NZ227470A

NZ227470A - Acyl derivatives of substituted cephem compounds; pharmaceutical compositions and methods for preparation and treatment

Info

Publication number: NZ227470A
Application number: NZ227470A
Authority: NZ
Inventors: Chan Ka-Kong; Dennis Dalton Keith
Original assignee: Hoffmann La Roche
Priority date: 1987-12-28
Filing date: 1988-12-22
Publication date: 1991-06-25
Also published as: JPH01203395A; FI885988A; MC2000A1; EP0322810A3; AU2755488A; HUT48896A; NO885780D0; EP0322810A2; IL88775A0; AU621328B2; HU205361B; YU219789A; DK722988D0; YU234688A; KR890009942A; NO885780L; PT89353A; DK722988A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £27470 WO DRAWINGS Priority Date(s): S?.7,1 ..7J Complete Specification Fit}&%*%' Class: . fcrvtol .\s& i ( .& 4v.q : Paction Da,: ....2.?..^..W" P.O. Journal, No: 1 227470 NEW ZEALAND PATENTS ACT. 1953 No.: Date: COMPLETE SPECIFICATION ACYL DERIVATIVES P fiN lz22DEC 19882, c"C- •4-/We. F. HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT 124-184 Grenzacherstrasse, Basle, Switzerland, a Swiss Company, hereby declare the invention for which I / we pray that a patent may be granted to ms-/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 (followed by page la) 227 4 70 RAN 4410/215 The pcesenc invention celates to acyl derivatives o£ the formula wherein tn is zero. 1 or 2. R is hydrogen or an acyl 2 group; R is hydrogen, lover alkoxy, lower alkylthio or lower alkanoylamino; R31 is hydrogen, lower alkyl. lower alkenyl, C_-C_ cycloalkyl. halo-lower alkyl. 30 phenyl or mono-, di- or tri-halo-phenyl; Z is R -C or nitrogen: R30 is hydrogen or halogen, or R30 and R31 when taken together represent a C3~C5 alkylene group, a C_-C alkylene mono-oxy group or a C. -C, 32 12 alkylene dioxy group; R is hydrogen, halogen, lower alkyl or an optionally substituted 5- or 6-membered heterocyclic ring containing one, two or three oxygen, 33 nitrogen and/or sulphur atoms; and R is hydrogen or 32 33 halogen, or R and R when taken together represent a C1-C4 alkylene dioxy group. and the readily hydrolyzable esters or salts of these compounds and hydrates of the compounds of formula I or of their esters or salts. Mn/19.10.88 227 4 70 - 2 - In the above formula I m is preferably 0. As used in this specification, the term "lower allcyl" or "alkyl" refers to both straight and branched chain saturated hydrocarbon groups having 1 to 8 and Preferably, 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, iso-propyl, t-butyl and the like. As used herein, the term "lower alkoxy" or "alkoxy" refers to a straight or branched chain hydrocarbonoxy groups wherein the "alkyl" portion is a lower alkyl group as defined hereinbefore. Exemplary are methoxy. ethoxy. n-propoxy and the like. The term "halo" or "halogen" as used herein represents all four forms thereof, i.e. chloro. bromo. iodo or fluoro unless otherwise specified. By the term "aryl" is meant a substituted or unsubsitu-ted aromatic moiety, such as phenyl, tolyl, xylyl. mesityl. cumenyl. naphthyl and the like, wherein said aryl group may have 1 to 3 suitable substituents. such as halo (e.g. fluoro, chloro. bromo). hydroxy and the like. By the term "lower alkanoyl" or "alkanoyl" as utilized herein is intended a moiety of the formula 25 wherein R is hydrogen or to Cfi alkyl. Exemplary of such groups are acetyl, formyl. propionyl. n-butyryl and the like. By the term "substituted phenyl" is meant phenyl, mono-or di-substituted by halo (e.g. chloro. bromo. fluoro), lower alkyl, amino, nitro or trifluoromethyl. ! c 6 111 4 70 - 3 - By the teem "substituted alkyl" is meant a "lower alkyl" moiecy substituted by. for example, halo (e.g. chloro. fluoro. bromo). crifluoromechyl. amino, cyano, ecc. By Che cecm "lowec alkenyl" or "alkenyl" is meant a straight or branched chain hydrocarbon group which contains an olefinic double bond having 2 Co 6 carbon acoms. i.e. Che radical of compounds of che formula C H wherein n is 2 n 2n co 6. e.g. allyl. vinyl, ecc. 10 By che cerm "aralkyl" is meanc a hydrocarbon group having boch aromatic and aliphacic structures, chac is, a hydrocarbon group in which a lower alkyl hydrogen acom is subscicuced by a monocyclic aryl group, e.g. by phenyl. 15 colyl. ecc. The expression "5-. 6- or 7-membered hecerocyclic ring concaining 1-4 oxygen, nicrogen and/or sulfur acoms" is incended co represenc e.g. a 6-membered nitrogen-containing 20 hetero ring such as pyridyl. piperidyl. piperidino. N-oxido--pyridyl. pyrimidyl. piperazinyl, pyridazinyl, N-oxido--pyridazinyl, ecc.. a S-membered nitrogen-containing hetero ring such as pyrrolidinyl, pyrazolyl. imida2olyl, thiazolyl, 1,2. 3-thiadiazolyl, 1,2,4-Chiadiazolyl. 1.3.4-Chiadiazolyl. ^ 25 1,2.3-oxadiazolyl, 1,2,4-oxadiazolyl. 1,3,4-oxadiazolyl. 1,2.5-oxadiazolyl. 1,2.3-triazolyl. 1,2.4-triazolyl. lH-tetrazolyl. 2H-tetrazolyl, ecc.. and ochers. Each of chese hetero rings may be further subscituted and. as the substituents. there may be mencioned, for example, lover ^ 30 alkyls such as mechyl, echyl, n-propyl, ecc.. lower alkoxys such as mechoxy. echoxy. etc.. halogens such as chlorine, bromine, etc.. halogen subscicuced lower alkyls such as crifluoromethyl. trichloroechyl. ecc., amino, mercapco, hydroxy, carbamoyl or carboxy ecc. 35 By the term "cyclo-lower-alkyl" or "cycloalkyl" is meant a 3-7 membered saturated carbocyclic moiety, e.g. cyclo- 227470 4 - propyl, cyclobutyl. cyclohexyl, etc. R30 and R31 can together mean "C^-C^ allcylene". ^ e.g. -(CH2)3-, -(CH2)4-. -(CH2)5 or -CH(CH3)-(CH2) -; 5 or also "c2-c4 alkylene mono-oxy". e.g. -(CH2>2-0-. -(CH2)3-0-, -(CH2)4-0- or -CH<CH3)-CH2-0-; or alternatively "Cj^-Cj allcylene dioxy". e.g. -0-CH2-0-, ^ -0-(CH2)2-0- or -0-CH(CH3)-0-. Preferably a 5- or 6-membered condensed ring is formed. R32 and R33 can 10 together mean "c1_c4 allcylene dioxy". e.g. -0-CH2-0-. -O-(CH2)2-O-. -O-(CH2)3-O-. -O-(CH2J4-O-. -0-CH(CH3)-0-. -0-CH(CH3)-CH(CH3)-0- or the like. Preferably a 5- or 6-membeced condensed ring is formed. 15 The term "acyl". as used in conjunction with R1 herein, means and includes all organic radicals derived from an organic acid (i.e.. a carboxylic acid) by removal of the hydroxy group. Although the group R1 may be any one of many acyl radicals, certain acyl groups are preferred. 20 O Exemplary acyl groups are those acyl groups which have been used in the past to acylate fl-lactam antibiotics including 6-aminopenicillanic acid and derivatives and 7-arainocephalosporanic acid and derivatives; see, for 25 example. Cephalosporins and Penicillins, edited by Flynn, Academic Press (1972), British patent 1,603,212, British patent 1,604.740. United States patent 4,152,432, issued May 1, 1979, United States patent 3,971,778, issued July 27, 1976, 30 and United States patent 4,173,199, issued October 23, 1979, t The portions of these references describing various acyl groups are incorporated herein by reference. The following list of acyl groups is presented to further exemplify the term "acyl"; it should not be regarded as limiting that 35 term. Exemplary acyl groups are: '8 MAY 1991$ 227 4 7 0 - 5 - (a) Aliphatic groups having Che formula R5-CO- 10 wherein R is lower alkyl, C3-C? cycloalkyl. lower alkoxy. lower alkenyl. C3-C7 cycloalkenyl or cyclo-hexadienyl; or lower alkyl or lower alkenyl subscicuced wich one or more halogen, cyano. nicro. amino, mercapco, lower alkylchio. or cyanomechylchio groups. (b) Carbocyclic aromacic groups having one of che formulas 15 20 25 NS^-p0-t- 30 ^1ch2-OJ. 35 227470 - 6 - R7 «' I ,rB N01s.H2J 6 7 8 wherein n is 0. 1, 2 or 3; R . R and R each is independently hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms. 9 0 alkoxy of 1 to 4 carbon atoms or arainomethyl; and R is amino, acylamino, hydroxy, a carboxy salt, protected carboxy. such as benzyloxycarbony1. formyloxy or azido; and M is a cation. - 7 - 227470 Preferred carbocyclic aromatic acyl groups include those having Che formulas ? CH,— C— O O 10 ■(y-wj- 15 20 t i Vy 25 O-f^ c 30 90 35 (R is preferably an amino group, a hydroxy group, or a carboxy salt or sulfo salt) . ^8MAYl99l£ c o c c 227 4 70 - 8 - Examples of other acyl groups suitable for the purposes of the present invention are sulfophenylacetyl. hydroxysulfonyloxyphenylacetyl. 5 sulfamoylphenylacetyl. (phenoxycarbonyl)phenylacety1. (p-tolyloxycarbony1)phenylacetyl. formyloxyphenylacetyl, carboxyphenylacetyl, 10 formylaminophenylacetyl. benzy1oxycarbony1phenylacetyl, 2- (N.N-dimethylsulfamoyl)-2-phenylacetyl, 2-bromo-2-thienylacetyl. etc. 15 (c) Heteroaromatic groups having the formulas r101-(ch2)n-co- 101 20 r -ch-co- R90 101 25 r -0-ch2-c0- r101-s-ch2-co- or .o- 30 35 227 470 - 9 - 90 wherein n is 0, 1. 2 or 3; R is as defined above; and R101 is a substituted oc unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1. 2, 3 or 4 (preferably 1 or 2) nitrogen, oxygen and/or sulfur atoms. Exemplary heterocyclic rings are thienyl. furyl, pyrrolyl. pyridinyl. pyrazinyl, thiazolyl, pyrimidinyl and tetrazolyl. Exemplary substituents are halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms oc alkoxy of 1 to 4 carbon atoms. Preferred heteroaromatic acyl groups include those groups of the above formulas wherein R101 is 2-amino-4--thiazolyl. 2-amino-5-halo-4-thiazolyl, 4-aminopyridin-2-yl, 2-amino-l,3,4-thiadiazol-5-yl, 2-thienyl, 2-furanyl, 4-pyri-dinyl or 2,6-dichloro-4-pyridinyl. (d) [[(4-Substituted-2.3-dioxo -1-piperazinyl)carbonyl]-aminojarylacetyl groups having the formula wherein R111 is lower alkyl, hydroxy-lower alkyl or an aromatic group (including carbocyclic aromatics) such as those of the formula 227 4 70 - 10 - 6 7 8 whecein R . R and R ace as previously defined; oc a heterocyclic ring as included within the definition of R101; and R1,20 is lower alkyl oc substituted lowec alkyl (wherein the lower alkyl group is substituted with one or more halogen, cyano, nitro. amino and/oc mercapto groups), e.g. 4-lower alkyl (preferably ethyl or methyl)-2.3-dioxo-l-piperazinecarbony1-D-phenylglycyl. (e) (Substituted oxyimino)-arylacetyl groups having the formula R130-O-N-C-CO- I R101 wherein R*01" is as defined above and R130 is hydrogen, lower alkyl. C3-C? cycloalkyl. carboxy--C3-C7-cycloalkyl oc substituted lower alkyl (wherein the lower alkyl group is substituted with one or more halogen, cyano, nitro, amino, mercapto. lower alkylthio, aromatic group (as defined above by R111). carboxy (including salts thereof), lower alkanoylamino, lower alkoxycacbonyl, phenylmethoxycarbonyl, diphenyl-methoxycarbony1. hydroxy-lower-alkoxyphosphinyl. dihydroxyphosphinyl. hydroxy-(phenylmethoxy)-phosphinyl or di-lower-alkoxyphosphinyl" substituents). 130 Examples of R -0-N=C-C0- I R101 grouping are 227 4 7 0 li 2- [(2-chloroacecamidochiazol-4-yl)]-2-[(p-nicrobenzyloxy-carbony1)mechoxyimiao]acetyl. 2-(2-chloroacecamidochiazol-4--yl)-2-mechoxyiminoacecyl. 2-(2-aminochiazol-4-yl)-2-isopro-poxy-iminoacecyl , 2-(2-aminochiazol-4-yI)-2-methoxyiraino-acecyl . 2-(2-arainochiazol-4-yl)-2-hydroxyiminoacecy1, 2-chienyl-2-raechoxyiminoacecyl. 2-furyl-2-mechoxyimino-acecyl. 2-(4-hydroxyphenyl)-2-raechoxyiminoacecyl, 2-phenyl--2-raechoxy-iminoacecyl. 2-pheny 1-2-hydroxyiminoacecy1, 2-chienyl-2-hydroxyiminoacecyl. 2-cnienyl-2-(dichloroacecyl-oxyiminojacecyl. 2-[4-(Y-D-glucarayloxy)phenyl]-2-hydroxy-iminoacecyl. 2-[4-(3-araino-3-carboxypropoxy)phenyl]-2--hydroxyirainoacecyl, 2-(5-chloro-2-chloroacecamidochiazol--4-yl) -2-mechoxyiminoacecyl, 2-(5-chloro-2-aminochiazol-4--yl)-2-mechoxyiminoacecyl. 2-[2-(c-bucoxycarbony1)isopro-poxyimino]-2-(2-sulfoamino -thiazol-4-yl)acetyl. 2-[2-(c-bucoxycarbony1)isopropoxyiminoJ-2 -(2-criphenyl--mechylamino-chiazol-4-yl)acecyl, 2-(2-chloroacecamido-Chiazo1-4-y1)-2-isopropoxyiminoacecy1. 2-methoxyimino-2-(2--sulfoaminothiazo1-4-yl)acecyl, 2-(2-aminochiazol-4-yl)-2--(carboxymethoxyimino)acetyl. 2-(2-mesylaminochiazol-4-yl)--2-isopropoxyiminoacecy1. 2-(2-iraino-3-mesyl-4-chiazolin--4-yl)-2-isopropoxyiminoacecyl, 2-(2-aminothiazol-4-yl)-2--(carboxyisopropoxyimino)acetyl ecc. (£) (Acylamino) arylacecyl groups having che formula R 140 -CO-NH-CH-CO- R 111 wherein R111 is as defined above and R140 is R 7 mm ! mamimmfmmmmm > v >j-r. fT* 227470 O 10 - 12 - 6 7 8 (where R . R . R and n are as previously defined), hydrogen, lower alkyl. subscicuced lower alkyl. amino, lower alkylamino. (cyanoalkyl)-amino or acylamino. Preferred (acylamino) arylacetyl groups of che above 140 formula include chose groups wherein R is amino or acylamino. Also preferred are chose groups wherein R*'^ is phenyl or 2-chienyl. (g) ft[3-Subscicuced-2-oxo-1-iraidazolidinyl]carbony1]amino]-arylacetyl groups having che formula - 15 .15 0 II R*J—NK ^N—CO—NH—CH—CO- r im CH^—OH2 r c 20 25 wherein R111 is as defined above and R15 is hydrogen, lower alkylsulfony1, arylmechyleneamino (i.e., -N-CHR111 wherein R111 is as defined above), R16CO ,16 (wherein R w is hydrogen, lower alkyl or halogen subscicuced lower alkyl). an aromatic group (as defined by R111 above), lower alkyl or subscicuced lower alkyl (wherein che lower alkyl group is subscicuced wich one or more halogen, cyano, nitro. amino and/or mercapto groups). Preferred [[[3-substituced-2-oxo-l-iraidazolidinyl]car-30 bonyl]amino]arylacecyl groups of che above formula include chose wherein R 111 is phenyl or 2-chienyl. Also preferred are those groups wherein R15 is hydrogen, methylsulfonyl. phenylraethylenearaino or 2-fur*ylmethylenearaino. 35 In a preferred embodimenc of che quinolonyl or .30 azaquinolonyl subscicuent in 3-position Z is R -C wherein ,30 is hydrogen, chlorine or fluorine, most preferably \ - 13 - 227 4 7 0 hydrogen or fluorine: R31 is preferably lower alkyl, most preferably ethyl. (—s or halogen-lower alkyl, most preferably fluoroethyl. or ^ 5 C3-C7-cycloalkyl. most preferably cyclopropyl; 3 2 R is preferably lower alkyl. most preferably methyl, or piperazinyl which may be substituted on the 4-nitrogen atom with a lower alkyl group, most preferably methyl; O c 10 R is preferably hydrogen, chlorine or fluorine, more preferably hydrogen or fluorine, and still more preferably fluorine. 15 As used herein the quinolonyl or azaquinolonyl substi- tuents in 3-position include, among others, groups of the formulas 20 25 ' " 30 rv 227 4 7 0 - 14 O 10 15 CH 20 \__ 25 30 35 CHO i 4 m CD - 15 - NCH. 227470 c 'i 10 15 20 NHCH C 25 NCH. © D 10 15 20 25 30 35 227 4 70 - 16 - k O k o Y 0—C(CH3)3 227 4 7 0 - 17 - OCHjCClj och,—ch—ch, H. Mirrrifi .... .. 2274 - 18 - A preferred class of compounds are of che formula ch.sco 4 COOH wherein is as above, R20 is hydrooen or an amino protecting group such as tricyl or chloroacetyl, preferably 21 hydrogen, R is hydrogen, lower alkyl. or a group of che formula R22 I -C-COOH I R23 22 2 3 wherein R and R are selecced from che group 2 2 consisting of hydrogen and lower alkyl. or R and 2 3 R caken cogecher with the carbon atom to which they are attached form a 3-7 membered carbocyclic ring, e.g. cyclopropyl, cyclobutyl or cyclopentyl. Still more preferred are compounds of the formula lb in which R 20 is hydrogen and R 21 is methyl or a group of the formula R22 -C-COOH .23 22 2 3 wherein R and R are selected from the group consisting of hydrogen and methyl. // "•v i ^ i.' 8 MAY 1991 wmM 227 4 7 0 - 19 - N-O-R130 N-O-R21 II II Preferably, the -C- and -C- groupings are in the syn-forra, i.e.. the Z-forra, or as , 5 mixtures in which the syn-form predominates. i As readily hydrolyzable esters of the compounds of , formula I there are to be understood compounds of formula I. the carboxy group(s) of which (i.e. the 2-carboxy group and 10 any other carboxy group present) is/are present in the form of readily hydrolyzable ester groups. Example of such esters, which can be of the conventional type, are the lower * alkanoyloxyalkyl esters (e.g. the acetoxymethy1. pivaloyl-oxymethyl. 1-acetoxyethyl and 1-pivaloyloxyethyl ester), the 15 lower alkoxycarbonyloxyalkyl esters (e.g. the methoxycar-bonyloxymethyl. 1-ethoxycarbonyloxyethyl and 1-isopropoxy-carbonyloxyethyl ester), the lactonyl esters (e.g. the * phthalidyl and thiophthalidyl ester), the lower alkoxymethyl ; esters (e.g. the methoxymethyl ester) and the lower \ 20 alkanoylaminomethyl esters (e.g. the acetamidomethyl ester). Other esters also be used, j Other esters (e.g. the benzyl and cyanoroethyl esters) can Examples of salts of the compounds of formula I are 25 alkali metal salts such as the sodium and potassium salt, the ammonium salt, alkaline earth metal salts such as the calcium salt, salts with organic bases such as salts with amines (e.g. salts with N-ethyl-piperidine, procaine, dibenzylamine, N,N'-dibenzylethylenediamine. alkylamines or . 30 dialkylamines) as well as salts with amino acids such as. for example, salts with arginine or lysine. The compounds of formula I, when they contain a basic functional group such as an amine, also form addition salts 35 with.organic or inorganic acids. Examples of such salts are hydrohalides (e.g. hydrochlorides, hydrobromides and hydro- 20 227470 iodides) as veil as other mineral acid salts such as sulphates. nitrates, phosphates and the like, lower alkylsul-phonates and monoarylsulphonates such as ethanesulfonates. toluenesulphonates. benzenesulphonates and the like and also other organic acid salts such as acetates, tartrates, aaleates, citrates, benzoates. salicylates, ascorbates and the like. The compounds of formula I as veil as their salts and readily hydrolyzable esters can be hydrated. The hydration can be effected in the course of the manufacturing process or can occur gradually as a result of hygroscopic properties of an initially anhydrous product. The acyl derivatives aforesaid are manufactured in accordance with the present invention by a process vhich comprises (a) for the manufacture of an easily hydrolyzable ester of a cacboxylic acid of formula I reacting a compound of the formula II COOR' wherein m. R1 and R2 are as above. Hal is halogen and R' is the residue of an easily hydrolyzable ester, with a salt of a carbofchioic acid of the formula - 21 - 227 4 7 H9C0 III wherein R \ R32 and R33 are as above. or (b) for che manufaccure of a carboxylic acid of formula I converting an ester of che formula Col COOR ,33 .32 IV 1 2 31 32 , 3 3 wherein ra, R , R . R , R and R are as above and R is an escer proceccing group, to che carboxylic acid of formula I, or (c) for che manufaccure of a compound of formula I, in which m is zero, reducing a compund of the formula O - 22- 227 4 7 0 1 2 31 32 J 3 3 wherein R . R , R . R and R are as above. or (d) for the manufacture of a compound of formula I. in which 5 m is 1 or 2. or an ester or salt thereof oxidizing a compound of the formula n w 10 ch2sco COOH vi 15 31 32 33 20 wherein R . R , R . R and R are as above and the dotted lines indicate the presence of a A2 or A3 double bond. or an ester or salt thereof, or e) for the manufacture of a compound of formula I, in which contains an amino substituent, or an ester or salt thereof, cleaving off the amino-protecting group in the substituent rIO 0£ a compound of the formula 25 10) R2 H t R10nh —I m 30 chjs co- COOII VII wherein m, R2, R31, R32 and R33 are as above and r!0 is an acyl group containing a protected amino group, or of an ester or salt thereof, or 227470 - 23 - (f) for the manufacture of a readily hydrolyzable ester of a compound of formula I subjecting a carboxylic acid of formula I to a corresponding esterification. or (g) for the manufacture of salts or hydrates of a compound of formula I or hydrates of said salts converting a compound of formula I into a salt or hydrate or into a hydrate of said salt. The reaction of compounds II with the salts of compounds III according to embodiment (a) is preferably carried out in a nonhydroxylic solvent, such as. dimethylformamide. methylene chloride or N.N'-dimethylacetamide. Other nonhydroxylic solvents may also be utilized. Suitable salts of the guinolone acid are. for example, sodium, potassium, cesium, tetrabutylammonium or tetramethylammonium. Hal is a halogen, preferably bromine or iodine. The reaction is Preferably run at about 0°C to 80°C with about room temperature as preferred. © 227 4 70 - 24 - o The deprotection of che escers IV according to embodiment (b) is effected using agents compatible with the ester protecting group utilized. As ester protecting groups R one may utilize an escer form which can be easily converted into 5 a free carboxyl group under mild conditions, the ester protecting group being exemplified by. for example, c-butyl. p-nicrobenzyl, benzhydryl. allyl. ecc. Also che residues of che readily hydrolyzable escers mencioned above as end produces may be employed. For example che following reagents 10 and their corresponding compacible escers are ucilized: p-nicrobenzyl removed by hydrolysis in che presence of sodium sulfide ac abouc or below 0°C co room cemperacure in a solvent, such as. dimechylformamide (aqueous); c-bucyl removed by reaccion wich trifluoroacetic acid in the 15 presence of anisole at about 0°C to room temperature wich or wichouc a co-solvent, such as mechylene chloride; or allyl removed by a palladium (0) catalyzed transallylation reaction in the presence of sodium or potassium salt of 2-ethyl hexanoic acid, see for example J. Org. Chem. 1982. 20 42. 587. C The reduction of the sulfoxides V according to embodiment (c) is effected utilizing one of a variety of reactions. for example, treatment with phosphorus trichloride in 25 dimethylformamide or trifluoroacetic anhydride in the presence of sodium iodide in acetone/methylene chloride. Both of the above reactions can be carried out at about 0°C to -20°C with about 0°C preferred. 30 The oxidation of the compounds VI according to embodi ment (d) isoraerizes any A2- isomer VI to the corresponding A3 isomer of formula I wherein n is 1 or 2. The oxidation is carried out by treatment with an organic or inorganic oxidizing agent. Various compounds which readily yield 35 oxygen can be used as the oxidizing agent; for example. organic peroxides such as monosubstituted organic peroxides (e.g. C -C alkyl- or alkanoylhydroperoxides such as 1 4 I 227470 - 25 - t-butylhydroperoxide), performic acid and peracetic acid, as well as phenyl-substituted derivatives of these hydroperoxides such as cumenehydroperoxide and perbenzoic acid. The phenyl substituent can. if desired, carry a further lower group (e.g. a alkyl or alkoxy group), a halogen atom or a carboxy group (e.g. 4-methylperbenzoic acid. 4-methoxy-perbenzoic acid. 3-chloroperbenzoic acid and monoperphthalic acid). Various inorganic oxidizing agents can also be used as the oxidizing agent; for example, hydrogen peroxide, ozone, permanganates such as potassium or sodium permanganate, hypochlorites such as sodium, potassium or ammonium hypochlorite, peroxymonosulphuric and peroxydi-sulphuric acid. The use of 3-chloroperbenzoic acid is preferred. The oxidation is advantageously carried out in an inert solvent, for example, in an aprotic inert solvent such as tetrahydrofuran, dioxan, methylene chloride, chloroform, ethyl acetate or acetone or in a protic solvent such as water, a lower alkanol (e.g. methanol or ethanol) or a lower alkanecarboxylic acid which may be halogenated (e.g. formic acid, acetic acid or trifluoroacetic acid). The oxidation is generally carried out at a temperature .in the range of -20°C to +50"C. When the oxidizing agent is used in eguimolar amounts or in slight excess in relation to the starting material there is mainly obtained the corresponding sulfoxide, i.e. a compound of formula I in which m stands for 1. When the amount of oxidizing agent is increased to double the stoichiometric ratio or more, there is obtained the corresponding sulfone, i.e. a compound of formula I in which m stands for 2. It is also.possible to obtain the sulfone from the corresponding sulfoxide by treatment with an equimolar or greater amount of the oxidizing agent. The process conditions are essentially the same as in the manufacture of the sulfoxides. n 227 4 ^ 26 - The cleavage of the amino-protecting group in the substituent R10 of a compound VII according to embodiment (e) gives corresponding compounds of formula I carrying a free amino group. Possible amino-protecting groups are those 5 employed in peptide chemistry, such as an aiicoxycarbonyi group, e.g., t-butoxycarbonyl, etc., a substituted alkoxy-carbonyl group, e.g.. trichloroethoxycarbonyl, etc., a substituted aralkyloxycarbonyl group, e.g.. ^ p-nitrobenzyloxycarbonyl. an aralkyl group such as trityl or w 10 benzhydryl or a halogen-alkanoyl group such as chloroacetyl, bromoacetyl, iodoacetyl or trifluoroacetyl. Preferred protecting groups are t-butoxycarbonyl (t-BOC) V and trityl. 15 The amino protecting groups may be cleaved off by acid ■ hydrolysis (e.g. the t-butoxycarbonyl or trityl group) or by basic hydrolysis (e.g. the trifluoroacetyl group). The chloroacetyl, bromoacetyl and iodoacetyl groups are cleaved ] 20 off by treatment with thiourea. i Amino-protecting groups which are cleavable by acid hydrolysis are preferably removed with the aid of a lower alkanecarboxylic acid which may be halogenated. In parti-25 cular, formic acid or trifluoroacetic acid is used. The acid hydrolysis is generally carried out at room temperature, although it can be carried out at a slightly higher or slightly lower temperature (e.g. a temperature in the range of about 0°C to +40°C). Protecting groups which are cleavable 30 under basic conditions are generally hydrolyzed with dilute aqueous caustic alkali at 0°C to 30°C. The chloroacetyl. bromoacetyl and iodoacetyl protecting groups can be cleaved off using thiourea in acidic, neutral or alkaline medium at about 0°C-30°C. 35 1 227 4" - 27 - In order Co manufaccure a readily hydrolyzable escer of che carboxylic acids of formula I in accordance wich embodi-menc (f) of che process provided by che presenc invencion. a carboxylic acid of formula I is preferably reacced wich a corresponding halide, preferably an iodide, containing che desired escer group. The reaccion can be acceleraced wich che aid of a base such as an alkali mecal hydroxide, an alkali mecal carbonace or an organic amine such as criechyl-araine. The escerificacion is preferably carried ouc in an inerc organic solvenc such as dimechylacecamide, hexamechyl-phosphoric acid criamide. dimethyl sulfoxide or. especially, dimechylformamide. The reaccion is preferably carried ouc ac a temperature in che range of abouc 0°C-40°C. The manufaccure of Che sales and hydraces of che compounds of formula I or che hydraces of said sales in accordance wich embodimenc (g) of che process provided by che presenc invencion can be carried ouc in a manner known per se; for example, by reaccing a carboxylic acid of formula I wich an equivalenc amount of che desired base, conveniently in a solvent such as water or an organic solvent (e.g. echanol, methanol, acetone and the like). The temperature at which the salt formation is carried out is not critical. The salt formation is generally carried out at room temperature, but ic can be carried ouc ac a temperature slightly above or below room temperature, for example in the range of 0°C to +50°C. The manufaccure of che hydraces usually cakes place automatically in the course of the manufacturing process or as a result of the hygroscopic properties of an initially anhydrous product. For the controlled manufacture of a hydrate, a completely or partially anhydrous carboxylic acid of formula I or salt thereof can be exposed to a moist atmosphere (e.g. at about +10°C to +40°C). 227 4 - 28 - Examplacy of che process for obcaining produces In accordance wich the invencion is che following ceaccion scheme I: 227 4 7 0 - 29 - Scheme I R1. R2. R31. R32, R33, R. Z and the dotted bonds are all as defined above and X is a cation. 227470 - 30 - Scheme I The carboxylic acid form of che corresponding quinolone was accivaced by creacmenc wich 2-ffluoro-l-mechylpyridinium sale. Exposure of che accivaced acid co criphenyl-mechylmercapcan and 4-dimechylaminopyridine gave che chio ester of che formula 31 32 33 wherein R , R . R and Z are as above and Ph is phenyl. The compound of che formula IX was creaced wich an aqueous acid, preferably hydrochloric acid and Chen neucrali- zed wich a base, preferably pocassium hydroxide, co give Che chioic acid sale of che formula 31 32 33 + wherein R , R . R and Z are as above and X is a cation. WIBMWMW^''■*v-" '"V -r.v 227470 31 C»^ 1 c i \ , I '• I <!.' i j i I la -> VIII The compound oC formula Ila which is known oc made by analogy, see. for Example U.S. Patent No. 4.406,899 and U.S. Patent No. 4,266,049 is reacted with the salt of the chosen 5 quinolone, viz, a compound of formula X. The ceaction is caccied out as desccibed above foe pcocess altecnative (a). Depending on the ester protecting group chosen and the halogen employed, the double bond in the cephem ring of the reaction product of formula VIII may be A3 or A2 with 10 regard to the sulfur atom due to isomerization. VIII -> la and Via The compound of formula VIII thereafter is deprotected as described above for process alternative (b) resulting in a 15 cacboxylic acid of formula la or a mixture thereof with the A2 isomer of formula Via. Via -» V If isomerization of the double bond occurs, the compound of 20 formula Via is thereafter oxidized as described for process alternative (d). e.g. with a peracid, such as metachloroper-benzoic acid, in a solvent, such as methylene chloride, at a reaction temperature of about -20°C to 40°C, preferably at about 0°C. 25 V -» la The compound of formula V is itself an end product falling under formula I. However, it can be reduced to an end product la as described above for process alternative (c). 30 Compounds of formula I containing the groupings N-O-R 130 N-O-R 21 II II 35 -C- or -C- 227470 - 32 - (cC. above) preferably exist as syn-forms. Such syn forms can be obtained by utilizing starting materials containing this grouping pre-focmed in the syn-form. Alternatively, a syn/anti mixture obtained can be separated into the corresponding syn and anti forms in usual manner, e.g. by recrystallization or by chromatographical methods using a suitable solvent or solvent mixture. Compounds of formula I. their salts and corresponding hydrates and esters can be used as agents to combat bacterial infections (including urinary tract infections and respiratory infections) in mammalian species, e.g., dogs cats, horses, etc., and humans. These cephalosporins are antibacterially active and exhibit activity against a broad range of both gram-negative and gram-positive bacteria. The in vitro activity of the compounds of the present invention as measured by the Minimum Inhibitory Concentration in microgtam8/ml utilizing the Broth Dilution Method against a variety of Gram-positive and Gram-negative organisms can be represented by the following: In vitro activity of [6R-[6a,7fl(2)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[[6,8-difluoro-l-(2-fluoroethyl)-l, 4-dihydro-7-(4-methy1-1-piperazinyl)-4-oxo-3-quinolinyl]carbony1]thio]methyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt trihydrate was as follows: 227 4 70 - 33 n Escherichia coli 257 dco dc, MIC 0.0625 0.125 <0.0157 ED 50 <2 O 10 15 Pseudomonas aeruginosa 56 Staphylococcus aureus Smith Streptococcus pneumoniae 6301 64 <0.0157 43 a) MIC in ug/ml b) ED&0 in mg/kg For combatting bacterial infections in mammals, a 20 compound of this invention can be administered to a mammal in need thereof in an amount of about 5 mg/kg/day to about 500 mg/kg/day. preferably about 10 mg/kg/day to 100 mg/kg/day. most preferably about 10 mg/kg/day to about 55 mg/kg/day. 25 All modes of administration which have been used in the past to deliver penicillins and cephalosporins to the site of the infection are also contemplated for use with the novel family of the dual action cephalosporins of this invention. Such methods of administration include intravenous. 30 intramuscular and enteral administration. The cephalosporin derivatives provided by the present invention can be used as medicaments; for example, in the form of pharmaceutical preparations which contain them in 35 association with a compatible pharmaceutical carrier material. This carrier material can be an organic or inorganic inert carrier material which is suitable for I fl •.r,.K, o - 34 - 227470 c enteral or parenteral administration such as. for example, water, gelatin, gum arabic. lactose, starch, magnesium stearate, talc, vegetable oils, polyalkyleneglycols, petroleum jelly etc. The pharmaceutical preparations can be 5 made up in solid form (e.g. as tablets, dragees, suppositories or capsules) or in liquid form (e.g. as solutions, suspensions or emulsions). The pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preserving, stabilising, wetting or emulsifying agents, salts 10 for varying the osmotic pressure, anaesthetics or buffers. < The pharmaceutical preparations can also contain other ! therapeutically valuable substances. The carboxylic acids of *j formula I as well as their salts and hydrates are especially y! suitable for parenteral administration and for this purpose ' 15 they are preferably made up in the form of lyophilisates or dry powders for dilution with customary agents such as water •i or isotonic sodium chloride solution, as well as solvent ; mediators such as propylene glycol. The readily hydrolyzable | esters of formula I are also suitable for enteral admini- | 20 stration. t l i The following examples are illustrative but not limitative of the invention. 25 Example 1 A suspension of 2-fluoro-l-methylpyridinium p-toluene-sulfonate (21.25 g, 0.075 mol) in dry dichloromethane (300 ml) was cooled to -15° to -10°C in an ice-salt bath and •0 30 stirred under argon. To this mixture 6,8-difluoro-l-(2- -fluoroethyl)-l.4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo--3-quinoline carboxylic acid (22.16 g, 0.06 mol) and 4-dimethylaminopyridine (7.32 g, 0.06 mol) were added slowly at -10°C. The yellow reaction mixture was stirred at -10°C 35 for 30 minutes and then treated with triphenylmethyl- mercaptan (16.6 g, 0.06 mol) and 4-dimethylaminopyridine I ■I 227470 n 35 - (7,32 g. 0.06 mol) at -20°C. the mixture was equilibrated slowly to 23°C and stirring was continued for 16 hours, it was diluted with CH2C12 (about 1.0 I). Concentration of solvent at reduced pressure yielded 45 g of yellow oil, which 5 was purified twice by flash chromatography on silica gel (100 g) and eluted with 20* acetone in CH2C12. The fractions containing the desired product were combined and concentrated in vacuo to give 6,8-difluoro-l-(2-fluoroethyl)--1.4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3-quinolinecarbo-10 thioic acid S-triphenylmethyl ester semihydrate. >f Example 2 A /- A mixture of 6,8-difluoro-1-(2-fluoroethyl)-l,4-dihydro- 15 -7-(4-methyl-l-piperazinyl)-4-oxo-3-quinoline carbothioic acid S-triphenylmethyl ester semihydrate (6.1 g, 9.6 mmol) 1 and aqueous 6N HC1 (8 ml) in tetrahydrofuran (30 ml) was stirred at 23°C under argon for 16 hours. It was concentrated at 30°C and was then taken into water (50 ml) and CHC13 (50 ,, 20 ml). The mixture was treated with 1.0N KOH aqueous solution (about 55 ml) to pH about 11. It was extracted with CHCl3 (2 x 50 ml). The combined CHCl^ extracts were back extracted with water (2 x 50 ml). The organic extracts were dried (MgSO^) and concentrated to give 2.57 g of foam which 25 was shown by thin layer chromatography to be mostly the starting thioester. The combined aqueous phases were passed through a C18 reverse phase chromatography column (100 g) and eluted with a gradient of 3% to 20% acetonitrile-water. The fractions containing the desired product were combined ' 30 and concentrated in vacuo to remove acetonitrile. The aqueous solution was lyophilized to give 6.8-difluoro-1-(2-fluoroethyl )-1,4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3--quinoline carbothioic acid potassium salt hydrate as a yellow solid. 35 IIJIIHW<w i WW >»IUIW<*miiwjmw m**mM&*r,l*r-'' Hfn,- r- 2 2 7 4 7 C - 36 -Example 3 A mixture of 6.8-difluoro-1-(2-fluoroethyl)-1,4-dihydro--7-(4-methyl-l-piperazinyl)-4-oxo-3-quinolino line carbothioic 5 acid potassium salt hydrate (1.8 g. 4.07 mmol) and 2.0 g of propylene oxide in 20 ml of dry dimethylformamide was stirred at 23°C under argon. To this mixture a solution of [ 6R-[6a.7fl(Z)]]-7-[[[[(methoxyimino)-2-(triphenylmethyl)-amino]-4-thiazolyllacetyl]amino]-3-(iodomethyl)-8-oxo-5-thia-1-10 azabicyclo[4.2.0]- oct-2-ene-2-carboxylic acid t-butyl ester (3.69 g. 4.5 mmol) in dry CH2C12 (25 ml) was added and stirring was continued for 36 minutes under argon. The reaction mixture was taken into ethylacetate (100 ml) and washed with water (1 x 100 ml) and brine (2 x 100 ml). The aqueous 15 washings were back extracted with ethyl acetate (2 x 100 ml). The organic extracts were combined, dried (MgS04) and filtered. The solvent was concentrated at reduced pressure to give 4.1 g of crude produce which was flash chromatographed on silica gel (125 g). Elution with 2\ to 4* CH3OH in 20 CHC13 qave fractions 6 to 13 containing the desired product. Evaporation of solvent to dryness at reduced pressure afforded a tan solid: [6R-[6a.7B(Z)]]-3 — CCCC6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3-quinol inyl ] car bony 1 ]thio]methyl]-7-25 [ [ [ [(methoxyimino)-2-(triphenylmethyl)amino]-4-thiazolyl]-acetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,l-dimethylethyl ester. ^ 30 Example 4 A solution of [6R-[6a,7fl(Z)]]-3-[[[[6,8-difluoro-1--(2-fluoroethyl)-l.4-dihydro-7-(4-methyl-l-piperazinyl)-4--oxo-3-quinolinyl]carbonyl]thio]methyl]-7-[[[[(methoxyimino)-2--(triphenylmethyl)amino]-4-thiazolyl]acetyl]amino]-8-oxo-5-35 -thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1. l-dimethylethyl ester (1.9 g. 2.2 mmol). 2 ml of anisole. and 0.1 ml of 1.2-ethanedithiol in 20 ml of CH2C12 was cooled to 0°C and treated with 20 ml of cold trifluoroacetic 227470 - 37 - acid. The reaccion mixture was kepc ac -20°C for 17 hours, and Chen evaporated in a rotary evaporacor ac abouc 4°C and ac reduced pressure. The residue was caken into CH CI w A (10 ml), and eCher (100 ml) was added quickly. The 5 precipicace was collected and washed well with ether to yield 2.03 g of solid. This macerial was dissolved in 1:1 aceconicrile-H20 (20 ml) and creaced wich 5* aqueous NaHC03 solution. During this process, dimechylformamide (5 ml) was added Co dissolve che gummy macerial. More 10 bicarbonace solution was added uncil Che solution reached pH 9.0. The aqueous solution was Chen chromacographed on a reverse phase chromatography (C,_ absorbent) column and 1 O eluted wich 5* Co 60% acetonitrile in water. Fractions 11-16 (eluted with 20* to 25* CH3CN/HzO) were combined. 15 concentraced in vacuo, and Chen lyophilized co give che produce as a white powder: [6R-[6a,7fl(Z)]]-7--[[2-amino-4-chiazolyl)(mechoxyimino)acecyl]amino]-3-[[[[6,8--difluoro-1-(2-fluoroethyl)-1.4-dihydro-7-(4-mechy1-1-pipera-zinyl)-4-oxo-3-quinolinyl]carbonyl ]chio]meChyl]-8-oxo-5-chia-l-20 azabicyclo[4.2.0]occ-2-ene-2-carboxylic acid monosodium sale crihydrace. Following the procedures sec forth in the Examples, the following compounds are prepared: 25 [6R-(6a,7B)]-3-[[[[6,8-difluoro-1-(2-fluoroethyl)-1.4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3-quinolinyl]-carbony1]thio]methyl]-8-oxo-7-[(phenoxyacetyl)amino]-5-thia-l-azabicyclo[4.2.0Joct-2-ene-2-carboxylie acid, 30 [6R-[6a.7B(Z)]]-7-[[(2-amino-4-thiazolyl)methoxyimino]- acetyl]amino]-3-[[[[ l-cyclopropy1-6-fluoro-1.4-dihydro-4-oxo-7 - (1-piperazinyl)-3-quinolinyl]carbonyl]chio]mechyl]-8-oxo-5-Chia-l-azabicyclo[4.2.0]ocC-2-ene-2-carboxylie acid. [6R-(6a.78)]-7-[(cyanoacecyl)amino]-3 -[ [ [ [6. 8-difluoro-35 l-(2-fluoroechyl)-l,4-dihydro-7-(4-meChy1-1-piperazinyl)-4-oxo-3-quinolinyl]carbonyl]Chio]meChyl]-8-oxo-5-chia-l-azabicyclo-[4.2.0]ocC-2-ene-2-carboxylic acid. 227 4 7 0 - 38 - [6R-(6a.78)]-7-[[[[(4-ethyl-2.3-dioxo-1-piperazinyl)-carbonyl]araino]phenylacetyl]amino]-3-[[[[6,8-difluoco-1-(2-fluoroethyl)-1.4-dihydro-7-(4-methy1-1-piperazinyl)-4-oxo-3-quino1iny1]carbony1]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid. [6R-[6a.7B(Z)]]-8-[[(2-amino-4-thiazolyl)-[[(1-carboxy-1-methyl)ethoxy]imino]acetyl]araino]-3-t[[[6.8-difluoro-l-(2-fluoroethyl)-1.4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3-quinoliny1]carbony1]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, [6R-[6a.78(Z)]]-7-[[[(2-amino-4-thiazolyl)(carboxy-met hoxy) imino]acetyl]amino]-3-[[[[6,8-difluoro-l-(2-fluoroethyl )-l,4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3-quino 1 iny1]carbony1]thio]methyl]-8-oxo-5-thia-l-azabicyclo-[4.2.0]oct-2-ene-2-carboxylie acid. [6R-[6a.7B(Z)]]-7-[[[(2-amino-4-thiazolyl)methoxyimino]-acetyl ] amino]-3-[([[9-fluoro-3,7-dihydro-3-methyl-10-(4-methyl-l-piperazinyl)-7-oxo-2H-pyrido[l. 2.3-de]-1.4-benzoxazin-6-yl]-carbonyl]thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, [6R-(6a,78)]-a-[[[2-carboxy-3-[[ [ [6.8-difluoro-l-(2-fluoroethyl)-1.4-dihydro-7-(4-methy1-1-piperazinyl)-4-oxo-3-quinolinyl]carbonyl]thio]methyl]-8-oxo-5-thia-l-azabicyclo-[4.2,0]oct-2-ene-7-yl]amino]carbonyl]benzeneacetic acid. [6R-[6a.78)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-3-[[[[6-fluoro-l-(4-fluorophenyl)-1.4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3-quinolinyl]carbony1]thio]-methyl]-8-oxo-5-thia-l-azabicyclo[4.2.O]oct-2-ene-2-carboxylie acid. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 227 4 7 - 39 -Example A Production of dry ampoules for intramuscular administration: A lyophilisate of 1 g of [6R-[6a.78(Z)]]-7--[[2-amino-4-thiazolyl)(methoxyimino)acety1]amino]-3-[[[[6.8--difluoro-1-(2-fluoroethyl)-1.4-dihydro-7-(4-methy1-1-pipera-zinyl)-4-oxo-3-quinolinyl]carbony1]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt trihydrate is prepared in the usual manner and filled into an ampoule. The sterile water ampoule contains 10% propylene glycol. Prior to the administration, the lyophilisate is treated with 2.5 ml of a 2% aqueous lidocaine hydrochloride solution. 227 4 70 - 40 - WHAT ^v/* • Claims

1. Acyl derivatives of the formula wherein m is zero. 1 or 2. R1 is hydrogen or an acyl 15 group; R is hydrogen, lower alkoxy. lower alkylthio or lower alkanoylamino; R31 is hydrogen, lower alkyl. lower alkenyl. C3~C7 cycloalkyl, halo-lower alkyl, phenyl or mono-, di- or tri-halo-phenyl; Z is R30-C or nitrogen; R30 is hydrogen or halogen, or R30 and 31 20 R when taken together represent a C3-C5 alkylene group, a C -C alkylene mono-oxy group or a C -C 32 alkylene dioxy group; R is hydrogen, halogen, lower alkyl or an optionally substituted 5- or 6-membered heterocyclic ring containing one. two or three oxygen, 33 25 nitrogen and/or sulphur atoms; and R is hydrogen or 32 33 halogen, or R and R when taken together represent a C1-C4 alkylene dioxy group, and the readily hydrolyzable esters or salts of these compounds and hydrates of the compounds of formula I or of 30 their esters or salts. 2

2. A compound as in claim 1 wherein m is zero and R is hydrogen. 30 35

3. A compound as in claim 1 or 2. wherein Z is R -C. wherein R30 is hydrogen or halogen, R31 is lower alkyl, 3 2 halo-lower alkyl or C3~C? cycloalkyl, R is lower n 227 4 70 - 41 - alkyl. piperazinyl or lover alkylpiperazinyl and R hydrogen or halogen. 33 is 30

4. A compound as in claim 3 wherein R is hydrogen or 31 32 5 fluorine. R is ethyl, fluoroethyl or cyclopropyl. R 3 3 is piperazinyl or 4-methylpiperazinyl. and R is hydrogen or fluorine.

5. A compound as in any one of claims 1-4 wherein R is 10 an acyl group selected from the group consisting of A 15 20 (a) an aliphatic group of the formula R-CO- wherein R is selected from the group consisting of lower alkyl. C3-C7 cycloalkyl, lower alkoxy, lower alkenyl, c3~c7 cycloalkenyl or cyclohexadienyl; or lower alkyl or lower alkenyl substituted with one or more halogen, cyano. nitro, amino, mercapto. lover alkylthio or cyanomethylthio groups; 25 30 35 (b) a carbocyclic aromatic group selected from the group consisting of <CH2>n-C- R6V J!8 I - 42 .7 W:-ch,x 227470 o 10 15 20 NW~ fH~*~ X=/ S03 M + o 25 '■&V- SO," M + Q 6 7 8 wherein n is 0, 1. 2 or 3; R. R and R each is independently selected from the group consisting of 30 hydrogen, halogen, hydroxy, nitro. amino, cyano. trifluoromethyl. alkyl of 1 to 4 carbon atoms, alkoxy of 90 1 to 4 carbon atoms or aminomethyl; and R is selected from the group consisting of amino, acylamino, hydroxy, a carboxy salt, protected carboxy, formyloxy or azido; and M is a 35 cation; J ~ (c) a heteroaromatic group selected from the group consisting "-8MM1991^o£ \ /O/' -4 o 227 4 7 0 - 43 - Rl0l-(CH2)n-CO- R101-CH-CO- B 90 10 R10l-O-CH2)-CO- R10l-S-CH2)-CO- 15 R101-CO-CO- 20 .90 is as defined above; and wherein n is 0. 1. 2 oc 3; R' R101 is a substituted oc unsubstituted 5-, 6- oc 7-membeced hetecocyclic cing containing 1, 2, 3 oc 4 nitcogen, oxygen and/oc sulfur atoms; (d) a [[4-substituted-2.3-dioxo-l-pipecazinyl)cacbonyl]-aminojacylacetyl gcoup of the focmula 25 R120- 30 —CO—NH—CH—CO- A111 35 A ) c w c 227470 - 44 - wherein R111 is lower alkyl. hydroxy-lower alkyl or an aromacic group of che formula _7 r6^1r8 6 7 8 wherein R , H and R are as previously defined, or .101 .120 a heceroaromacic as defined for r and R is 10 lower alkyl or subscicuced lower alkyl (wherein Che alkyl group is subscicuced wich one or more halogen, cyano, nicro. amino and/or mercapto groups); 15 G 30 (e) a (substituted oxyimino) arylacetyl group of the formula r130-o-n-c-co- I r101 wherein r101 is as defined above and r130 is 20 hydrogen, lower alkyl, C3-C7 cycloalkyl, carboxy- C3-C7~cycloalkyl or substituted lower alkyl (wherein the alkyl group is substituted with one or more halogen, cyano. nitro, amino, mercapto. lower alkylthio, aromatic group (as defined by r111), carboxy (including salts 25 thereof), lower alkanoylamino. lower alkoxycarbonyl. phenylmethoxycarbonyl. diphenylmethoxycarbonyl. hydroxy-lower-alkoxyphosphinvl, dihydroxyphosphinyl. hydroxy-(phenylmechoxy)-phosphinyl or di-lower alkoxy-phosphinyl subscicuencs); (f) an (acylamino) arylacecyl group of the formula 35 s MAY 1991, •> i V 227470 - 45 - R140-CO-NH-CH-CO-I RU1 wherein R^*1 is as defined above and R*-4® is 6 7 8 (whee R . R . R and n are as previously defined) hydrogen, lower alkyl. substituted lower alkyl. amino, alkylamino. (cyanoalkyl) amino, or acylamino; and (g) a [ [ [3-substituted-2-ojco-l-imidazolidinyl Jcarbonyl]-arainoJarylacetyl group of the formula chy—oh —CO—NH—CH—CO— ,111 wherein R111 is as defined above and R15 is hydrogen, alkylsulfonyl, -NaCH-R111 (wherein R111 is as defined above). R16CO- (wherein R16 is hydrogen, alkyl or halogen substituted alkyl). an aromatic group (as defined by R111 above), lower alkyl or substituted lower alkyl (wherein the lower alkyl group is substituted with one or more halogen, cyano. nitro. amino and/or mercapto groups).

6. A compound as in any one of claims 1-4 wherein R1 is an acyl group comprising a carbocyclic aromatic group of the formula 227470 - 46 - 90 wherein R is selected from the group consisting of amino, acylamino. hydroxy, a carboxy salt, benzyloxy- 6 7 8 carbonyl. formyloxy and azido. and R . R and R are selected from the group consisting of hydrogen, halogen, hydroxy, nitro. amino, cyano. trifluoromethyl. C1-C4 alkyl. C1-C4 alkoxy and aminomethyl. 6 7 8

7. A compound as in claim 7 wherein R . R . R are 90 . hydrogen and R is hydrogen or hydroxy.

8. A compound as in any one of claims 1-4 wherein R1 is an acyl group comprising a group of the formula R130-O-N«C-CO- R101 wherein R101 is an unsubstituted or substituted 5-. 6- or 7-membered heterocyclic ring containing 1. 2, 3 or 4 nitrogen, oxygen and/or sulfur atoms wherein the heterocyclic ring may be substituted by halogen, hydroxy. nitro. amino, cyano, trifluoromethyl. C,-C. alkyl or 130 C1-C4 alkoxy and R is hydrogen, lower alkyl. C3~C7 cycloalkyl. carboxy-C3-C7-cycloalkyl or substituted lower alkyl. wherein the lower alkyl is substituted with one or more halogen, cyano, nitro, amino, mercapto, lower alkylthio, aromatic group (as defined by R111 in claim 5), carboxy (including salts thereof), lower alkanoylamino, lower alkoxycarbonyl, phenylmethoxcarbony1, diphenylmethoxycarbonyl, hydroxy-lower-alkoxphosphinyl, dihydroxyphosphinyl, o 227 4 7 - 47 - hydroxy(phenylmethoxy)phosphinyl or di-lower-alkoxy-phosphinyl.

9. A compound as in any one of claims 1-4 wherein R1 is 5 an acyl group of the formula DOR 21 10 JO r 20 ^ 15 wherein R is hydrogen or an amino protecting group 21 . R is hydrogen, lower alkyl or a group of the formula R22 I -C-COOH 20 R23 22 23 wherein R and R are selected rom the group consisting of hydrogen, lower alkyl or taken together with the carbon atom to which they are attached form a 25 3-7-membered carbocyclic ring. 20

10. A compound as in claim 9 wherein R is hydrogen. 21 R is methyl or 30 R22 I -C-COOH I R23 35 22 2 3 wherein R and R are selected from the group consisting of hydrogen and methyl. e^ys<lS^,v ■ *•K \ 4 MNaWmWIMWMKK '£ Si \ - 48 C 227470

11. A compound as in claim 1 of the formula R20NH 10 wherein R20 is hydrogen or an amino protectinq 21 group# R has the meaning given in claim 9 and Z, 31 32 33 R , R and R have the meaning given in claim 1. 15

12. A compound as in claim 11 wherein R21 is methyl or a group of the formula R22 \ I 20 -C-COOH I c I R23 22 23 wherein R and R are hydrogen or methyl, Z is 25 R30-C wherein R30 is hydrogen and halogen, R31 is lower alkyl, halo-lower alkyl or C_-C_ cycloalkyl. 32 R is lower alkyl, piperazinyl or lower alkyl- 3 3 piperazinyl and R is hydrogen or halogen. 30

13. A compound as in claim 12 wherein R30 is hydrogen 31 or fluorine, R is ethyl, fluoroethyl or cyclopropyl, 3 2 R is methyl. 4-methyl-piperazinyl or piperazinyl and 3 3 R is hydrogen or fluorine. 35

14. A compound as in claim 1 which is [6R-[6a,7fl(Z)]]- 21 7-[[(2-amino-4-thiazolyl)(R -oxyimino)acetyl]amino]-3- [[[[6-R33,8-R3°-l-Cl-R31)-1.4-dihydro-7-(4-R34-l- >*-.,S«PSCT' ' -; E" V «» 5 * • 8 MAY I99li J ^ y, n. <mmm»www «m ■—wwiwiw •■■. O 22 7 4 ? n - 49 - piperazinyl)-4-oxo-3-quinoliny1jcarbonyl]thio ]methyl J-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and its pharmaceutically acceptable salts and hydrates of these acids and salts, wherein R33 and R30 is hydrogen or halogen. 3 3b 34 5 R is hydrogen, lower alkyl or halogen-lower alkyl, B is hydrogen or lower alkyl and R21 is the group B22 I -C-COOH V~" 10 I B23 22 23 wherein B and R are selected from the group consisting of hydrogen and lower alkyl. 15

15. A compound as in claim 14 wherein R22 and R23 are both methyl.

16. A compound as in claim 15 wherein B33 and R30 are 31 hydrogen and fluorine, R is ethyl or 2-fluoroethyl and 34 20 R is methyl.

17. A compound as in claim 15 wherein R33 and R30 are 31 fluorine, and R is 2-fluoroethyl. 33 25

18. A compound as in claim 14 wherein R is fluorine, a 0 1 1 A R is fluorine, R is 2-fluoroethyl and R is methyl. 3 3

19. A compound as in claim 14 wherein R is fluorine. >-«». R30 is hydrogen, R31 is ethyl and R34 is methyl. 30 3 3

20. A compound as in claim 14 wherein R is fluorine, R31 is 2-fluoroethyl, R30 is hydrogen and R34 is methyl.

21. A compound as in any one of claims 8-20 wherein the oc ., _ -13 0 21 35 N-O-R N-O-R II II -C- and -C- groupings are in the syn-forra, i.e.. the Z-form, or as mixtures in which the syn-form predominates. 227470 - 50 -

22. A compound as in claim 1 which is t6R-[6a,78(Z)J]-7-[[2-Amino-4-thiazoly1)(methoxyimino)-acetyl]araino]-3-[[[[6,8-difluoro-1-(2-fluoroethyl)--l,4-dihydco-7-(4-methy1-1-piperazinyl)-4-oxo-3-quino liny1]-5 carbony1]thio] methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2--ene-2-carboxylic acid as well as salts of this compound and hydrates of this compound and salts.

23. Compounds as set forth in any one of claims 1-22 as 10 pharmaceutical^ active substances.

24. Compounds as set forth in any one of claims 1-22 as pharmaceutically active substances for the treatment and prophylaxis of infectious diseases. 15

25. A pharmaceutical preparation containing an acyl derivative according to any one of claims 1-22.

26. A pharmaceutical preparation for the treatment and 20 prophylaxis of infectious diseases containing an acyl derivative according to any one of claims 1-22.

27. A process for the manufacture of the acyl derivatives according to any one of claims 1-22, which comprises 25 30 c (a) for the manufacture of an easily hydrolyzable ester of a carboxylic acid of formula I reacting a compound of the formula RNH —r-—" CH2 Hal COOR' 35 4 „1 , 2 wherein m, R and R are as defined in claim 1, Hal is halogen and R* is the residue of an easily hydrolyzable ester. 8MAY!99i:. rh • salt of a carbothioic acid of the formula '«iff! -M*4 - 51 - 227470 n HSCO III A c . , 31 32 . _33 , ,. wherein R . R and ?. are as defined in claim 1, 10 or (b) for che manufaccure of a carboxylic acid of formula I convercing an escer of che formula 15 20 to] 2 H t m •CHjSCO- COOR IV 25 1 2 31 32 33 wherein m. R . R . R . R and R are as defined in claim 1 and R is an escer procecting group, 30 to che carboxylic acid of formula I, or (c) for che manufacture of a compound of formula I, in which m is zero, reducing a compund of che formula 35 MMl99l£ji V( t - 52 - 227470 o wherein R1. R2. R31. R32 and R33 are as defined in claim 1, or (d) Cor the manufaccure of a compound of formula I, in which m is 1 or 2. or an escer or sale thereof oxidizing a compound of che formula •ch2sco- COOH VI wherein Rl, r2, r31, r32, and r33 are as defined in claim 1 and che dotced lines indicace che presence of a A2 oc A3 double bond, or an escec oc sale checeof, oc e) for the manufacture of a compound of formula I, in which r! contains an amino substituent, or an ester or salt thereof, cleaving off the amino-protecting group in the substituent RlO of a compound of the formula - 53 - 227470 R10NH CH^SCO 1 R 33 32 VII 5 coon R R 31 10 wherein m, r2, r31, r32 and r33 are as defined in claim 1 and RlO is an acyl group containing a protected amino group, or of an ester or salt thereof, or (f) for the manufacture of a readily hydrolyzable ester of a 15 compound of formula I subjecting a carboxylic acid of formula I to a corresponding esterification. or (g) for the manufacture of salts or hydrates of a compound of formula I or hydrates of said salts converting a compound 20 of formula I into a salt or hydrate or into a hydrate of said salt.

28. Process according to claim 27, characterized in that 25 one of the process alternatives (a), (b), (c) and (d) is carried out. 30 35 O O h' / M A « / •! / 0 - 54 -

29. The use of che compounds according co any one of claims 1-22 in che creacmenc or pcophylaxis of illnesses O other than in humans.

30. The use of che compounds according co any one of 5 claims 1-22 in che creacmenc or pcophylaxis of infeccious diseases other than in humans. C 31 * The use of che compounds according co any one of claims 1-22 foe the manufactuce of medicaments foe che 10 tceatment or pcophylaxis of infectious diseases. O 15 20 25 30 35 MAY 1991*1 V J/ 227470 - 55 -

32. Compounds according to any one of claims 1-21 whenever prepared according to the process claimed in claim 27 or 28 . 5 10 15 20 25 30 35 t-\ - 8 MAY I99l»„ - 56

33. An acyl derivative according to claim 1 substantially as described herein with reference to any one of Exarrples 1 to 4.

34. A pharmaceutical preparation containing an acyl g derivative according to claim 1 substantially as described herein with reference to Exanple A.

35. A process for the manufacture of the acyl derivatives according to claim 1 substantially as described ^ herein with reference to any one of Examples 1 to 4. dated this day 0f A. J. PARK & SpN / j per /J agents for THE APPLICANTS 15 20 c 25 30 35 * -8 MAY 1991 </div>