tritylaminothiazol)-4-ylJ 10 acetami do]-3-iodomethyl-3-cephem-4-carboxylate (VIId) A mixture of Compound Vid (2.50 g, 2.65 mmoles) and sodium iodide (2 g, 15.5 mmoles) in acetone (15 mL) was stirred for 1 hour at room temperature and then evaporated under reduced pressure. A solution of the oily residue in ethyl acetate (200 mL) was washed with 10% sodium thiosulfate and water, evaporated under reduced pressure to afford Compound V11d as an amorphous powder, which was used in the next step without further purification. Yield 2.52 g (99%).
C. 7-((2j-2-Allyloxyimino-2-(2-aniinothiazol-4-yl)acetamido]-5-[(lmethyl-1-pyrrolidiniumjmethy1]-3-cephem-4-carboxylate (Id) 2o A mixture of Compound Vlld (478 mg, 0.5 mmole) and N-methylpyrrolidine (0.05 mL, 0.5 mmole) in methylene chloride (5 mL) was stirred for 20 minutes at room temperature and diluted with ether (50 mL) to precipitate the quaternized product (yield 500 mg). A mixture of the quaternized product and TFA (2 mL) was allowed to stand at room temperature for 1.5 hours and diluted with ether to precipitate the crude TFa salt of the product (yield 265 mg), which was chromatographed on a column of HP-20 (1.8 x 18 cm). The column was eluted with water and 30% aqueous methanol. The methanolic eluate was evaporated under reduced pressure and the residue was freeze-dried to give an amorphous powder (yield 124 ing), which contained the desired product (17%) and the corresponding δ 2 isomer (83%). The mixture was purified by HPLC (Lichrosorb KP-18; 0.01M NH^H^PO^ (pH 7) :CH~OH = 85: IS). The eluate was acidified to pH 3 with dilute HCl and chromatographed on a column of HP-20 (1.8 x 10 cm). The column was eluted with water and then with 30% aqueous methanol. The methanolic eluate was evaporated under reduced pressure and the residue was freeze-dried to afford the title compound (Id) as an amorphous powder (yield 13 mg, 5-1%). Mp. 155°C (dec).
IK : KBr V max cm'1 3600-2800, 1770, 1670, 1610, 1530, 1200. 10 UV : pH 7 λ max buffer nm(e ) 235 (16600), 253 (15600). NMK δ 1)20 ppm 2. 1-2.5 (4H, m, pyrrolidine-H), 3-10 (3H, s, + NCH^J, 3.4-3.8 (4H, m, pyrrolidine-H), 5.95 (IH, d, 4Hz, "-H), 7.10 (IH, s, thiazole-HJ.
Example 7 7-(2-(2-Aminothiazol-4-y1)-(2)-2-(2-carboxyprop-2-oxyimino)-acetamido] -3-((1-methyl-1-pyrrolidiniumJmethyl]-3-cephem-4-carboxylate (Ie) A. Benzhydryl 5-Chloromethyl-7-[(2)-2-(2-t»butoxycarbonylprop-2oxyimino-2-(2-tritylaminothiazol-4-yljacetamido)-3-eephem-4-carboxylate (Va) Procedure 1 Λ mixture of (2)-2-(2-t-butoxycarbonylprop-2-oxyimino)-2-(2tritylaminothiuzol-4-yl)acetic acid (Illa'J (1,94 g, 3.6 nunoles) UDC (742 mg, 3.6 mmoles) and N-hydroxybenztriazole (486 mg, 3.6 mmoles) in tetrahydrofuran (THF) (45 mL) was stirred at room temperature for 45 minutes, during which dicyclohexylurea separated. The dicyclohexylurea was removed by filtration and the filtrate was mixed with V (1.5 g, 3.6 mmoles). The mixture was stirred overnight at room temperature and then evaporated in vacuo. The residual oil was dissolved in CHCl^ (20 mL), washed with saturated aqueous NaHCO^ and saturated aqueous NaCl, dried over MgSO^ and evaporated to dryness. The residue (3.9 g) was dissolved in n-hexane:CHClj (1:2) and passed through a silica gel column (40 g) using the same solvent system. Fractions containing the title compound were evaporated in vacuo to give 1.3 g (39%) of Va melting at >100°C (dec.).
IR : vKBr cm'1 3990, 1790, 1715, 1690. max UV : xEt0H nm 240 IE1* 280), 265 (E1* 190). max 1 cm 1 cm NMR iCbC13 ppm 1.45 (9H, s), 1.63 5 1.66 (6H, each s), 5.49 (2H, broad s), 4.34 (2H, s), 4.96 (IH, d, J=4.5Hz), 5.90 (lri, d-d, J=4.5 8 7.5), 6.66 (IH, s), 6.86 (IH, s), 7.0-7,5 (25H, m), 8.23 (IH, d, J-7.5HZ).
Procedure 2 A solution of V (1.86 g, 4.49 mmoles) in CH-CN (46.5 mL) was 25 treated with BSA (3.33 mL, 13.5 mmoles) at room temperature for 5ϋ minutes to give a clear solution. To the solution was added an acid A chloride solution which had been prepared from Ilia' (2.56 g, 4.49 mmoles) and PCl^ (1.12 g, 5.38 mmoles) in methylene chloride (26 mL). The mixture was stirred at room temperature for 30 minutes, poured into cold water (100 mL) and extracted with ethyl acetate (3 x 50 mt). The combined extracts were washed with aqueous NaCl, dried and evaporated. The residual syrup (5 g) was chromatographed on a silica gel (100 g) column by eluting with 10:1 mixture of toluene and ethyl acetate- The fractions containing the desired compound were combined and evaporated to afford 2.84 g (65¾) of Va. tt. Benzhydryl 7-[(2)-2-(2-t-Butoxycarbonylprop-l-oxyimino)-2(2-tritylaminothiazol-4-yljacetamidol-3-iodomethyl-3-cephem-4carboxylate (Via) A mixture of Va (500 mg, 0.53 mmole) and Nal (240 mg, 1.6 mmoles) in acetone (3 mL) was stirred for 2 hours at room temperature and then evaporated in vacuo. To the residue were added CH^Cl^ (20 mL) and water (10 mL). The organic layer was washed with 10% s/v sodium thiosulfate (5 mL) and aqueous NaCl (5 mL), dried over MgSO^ and evaporated to dryness to give 540 ing (90%) of Via as an amorphous powder melting at 106°C (dec.).
, KBr _ -1 3350, 1790, 1690. in . cm max UV : *EtUH nm 240 (E1* 2701 , 265 (E1* 19QJmax 1 cm 1 cm NMR : sCUC13 ppm 1.44 (9H, si, 1.65 (6H, s), 5.54 (IH, 4.28 (2H, si, 4.98 (IH, d, J=4.5Hzl, 5.85 (IH, d-d, J=4.5 8 7.5Hzl, 6.70 (IH, si, 6.90 (IH, si, 7.1-7.5 125H, m).
A C. 7-(2-(2-Aminothiazol-4-ylJ£ J-2-(2-carboxyprop-2-oxyimino)acetamido J - 3 - ( (1-methy 1-1-pyrrol idiniumjmethy 1 ] -3-cephem-4carboxylatc (le) A mixture of the iodomethyl derivative Via (538 mg, 0.51 mmole) and N-methylpyrrolidine (0.079 mL, 0.076 mmole) in CH^C^ (10.8 mL) was allowed to stand at room temperature for 30 minutes and then diluted with ether (80 mL). The precipitate which formed was collected by filtration and washed with ether to give 420 mg of the quatemized product (Ih) which was deblocked with 90?. trifluoroacetic acid (TFA) (4.2 mL) at room temperature for 1 hour. The reaction mixture was then evaporated to dryness. To the residue was added either to give crude TFA salt of la (245 mg, quantitative), which *as a 1:4 mixture of the and isomers. The crude was subjected to HPLC purification (Lichrosorb RP-18, 4 x 300 mm, eluted with 0,01 M ammonium phosphate buffer (pH 7.0) containing 10% CH^UH]. The fraction containing the desired product was collected and evaporated to a small volume. The concentrate was adjusted to pH ca. 2 by adding 1 M HC1 and passed through an HP-20 column (2 x 15 cm) to remove the inorganic salt. The column was washed with H^O (1000 mL) and eluted with 30% CH^UH. The eluant was evaporated and lyophilized to afford 21 mg (10%) of the title product (Ie) as a colorless powder. Mp. 160°C (dec.).
IK : KBr V max cm* 1 3400, 1775, 1610. UV : phosphate λ max buffer, pH 7 ηπ)(ε j 237 (15701)), 257 (155500) NMR : 5D2° ppm 1.05 (6H, sJ, 2.3 (4H, mJ, 3.09 (3H, s), 3.6 (4H, mJ, 4.0 (2H, mJ, 5.44 (IH, d, J-4.8HzJ, 5.94 (IH, dj, 7.15 (IH, sj.
Example 8 The general procedure of Example 7 is followed except that the (Z)-2-(2-t-butoxycarbonylprop-2-oxyimino)-2-(2-tritylaminothiazol-4-yl) acetic acid is replaced by an equimolar amount of 5 (Z)- 2-(t-butoxycarbonylmethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid, ί (Z)- 2-(1-1-butoxycarbonylethoxyimino)-2-(2-tritylaminothiazol-4-yl) acetic acid, (ZJ-2-(2-t-butoxycarbonylbut-2-oxyimino)-2-(2-tritylaminothiazol-4-yl1O acetic acid, (2)-2-(3-1-butoxycarbonylpent-3-oxyimino)-1-( 2-tritylaminothiazol-4-yl) acetic acid, (Z)-2-(1-1-butoxycarbonyIcycloprop-1-oxyimino)-2-( 2-tritylaminothiazol4-yl)acetic acid, (Z)- 2 - (1-t-butoxycarbonyIcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4yl)acetic acid and (Z)- 2-(1-t-butoxycarbonylcyclopent-1-oxyimino)- 2-{2-tritylaminothiazol-1 -yl)acetic acid, respectively, and there is thereby produced 7-(2-(2-aminothiazol-4-yl)-(Z)-2-(carboxymethoxylmino)acetamido 1-3-((1methyl-1-pyrrolidinium)methylJ-3-cephem-4-carboxylate, 7-(2-(2-aminothiazol-4-yl)-(Z)- 2-(1-carboxyethoxyimino)acetamido 1-3((1-inethyl-1-pyrrol id in ium)methy1]-3-cephem-4-carboxylate, 7-12-(2- aminothiazol-4-yl)-(2)-2-(2-carboxybut-2-oxyiminoJ-acetamido 1 3-((1-methyl-1-pyrrolidiniumJmethyl]-3-cephem-4-carboxylate, 7-l2-(2-aminothiazol-4~yl)-(Z)-2-(3-carboxypent-3-oxyimi noJ-aceturniew 3-[(1-methy1-1-pyrrolidiniumJmethyl]-3-ccphein-4-carboxylate, 7-12-(2-aminothiazol-4-y1J -(2)-2-(1-carboxycycloprop-1-oxyimino)- acetamido )-3- [ (1-methyl-1-pyrrol idinium Jmethyl ]-3-cephem-4-carboxylate, 7-12-(2-aminothiazol-4-yl)-(Z)- 2-(1-carboxycyclobut-1-oxyiminoJacetamido)--3-((1-methyl-1-pyrrolidinium)methyl)-3-cephem-4-carboxylate and IO 7-1 2 - ( 2-aininothiazol-4-y 1) - ( Z) - 2- (1-carboxycyc lopent Ί-oxy i mi no) acetamido J-3-[(1-methy1-1-pyrrolidiniumJmethyl)-3-cephein -4-carboxylate, respectively.
In the claims which follow (cf. Claim 21), as also in the foregoing description (cf. Procedure 1), DCC is to be understood as standing for dicyclohexylcarbodiimlde, as indicated in the foregoing Reaction Scheme 3,

Claims (15)

CLAIMS wherein R^ is hydrogen or a conventional amino-protecting group, and 2
1. - pyrrolidinium) methyl]-3-cephem-4-carboxylate or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof. * 2. 3 wherein B is a conventional amino-protecting group, B is a conventional carboxyl-protecting group and R 3 and R 4 are as defined above, to produce a compound of the formulae and subsequently removing all protecting group. 20. A process for the preparation of compounds of the formula wherein k is a straight or branched chain alkyl group containing 5 from 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or is a group C— r 4 I COOH
2. The compound of Claim 1 which is 7-[(Z)-2-methoxyimino-2-(2-aminothiazol-4-yljacetamidoJ-3-[ll-methyl-l-pyrrolidiniuin)-methyl]-3-cephem15 4-carboxylate, or a nontoxic pharmaceutically acceptable salt or solvate thereof. 3. -3-cephem-4-carboxylate, or 7-((2)-2-(2-propoxyimino)-2-(2-aniinothiazol -4-ylJacetaiaido]-3-{l-methyl-l-pyrrolidiniumjmethyl]-3-cephem-4carboxylate, or 7-({Z)-2-allyloxyimino-2-(2-aminothiazol-4-yl) acetamido]-3-I(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate, 3 4 wherein H and K each are independently hydrogen, methyl or 3 4 ethyl, or K and k , taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, and nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates thereof, which process comprises reacting a compound of the formulae XIV XlVa b ο wherein Κ^, and are as defined above, B 1 and B^ are conventional carboxyl-protecting groups, B is a conventional amino-protecting group, with N-methylpyrrolidine to produce a compound of the formulae and subsequently removing all protecting groups by conventional means. 21. The process of claim 19 or 20, for the preparation of 7-(2-(2aminothiazol-4-yl)-(2)-2-(2-carboxyprop-2-oxyimino)-acetamidoJ-3-[(lmethyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate (Ie) or a lo nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, which comprises reacting a mixture of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate, (2)-2-(2-t-butoxycarbonylprop-2-oxyimino)-2(2-tritylaminothiazol-4-yl) acetic acid, DCC, N-hydroxybenztriazole in an organic solvent to give 15 benzhydryl 3-chloromethyl- 7-((2)-2-(2-t-butoxycarbonylprop-2oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido J-3-cephem-4-carboxylate (If) or alternatively reacting a mixture of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate and bisCtrimethylsilylj acetamide with an acid chloride of (2)-2-(2-t-butoxycarbonylprop20 2-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid to give (If), then reacting (If) with iodide salt to give benzhydryl 7-((2)-2-(2t-butoxycarbonylprop-2-oxyimino)-2-(2-tritylaminothiazol-4-yl) ο ucetunddo]-3-ioclcinetliyl-3-cephaiH4-carbo«ylate (Via), then further reacting (Via) with N-methylpyrrolidine in an organic solvent to give a quaternized product (lh), and finally deblocking (lh) to give the title compound (le), melting at 160°C (dec) and/or if desired optionally converting (Ie) to 5 its nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates thereof. 22. The process of claim 19 or 20, for the preparation of compounds of the formula 3 4 wherein R and R each are independently hydrogen, methyl or ethyl, or R 3 and R 4 , taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, or a nontoxic pharmaceutically acceptable salt, 3 4 methyl or ethyl, or R and R , taken together with the carbon atom to which they are attached may be a cycloalkylidene ring containing from 3 to 5 carbon atoms or a nontoxic r pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof and an inert pharmaceutical carrier. 16. The composition of Claim 15 wherein the compound of Claim 1 is 7-(2-(2-aminothiazol-4-yl)-(Z)-2-(2-carboxyprop-2-oxyimino)acetamidol3-((1-methy1-3-((1-methyl-1-pyrrolidiniurnJmethyl]-3-cephem-4-carboxylate or a nontoxic pharmaceutically acceptable salt, physiologically 3 4 is as defined in Claim 1 and R and R each are independently 3 4 hydrogen, methyl or ethyl, or R and R , taken together with the carbon atom to which they are attached may be a cycloalkylidene ring containing from 3 to 5 carbon atoms or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, for use in a method of combatting Gram-negative bacterial infection in a warm-blooded animal.
3. The compound of Claim 1 which is 7-[(Z)-2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(l-methyl-l-pyrrolidinium)-methyl|-3-cepbem-4carboxylate, or a nontoxic pharmaceutically acceptable salt or solvate 20 thereof. l>
4. The compound of Claim 1 which is 7-((ZJ-2-(2-propoxyimino)-Z-(2aminothiazol-4-ylacetamido]-3 - (1-methyl-1-pyrrolidinium)methyl)-3cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt or solvate thereof.
5. And/or if desired converting said deblocked derivatives to nontoxic pharmaceutically acceptable salt or solvate thereof. 23. A method of combating bacterial infection in a warm-blooded, non-human animal in need of such treatment comprising administering i to said animal an antibacterially effective amount of at least one 5 physiologically hydrolyzable esters or solvate thereof, which comprises acylating a compound of the formula or an N-silyl derivative thereof, in which B 1 is hydrogen or a 10 conventional-protecting group, with an acylating derivative of an acid of tiie formulae q-coon N-t-C-CO = /X Β HN X S DR XVII or XVIIa COOB' 5 hydrolyzable ester or solvate thereof. 17. An antibacterial composition active against Gram-negative bacteria in unit dosage form comprising from 50 mg to 1500 mg of at least one compound of Claim 1 wherein R 3 is as defined in claim 1 and R 3 and k 4 each are independently hydrogen, methyl or 3 4 5 5. The compound of Claim 1 which is 7-[(Z)-2-A1lyloxyimino-2-(2 aminothiazol-4-y1)acetamido]-3-(l-methy1-1-pyrrolidiniumJmethyl)-3cephem-4-carboxylate, or a nontoxic pharmaceutically acceptable salt or solvate thereof. 5 carbon atoms, or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable esters or solvate thereof. 5 R is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl or is a group r3—c-^R 4 I COOH wherein R and R each are independently hydrogen, methyl or 3 4 ethyl, or R and R , taken together with the carbon atom to which ]O they are attached, may be a cycloalkylidene ring containing from 3 to
6. Medication comprising an antibacterially effective amount of 7. -(2-(2-aminothiazol-4-yl)-(L)-2-(2-carboxyprop-2-oxyimino)acetamido]3-((1-methyl-1-pyrrolidinium)methyl] - 3-cephem-4-carboxylate ora nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof. 20 19. A process for the preparation of compounds of the formula wherein H 1 is hydrogen or a conventional amino-protecting group, and R^ is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl or 3- butenyl, or is a group r3—C—'•R^ I COOH i 7-((Z)-2-methoxyimino-2-(2-aminothiazol-4-yl)-acetamido )-5-((1-methyl l-pyrrolidinium)methyl]-3-cephem-4-carboxylate or a nontoxic pharmaceutically acceptaole salt or solvate thereof.
7. Medication comprising an antibacterially effective amount of 7- [(Z)-2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido)-3- [(1methyl-l-nyrrolidinium)methyll-3-cephem-4-carboxylate or a nontoxic 15 pharmaceutically acceptable salt or solvate thereof, for use in a method of combatting bacterial infection in a warm-blooded animal.
8. An antibacterial composition comprising an antibacterially effective amount of at least one compound of Claim 1 and an inert pharmaceutical carrier. 20
9. The composition of Claim 8 wherein the compound of Claim 1 is 10. Compound according to any one of Claims 1 to 5. 24. A process according to Claim 19 or 20, substantially as * described in any of the foregoing Examples 1 to 8. 25. A compound according to Claim 1, whenever prepared by a process as claimed in any one of Claims 19 to 22 or 24. 10 wherein R^ is hydrogen and R^ is methyl, ethyl, isopropyl, or allyl, or a nontoxic pharmaceutically acceptable salt or solvate thereof, which comprises reacting a mixture of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate and bis(trimethylsilyl) acetamide with an acid chloride of (Z)-2-methoxyimino-2-(215 tritylaminothiazol-4-yl) acetic acid or (Z) -2-ethoxyimino-2-(2tritylamino-thiazol-4-yl) acetic acid or (Z)-2-(2-propoxyimino)-2(2-tritylamino-thiazol-4-yl)acetic acid or (Z)-2-allyloxyimino-2(2-tritylaminothiazol-4-yl) acetic acid to give the corresponding condensed derivative containing 2-methoxyimino or 2-ethoxyimino or 20 2-propoxyimino or 2-allyloxyimino group, then reacting said condensed derivative with iodide salt to give the corresponding 3-iodomethyl derivative, then further reacting said 3-iodomethyl derivative with N-inethyl-pyrrolidine in an organic solvent or a mixture of organic solvents to give the corresponding pyrrolidinium derivative and 25 finally deblocking said pyrrolidinium derivative to give 7-[(Z)-2methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(1-methy1-1pyrrolidinium)-methyl]-3-cephem-4-carboxylate, or 7-[(Z)-2-ethoxyimino -2-(2-aminothiazol-4-yl)acetamidoJ-3-[(1-methy1-1-pyrrolidi nium)-methvl| ι • Λ. - $2 10 ethyl, or R and R , taken together with the carbon atom to which they are attached may be a cycloalkylidene ring containing from 3 to 5 carbon atoms or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof and an inert pharmaceutical carrier. 15 18. The composition of Claim 17 wherein the compound of Claim 1 is
10. An antibacterial composition in unit dosage form comprising from 25 about 50 mg to 1500 mg of at least one compound of Claim 1 and an inert pharmaceutical carrier· 10 at least one compound of Claim 1, for use in a method of combatting bacterial infection in a warm-blooded animal.
11. The composition of Claim 10, wherein the compound of Claim 1 is 7-[(Z)-2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-((1-methyl-l-pyrrolidinium)methyl-3-cephem-4carboxylate or a nontoxic pharmaceutically acceptable salt or solvate thereof.
12. The compound of Claim 1 which is 7-(2-(2-aminothiazol4-yl)-(Z)-2-(carboxyprop-2-oxyimino)acetamido]-3-((1-methyl- 1
13. Medication comprising an antibacterially effective amount of at least one compound of claim 1, wherein R^
14. Medication comprising an antibacterially effective amount of 7-[2-(2-aminothiazol-4-yl)-(Z)-2-(2-carboxyprop2- oxyimino)-acetamido]-3-((1-methyl-l-pyrrolidinium)methyl]3- cephem-4-carboxylate or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, for use in a method of combatting Gramnegative bacterial infection in a warm-blooded 15. An antibacterial composition active against Gram-negative bacteria comprising an antibacterially effective amount of at least one compound of Claim 1 wherein R x is as defined 3 4 in Claim 1 and R and R each are independently hydrogen,
15. 26. Use of an antibacterially effective amount of at least one compound according to any one of Claims 1 to 5 in a method of combating bacterial infection in warm-blooded, human or nonhuman animal.
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NL193284C (en) 1999-05-06
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