AU624810B2 - Acyl derivatives - Google Patents

Abstract

Acyl derivatives of the general formula <IMAGE> in which R<1> denotes a substituted N-heterocycle of the formulae <IMAGE> in which R<1><0> represents one of the groups <IMAGE> and Q represents a substituted quinolinyl or naphthyridinyl group, where the N-heterocycle can optionally be substituted by one or more lower alkyl groups; and in which R<2> additionally represents hydrogen, lower alkoxy, lower alkylthio or lower alkanoylamino, R<3> represents an acyl group, m represents 0, 1 or 2 and A represents a pharmaceutically tolerable anion, and easily hydrolysable esters and pharmaceutically tolerable salts of these compounds and hydrates of the compounds of the formula I or of their esters and salts and a process for their preparation and pharmaceutical preparations which contain this compound, and also intermediates for the preparation of these compounds, and additionally the use of the compounds for the control of diseases and for the production of the preparations mentioned are described. The products have antibiotic activity.

Description

6 2 4 8 i0o 81 00 FORM 10 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1951 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE: Class Int Class Complete Specification Lodged: Accepted: Published: Priority: Related Art: Name and Address of Applicant: Address For Service: F Hoffmann-La Roche Co Aktiengesellschaft Grenzacherstrasse 124-184 4002 Basle

SWITZERLAND

Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Complete Specification for the invention entitled: Acyl Derivatives The following statement is a full description of this invention, including the best method of performing it known to me/us 5845/3

NV.

RAN 4410/216k Abstract Acyl derivatives of the general formula CH2

I

ala a a at a a a a*@ II 4 4 44 a ~,a 1* a 4 44 cN4 a, a a wherein R 1is a substituted N-heterocyclus of the f o rmu las

A

0 CH 3 (a) -0C0R 1 0 (c)

LU

where R 10is Ohd of the groups 0 (C2) (C3) -NHCH 2 -7 (C4) Q represents a substituted quinolinyl or naphthyridinyl group and the N-heterocyclic nucleus may optionally be substituted with one or more lower alkyl groups; R 2 is selected from the group consisting of hydrogen, lower alkoxy, lower alkylthio and lower alkanoylamino; R 3 is an acyl groups; m is zero, 1 or 2; and A is a pharmaceutically acceptable anion and readily hydrolyzable esters and pharmaceutically acceptable salts of these compounds and hydrates of the compounds of formula I or of their esters or salts.

The products are antibacterially active.

S 00 0 B# 0 02 0 2 0 0 i RAN 4410/216k The present invention relates to acyl derivatives of the general formula ii

I

I

0 0 ,0 00 0 0 0 0o b 0*0 *o 0 #00 0 00 0e 0 000 1 0O 0O00 0* wherein R1 is a substituted N-heterocyclus of the formulas 0

A

0

CH

3 A

(D'

CH 3

-OCOR

10 (c) where R 10 is one of the groups 3 0 -0 (cl) (c 2 -NH (C3)

-NCH

2

J:

(c) 1.89 I ~e 2 Q represents a substituted quinolinyl or naphthyridinyl group and the N-heterocyclic nucleus may optionally be d substituted with one or more lower alkyl groups; R is selected from the group consisting of hydrogen, lower 3 alkoxy, lower alkylthio and lower alkanoylamino; R is an acyl groups; m is zero, 1 or 2; and A is a pharmaceutically acceptable anion, and readily hydrolyzable esters and pharmaceutically acceptable salts of these compounds and hydrates of the compounds of formula I or of their esters or salts.

As used herein, the terms "lower alkyl" and "alkyl" refer to both straight and branched chain saturated S hydrocarbon groups having 1 to 8, and preferably 1 to 4, carbon atoms, for example, methyl, ethyl, n-propyl, o O isopropyl, t-butyl, and the like.

I As used herein, the term "lower alkoxy" or "alkoxy" refers to a straight or branched chain hydrocarbonoxy group wherein the "alkyl" portion is a lower alkyl group as defined above. Examples include methoxy, ethoxy, n-propoxy I "and the like.

The term "halogen", or "halo", used herein refers to all four forms, that is, chloro, bromo, iodo and fluoro, unless specified otherwise.

By the term "aryl" is meant a substituted or unsubstitu- S* 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 (fluoro, chloro, bromo, etc.), hydroxy and the like.

By the term "lower alkanoyl" or "alkanoyl" as utilized herein is intended a moiety or the formula R 3 3 wherein R 2 5 is hydrogen or C to C lower alkyl.

1 6 Examplary of such groups are formyl, acetyl, propionyl, n-butyryl and the like.

By the term "substituted phenyl" is meant phenyl monoor di-substituted by e.g. halo chloro, bromo, fluoro, etc.), lower alkyl, amino, nitro or trifluoromethyl.

By the term "substituted alkyl" is meant a "lower alkyl" moiety substituted by, for example, halo chloro, fluoro, bromo, etc.), trifluoromethyl, amino, cyano, etc.

By the term "lower alkenyl" or "alkenyl" is meant straight or branched chain hydrocarbon qgroups which contain an olefinic double bond having 2 to 6 carbon atoms, i.e. the radical of compounds of the formula C H2n wherein n is 2 to 6, e.g. vinyl, allyl, etc.

By the term "aralkyl" is meant a hydrocarbon group having both aromatic and aliphatic structures, that is, a l hydrocarbon group in which a lower alkyl hydrogen atom is 0 substituted by a monocyclic aryl group, e.g. by phenyl, 0 tolyl, etc.

The expression 6- or 7-membered heterocyclic ring containing 1-4 nitrogen, oxygen and/or sulfur atoms" is intended to represent the following groups: a 6-membered nitrogen-containing hetero ring, e.g. pyridyl, piperidyl, piperidino, N-oxido-pyridyl, pyrimidyl, piperazinyl, pytidazinyl, N-oxido-pyridazinyl, etc.; a nitrogen-containing hetero ring such as pyrazolyl, pyrrolidinyl, imidazolyl, thiazolyli, 1,2,3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1.2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triaxoLtyl, 1-tetrazolyl, 2H-tetrazolyl, etc., and others. Each of these hetero rings may be further substituted and, as the k LI1 -i I__L_1 1 4 substituents, there may be meirtioned, for example, lower alkyls such as methyl, ethyl, n-propyl, etc., lower alkoxys such as methoxy, ethoxy, etc., halogens such as chlorine, bromine, etc., halogen substituted alkyls such as trifluoromethyl, trichloroethyl, etc., amino, mercapto, hydroxy, carbamoyl or carboxy, etc.

By the term "cyclo-lower-alkyl" or "cycloalkyl" is meant a 3-6 membered saturated carbocyclic moiety, e.g.

cyclopropyl, cyclobutyl, cyclohexyl, etc.

3 The term "acyl" used in conjunction with R herein refers to all organic radicals derived from an organic acid, such as a carboxylic acid, by removal of the hydroxyl group.

3 Although the group R may be any one of many acyl o radicals, certain acyl groups are preferred, as described below.

Exemplary acyl group R are those groups which have been used in the past to acylate 1-lactam antibiotics, including 6-aminopenicillanic acid and derivatives and 00 7-aminocephalosporanic acid and derivatives; see, for o example, Cephalosporins and Penicillins, edited by Flynn, Academic Press (1972), Belgian patent 866,038, published October 17, 1978, Belgian patent 867,994, published December 11, 1978, United States patent 4,152,432, issued May 1, 1979, United States patent 3,971,778, issued July 27, 1976, and United States patent 4,173,199, issued October 23, 1979.

: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", without intending to limit that term to only those groups set forth: Aliphatic acyl groups having the formula R COr

A

wherein R 5is selected from the group consisting of hydrogen, lower alkyl, C 3

C

7 cycloalkyl, lower alkoxy, lower alkenyl, C3 7cycloalkenyl or cyclohexadienyl, or lower alkyl or lower alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, lower alkylthio or cyanomethylthio groups.

Aromatic acyl groups selected from the group consisting of it

I

I1

I

J

4 OttO 00 0 40 0 4 00 0 0 44 00 t 4 4 it a 4 I I t4 4* 94 t 4 4 4 4 4 i a 4'01 CH- Co-

CH

2

CO-

*O-H,-CO-

I-

6-H-C 4 R6 K~ 44CH- CO 1 20 1 o~ Ii j8 67 290 1hri to 4 s cabo a1om an or ino;etyl, and R ise ',LJ~jselected from the group consisting of amino, acylamino, hydroxy. a carboxy salt, protected carboxy,e.g. benzyloxycarbonyl, formyloxy, azido and a sulfo salt, and M is a cation.

Preferred carbocyclic aromatic acyl groups Include those having the formulas -7-

CH

2 Co- OC 2

-CO-

a 2

H-CO

R

90 4 0,a 0 200 R is arfrbya mn ruahdoygopo (pheoxysaetyol). slt Examples of other acyl groups suitable for the purposes of the present invention are sulfophenylacetyl, hydroxysulfonyloxyphenylacetyl, sulfamoylphenylacetyl, (phenoxycarbonyl)phenylacetyl., (p-tolyloxycarbonyl)phenylacetyl, forrnyloxyphenylacetyl. carboxyphenylacetyl, formylaminophenylacetyl, benzyloxycarbonylphenylacetyl, 2-(N,W--dimethylsulfamoyl)-.2-phenylacetyl, etc, 8 Heteroaromatic groups having the formula

R

10 (CH -CO- 2 n 101 R -CR-CO-.

R -Q-CR -CO- 2 101 R -S-CU -cO- or 0 -CO-CO- I whoxein n is 0, 1, 2 or 3 R is as defined above; and R is a substituted or unsubstituted 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 1i (preferably I or 2) nitrogen, oxygen and/or sulfur atoms.

Exemplary heterocyclic rings are thienyl. ftryl.

pyrrolyl, pyridinyl, pyrazinyl, thiazolyl., pyrimidinyl and tetrazolyl. Exemplary substituents are halogen, hydroxy, nitro, amino, cyano, trifliuoromethylo alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms, Preferred heteroaromatic acyl groups include those groups of the above formulas wherein R101 is 2,.amino- -4 thiazotyl, 2-amino-45-halo-4-thiazolyl, 4-aminopyidin- -2-yli 2-amnno-l03 o -thjad iazo 2" thienyl 2-turanya 4-pyridinyl or 2,6-ctchloro-4-pyridinyl.

4i; L.

2

F-

-9- Substituted-2.3-dioxo-l-piLperazifyl)carboflyl] aminojarylacetyl groups having the formula R'l2. -CO-NH-CH-CO- 0il 2 2 r~ wherein R is lower alkyl iydroxy-lower alkyl or an aromatic group (including carbocyclic aromatics) such as those of the formula 0 2r to 2 wherein R 6 fl and R are as previously defined and heteroaromatcs as included within the definition of R 0 1 and R 1 0 is lower alkyl, subetitlted alkyl (wherein the alkyl group is substituted with one or more s halogeRi cyano, nitro, amino or mercapto gtoups)o e.g., 4-lower alkyl (preerably ethyl or methyl) 2.3-.dioxo- -i-piperazlneabOnyt-D phenylglycyl ($ubstitUted oxyimino) arytacetyl groups having the fornula i i _r R wherein R is as defined above and R 13 is hydrogen, lower alKyl. C- cycloalkyl. carboxy- -C C 7 cycloalkyl or substituted lower alkyl [wh~erein the lower alkyl group i~s substituted with one or more halogen. cyano, nitro, amino. Inercapto. lower a lKylthio, aromatic group (as defined byR carboxy (including salts thereof), lower alkanoylanino.

carbainoyl, lower alkoxycarbolnyl, phenylmethao ycatboayl, diphenylrnethoxycarbonyl, hydroxy-lower-alkoxyphosphinyl.

dihydroxyphosphinyl. hydroxy(phenylmethoxy)phospiinyl, dilwraIxpophnlsbttet) Examples of the

R

1 3 0

=-O

R101 O~ grouping are (2-[(chloroacetyl)amino]-4-thiazoly1](methoxyamino)acetyl, (2-amlno-4-thiiazolyl) (1-methylethoxyimino)acetyl, (2-amino--4-thiazolyl) (methoxyimino)acetyl, (2-furyl)- (methoxyimino)acetyl, (4-hydroxyphenyl) (methoxylmino)acetyl, (methoxyiiuino)(phenyl)acetyl, (hydroxyImino) (phenyl)acetyl, (hydroxyimino)(2-thienyl)acety., (j(ichloroacetyl)oxylmino] (2-thienyl)acetyl, (5-cohloro-2-( (chloroacetyl)aminoj-4thiazolyl](iuethoxyimino)acetyl, (2-amino-5-chloro-4-thlazolyl)(methoxyilno)acetyl. Cftl-(l,2L-dimethylethoxy)car- (El-(l,1-imethylethoXycarbonyJ-l-methyethoxy)iminno' ([2-(ttiphenylmethyl)amlno3-4-thlazollyllacetyl, (methoxyimi-I no)(2-sulfoamino-4-thiazolyl)acetyl. ((Imethylethoy)Irn3noj- (2-4 (methylsu].fonyl)amino3-4-thiazolyllacetyl. t(3-methy'lsul-

F

-9 11 fornyl)-2C3H]-th4 azolimin--4-yl]-Cl-(methylethoxy)imino]acetyl, C E2-(chloracetyl)amdno]-4-thiazolylj C C C(4-nitrophenyl)methoxyjcarbonyl Imethoxy.imino]acetyl, (2-amino-4--thiazoly),(carboxymethoxy)iminojacetyl. (2-amino-4-thiazolyl)- (1-carboxy-(l-methylethoxy) imino-lacetyl, (2-amino-4-thiazolyl) CC(arinocarbonyl)methoxyjiminojacetyl.

(Acylamino)acetyl groups having tho formula in R -4_CO-NH-OH-CO.wherein R is as defined above and 4 04 4 00 0 0 4 00 0 00 44 4 4 4 44 4' 4 4 44 44 0 0 00 R6 R 8 (CH-o 4444.

4 4 6 7 8 (where R .R R 8 and n are as previously defined), hydrogen, lower alkyl, substituted lower alkyl, am~ino, lower alkylamino, di-lower-alkylamino, (cyano-lower-alkyl)amino, hydrazino, lower alkyl-hydrazino, aryl-hy'drazino or acyl-hydrazino.

Preferred (aoylamino)acetyl groups of the above formula Include those groups wherein R10is amino or acylantino.

Also preferred are those gro~ups wherein~ R il s phenyl or 2- thie nyl, substitu~ted oxyiminqacetyl groups having the torrnula 5845/3 fi -12- CO-C-0-N=C-CO- R23 ill wherein R iland R 10are as defined above, and R 22and R 23are independently selected from the group consisting of hydrogen and lower alkyl, or R 22 and R 23 taken together with the carboi 4 atom to which they are attached form a C 3-C7 carbocyclic ring, for example, cyclopropyl, cyclobutyl or cyclopentyl.

Preferred substituted oxyimino acetyl groups of the 140 above formula include those groups wherein R is amino.

Also preferred are those groups wherein R i s 2-afaino-4-thiazolyl.

00 40 0(h) [C L3-Substituited-2-oxo-l-imidazolidiiyljcarbonyl]amino~acetyl groups having the formula 4 W4 0 25444 C H C O wherein Rilis as defined above and R 15 is hydrogen, lower alkylsulfonyl, aryliuethyleneamino -Nt=CHR wherein R is as defined above), R16 co weenR16 is hydrogen, lower alk-'%-Yl or hal6gep. substituted lower alkyl). aroma~tic group (as defined by Rilabove), lower alkyl or substituted lower alkyl (wherein the lower alkyl group is 13 substituted with one or more halogen, cyano, nitro, amino or mercapto groups).

Preferred [[[3-substituted -2-oxo-l-imidazolidinyl]carbonyl]amino]acetyl groups of the above formula include 111 those wherein R is phenyl or 2-thienyl. Also preferred are those groups wherein R 5 is hydrogen, methylsulfonyl, phenylmethyleneamino or 2-furylmethyleneamino.

R in formula I is any of the substituted N-heterocyclio groups and above, preferably group (a) or group in which R10 is group (c R 1 can be any of the following groups: 15 Groups and (quaternary piperazinium salts) o 0 D Hereunder A represents a pharmaceutically acceptable o anion pertaining to a pharmaceutically acceptable organic or inorganic acid. Examples of such acids are hydrohalic acids hydrochloric acid, hydrobromic acid and hydroiodic acid) as well as other mineral acids such as sulphuric acid, t nitric acid, phosphoric acid arid the like; lower alkanesulphonic and arylsulfonic acids such as ethane-, tolueneand benzene-sulfonic acid, and also other organic acids such 4 4 4 as acetic acid, trifluoroacetic acid, tart tic acid, maleic acid, malic acid, citric acid, benzoic aci&, salicylic acid, ascorbic acid and others. Under A is also unterstood the anion formed from the 2-carboxy group of the cephalosporin nucleus after dissociating off a proton and thus forming a zwitterion which is neutralized by the accompanying positive charge on the quaternary nitrogen atom.

Preferred embodiments of the anion A are the iodide anion, the trifluoroacetate anion and the 2-carboxylate anion on the cephalosporin nucleus which forms an inner salt with the piperazinium moiety present in R 27 14 Qin groups and is a substituted quinolinyl or naphthyridinyl group, preferably of the formula 0 R,33

COOH

z N 101 wherein Z represents R -C or nitrogen. R represents hydrogen, halogen or an oxymethylene (-CH 2 O0-) bridge to the piperazine nucleus to form a fused six-mew~bered ring; R 31 represents hydrogen, lower alkyl, lower alkenyl, C- cycloalkyl, halo-lower alkyl or moaio-, di- or tri-halophenyl; R 3 11 Sand R wihezi taken together represent a C -alkylene group, a 2- C 4 alkylene mono-oxy group, a CI- C 2alkylene dioxy grotip or a gro~up of the formula 2 33 -OQCH 2

N(CHI

3 and R represents hydrogen ov hal.o gen, In a praferred embodiment ther~eof, Z is R 30 C wherein, 30.i to 25 R is hydrogqa, bromine, chlorine or fluorine, most preferably hydroqen or flourine; and R 31is lower alkyl, most preferably e *hyl, or halogen substittuted lower alkyl, most preferably fluoroethyl, or a'LternatiVely C-C7 -cycloalkyl. most preferably cyclopropyl; and R is hydrogen, chlorine or fluorine, most preferably hydrogen or fluorine.

As used herein the substituted piperazinium substituent R 1as groups and includes, among others, groups ot the fo.-mulae 0 F

C

2

H

N N N

N)

1 ii 0

N

16 0 F C0 2

H

4W

N>CH

0 002 N N1 NJ)

N

r 16, 0- F CO 2

H

N

N

N F FF CH3 140 10 F OC 2

H

N N N 43 fi

CH

3 PD O

F

L vD Fr CC02H 0 0 <o N

N

~N)

N N ss -J I 4 CH3 0 0r

F

NH

,rN I ')A n 1 17

CO

2

H

0 *00 r~o 0 0 00 00 o 000 00 0 0 00 0 00 00 0 0 00 0 00 00 00 00 0 0 0 0000 0 00 00 0 0 00 00 0 0 00 00 00 00 0 0 0000 0 0 0004 00 0* 00 0 0 0 IK (it) Group (urethanes) Q in group is preferably of the formula 30 wherein Z represents R 3_Cor nitrogen, X represents oxygen or sulfur, R represents hydrogen, halogen or an oxymethylene 2 bridge to the piperazine nucleus to form a fused six-membered ring; R 31 represents hydrogen, lower alkyl. lower alkenyl, c 3 c 7 cycloajlkyl, halo-lower a1tkyl or iuono-, di- or tri-halophenyl.: R, 30 and R 31 when taken together reprRsent a C 3

C

5 aIlkylene group, a C 2 -C 4 2 18 alkylene mono-oxy group, a C -C alkylene dioxy 33 group or a group of the formula -OCH 2

N(CH

3

R

34 is hydrogen or halogen; and R is hydrogen or amino.

In a preferred embodiment thereof, Z is R -C wherein 30 R is hydrogen, chlorine, bromine or fluorine, most preferably hydrogen or fluorine, R 31 is lower alkyl, most preferably ethyl, or halo-lower alkyl, most preferably fluoroethyl, or C3-C 7 -cycloalkyl, most preferably 33 cyclopropyl, and R is hydrogen, chlorine or fluorine, most preferably hydrogen or fluorine.

As used herein the urethane group as a meaning of R includes, among others, groups of the formulas I t F o"C0 2

H

0 20 o0

FCH

t

N

0

FCO

2

H

F s .C0'^H <Qc^r

NHCH

3 .1 19 C0 2

H

4 44 44~* 4 4 4.4 44 44.9 4.

4. 44 4 44 44 4 4 4.44 4.44 44. #4 4 4. 4 4444 4 4 44 4 4. 44 4 4 4 4* 44 44 44 4 4 4 4444 '4 44444 4.4 44 4 4 0 F ollC0 2

H.

N 0

CH

3 0 F o"C0 2

H

FX Xt) C0 2

H

,CO2H 1 0 F. C0 2

H

N N N I 0 FO C0 2

H

N: N F.C0 2

H

N NN o CNH 0 N 4 N 0 N 0 04 N4N 0 0 'k 0 rl-N

I

21 0 F or"C02H

NHCH

2 I

A-

NH

2 0 C 2

H

N N Preferred compounds within the purview of the present i' 2 invention are those of formula I in which m is zero and R is hydrogen. A still more preferred class of compounds are of the formula o- 2 S O I 64 21 ,NOR R2 *44R,2ON H COOHVR1

I

S3 .4 2 wherein R and R are as above, R is hydrogen or i- i an amino protecting group, for example, trityl or chloroaoetyl, or, preferably, hydrogen: and R 2 1 is hydrogen, lower alkyl or a group of the formula 4.

S222 1

-C-COP

1

R

2 3 I6 22 wherein R 22and R 23are as defined above and P is hydroxy or -NHR 19where R 19is hydrogen, lower alkyl, amino, lower alkylamino. aryl.=,no or acylamino.

Still more preferred are compounds of the formula la in which R 0is hydrogen, and R 1is methyl or a group of the f ormula R 22

-C-COOH

R

2 3

I

444444 4 4 44 #4 4 ~44 4 I 14 I 44 44 4 4 44 4 44 44 44 4 4 4 4 44 4 4 44 4 4 4 4 44 44 44 4 4 4 4 4 22 23 15 wherein R and R are selected from the group consisting of hydrogen and methyl, Preferably. the 130 20 R .O-N-C--CO- R22 140 I I R 2 R ll.

and NOR 21 11 -c-cO- If k -23groupings are in the syn-form, the Z-form, or as mixtures in which the syn-form predominates.

Still another preferred class of compounds are those of the formula q-C.i ONH CH R 11 l wherein, f is as above and R is one of groups (a) I and above, As readily hydrolyzable esters of the compounds of 20 formula I there are to be understood compounds of formrula i, the carboxy group(s) of which the 2-carboxy group) is/are present in the form of readily hydrolyzable ester groups. Examples of such esters, which can be of the a conventional type, are the lower alkanoyloxyalKyl esters the acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl V and )1-pivaloyloxyethyl ester), the lower alKoxycarboayloxyalkyl esters (eg. the methoxycarbonyloxymethyl, l-ethoxycarbonyloxyrethyl and 3-4sopropoxycarbonyloxyethyl U ester), the lactonyl esters the phthalidyl and thiophthali~yl ester), the lower alkoxymethyl esters the methoxymethyl ester) and the lower alkanoylaminomethyl esters the acetamidomethyl ester). other esters the benzyl and cyanomethyl estert4) can also be Used, 24 Examples of salts of the compounds of formula I are 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 salts with N-ethyl-piperidine, procaine, dibenzylamine, N,N'-dibenzylethylenediamine, alkylamines or 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 with organic or inorganic acids, Examples of such salts are hydrohalides hydrochlorides, hydrobromides and hydroiodides) as well as other mineral acid salts such as sul- 15 phates, nitrates, phosphates and the like, lower alkylsulphonates and monoarylsulphonates such as ethanesulfonates, toluenesulphonates, benzenesulphonates and the like and also S, other organic acid salts such as acetates, tattrates, I o maleates, citrates, benzoates, salicylates, ascorbates and 20 the like, The compounds of formula I as well as their salts and readily hydrolyzable esters can be hydrated. The hydration I o4 «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 which 30 comprises a) for the manufacture of a compound of formula I, in which

K

25 m is zero, reacting a compound of the general formula r 2 _U

H

2

NI

i -J H i COOH wherein R and R are as above, or a readily hydrolyzable ester or salt thereof with a I carboxylic acid of the general formula RJOH or a reactive derivative thereof, or b) for the manufacture of a compound of formula I, in which S" m is zero and R is one of the groups and I reacting a compound of the formula 1 22 j

H

1 25 CH'y'^y x II

OOH

wherein R and R 3 are as above and X is a leaving group, and amino, hydroxy and earboxy groups present may be protected, or a readily hydrolyzable ester or salt thereof with a compound of the formula 26

CH

3

C

3 IVa wherein Q is as above and the nitrogen atoms may be protected, ii

AI

444~44 4 4 *4 44 4 444 44 4 4 44 4 44 44 4 $4 S 44 44 44 4 4 4 S 4 4 44 4 4 44 44 4 5 44 *4 44 4

S

15 for the manufacture of a readily hydrolyzable ester of a carboxylic acid of formula I, in which m is zero and R 1is group reacting a compotind of the formula -j 3 NHi.

CH

2 0H wheei, 2and R3are as above and W~ is the residue of a readily hydrolyzabl~e ester, in the presence of a base with phosgene and reacting the reaction product obtained with a compound of formula R 10 6 in which R is as above, except that amino, hydroxy and/or carboxy functions thereof may be protected, ,oll .Wed by cleavage of any protecting group present, or d) for the manufacture of a carboxylic acid of formUla I converting an ester of the formula Ii 27 2.

COOR

1 2 3 wherein R R R and m are as above, and R is a carboxylic acid protecting group, to the carboxyl~ic acid of formula 1, or 15 e) for the manufacture of the compound of formula 1, izi whicQh m is zero, or a readily hydrolyzable ester or salt thereof reducing a compound of t~ie formula 444444 I~ 4 4* 4 4 4 00 4 04 44 0 4 0 4 44 44 44 44 4 4 Iii 04 44 4 4 44 4 4 4 4 44 00

R

2 *2

__OO_

VII.

44 44 44 wherein R 1, f2 anid R 3are as above, or a readily hydrolyzable ester or salt thereof, or f) for the manufacture of a compound of formula I in which m is I or 2 or a readily hydrolyzable ester or salt thereof oxidizing a com~pound of the formula -4 28 2 R 3NH- S

CH

2

R

1

VIII,

COOH

1 2 3 wherein R R and R are as above and the dotted lines indicates the presence of a 42 or A3 double bond, or a readily hydrolyzable ester of salt thereof, or Sg) for the manufacture of a compound of formula I, in which R contains an amino substituent, or a readily hydrolyzable ester or salt thereof cleaving off an amino 30 protecting group in the substituent R of a compound of 20 formula 444 (0) j 2 H II m Il C3-- R wherein R 2 and m are as above and R 30 is an acyl group containing a protected amino substituent, or of a readily hydrolyzable ester or salt thereof, or h) 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 1 -29i) 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 acids R3OH or their reactive derivatives according to embodiment can be carried out in a manner known per se. The carboxy group in compounds II can be protected; for example, by esterification to form a readily cleavable ester such as a silyl ester the trimethylsilyl ester). The carboxy group can also be protected in the form of one of the aforementioned readily hydrolyzable esters. Furthermore, the carboxy group can be protected by salt formation with an inorganic or tertiary organic base such as triethylamine.

Amino groups present in groups R can be protected.

*Possible protecting groups are, for example, protecting a ,l groups which are cleavable by acid hydrolysis the tert.butoxycarbonyl or trityl groups) or by basic hydrolysis S 20 the trifluoroacetyl group). Preferred protecting igroups are the chloroacetyl, bromoacetyl and iodoacetyl i groups, especially the chloroacetyl group. These lasti -mentioned protecting groups can be cleaved off by treatment 4, ,o with thiourea. The 7-amino group in compounds II can be protected, for example, by a silyl protecting group such as 4 the trimethylsilyl group.

Examples of reactive functional derivatives of acids of AM4t formula R OH are halides chlorides, bromides and 30 fluorides), azides, anhydrides, especially mixed anhydrides with strong acids, reactive esters N-hydroxysuccinimide esters) and amides (e.gt imidazolides).

In reacting a 7-amino compound of formula II with an 3 acid of formula R OH or a reactive functional derivative thereof, for example, a free acid of formula R 3 OH can be c i 4 -IIIL-_l S- 30 reacted with an aforementioned ester of a compound of formula II in the presence of a carbodiimide such as dicyclohexylcarbodiimide in an inert solvent such as ethyl acaetate, acetonitrile, dioxan, chloroform, methylene chloride, benzene or dimethylformamide, and subsequently the ester group can be cleaved off. Oxazolium salts (e.g.

N-ethyl-5-phenyl-isoxazolium-3'-sulphonate) can be used in place of carbodiimides in the foregoing reaction.

According to another embodiment, a salt of an acid of formula II a trialkylammonium salt such as the triethylammonium salt) is reacted with a reactive functional derivative of an acid of formula R 3O as mentioned earlier in an inert solvent one of the aforementioned solvents).

Qa According to a further embodiment, an acid halide, preferably the chloride, of an acid of formula R OH is i reacted with an amine of formula II. The reaction is o .20 preferably carried out in the presence of an acid-binding agent, for example in the presence of aqueous alkali, preferably sodium hydroxide, or in the presence of an alkali Smetal carbonate such as potassium carbonate or in the presence of a lower alkylamine such as triethylamine. As th 25 solvent there is preferably used water, optionally in admixture with an inert organic solvent such as tetrahydrofuran or dioxan. The reaction can also be carried out in an aprotic organic solvent such as dimethylformamide, dimethyl sulphoxide or hexamethylphosphoric acid triamide. When a 30 silylated compound of formula II is used, the reaction is carried out in an anhydrous medium.

Advantageous alternatives for acylation, where an amino group present in the group R 3 need not be protected, involves the use of a 2-benzothiazolyl thioester or a 1-hydroxybenzotriazole ester of the acid R 3 OH. For instance, the 2-benzthiazolyl thioester may be reacted with r ~J S- 31the compound II in an inert organic solvent such as a chlorinated hydrocarbon e.g. methylene chloride, in acetone, ethyl acetate or in a mixture of such solvents with water.

The 1-hydroxybenzotriazole ester can be employed by reacting acid R OH with l-hydroxybenzotriazole and a carbodiimice, especially N,N'-dicyclohexylcarbodiimide or N,N'-diisopropylcarbodiimide in an inert organic solvent, preferably methylene chloride, dimethylformamide, tetrahydrofuran, acetonitrile or ethyl acetate.

The reaction of a 7-amino compound of formula II with an acid of formula R OH or a reactive derivative thereof can conveniently be carried out at a temperature between about 0 C and +609C, e.g. at room temperature.

I S* The reaction of compounds III and their readily hydrolyo e zable esters and salts with the piperazine derivatives IV or O, IVa according to alternative of the present process is preferably effected by initially protecting the starting compounds III and their readily hydrolyzable esters and salts, preferably with a trimethylsilylating agent such as SN-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) I thereby protecting amino, hydroxy and carboxy groups I I, present. The leaving group X in compound III is preferably a halogen atom a chlorine, bromine, or, in particular, Si, an iodine atom) a lower alkyl- or aryl-sulfonyloxy group the mesyloxy or tosyloxy group) or the azido group.

Compound III can also be protected as described above for the starting materials of formula II. The piperazine S, 30 reactants IV and IVa are preferably N-protected, e.g. with MSTFA. The reaction is preferably carried and at about 0°C to room temperature and in an inert organic solvent such as chloroform, methylone chloride or acetonitrile. Zwitterionic forms of compounds I are obtainable by treating a halogenide salt obtained with a base such as sodium bicarbonate or sodium hydroxide or with sodium phosphate buffer.

S- 32 The reaction of compounds V with a base and phosgene and, subsequently, with compounds RI H according to alternative of the present process is preferably carried out in an inert organic solvent such as methylene chloride or chloroform and at a temperature of about 0°C to about 0 C. Amino groups present may be protected e.g. as trimethylsilyl derivatives as described above and carboxy groups may be protected, e.g. as the readily hydrolyzable esters described above or as esters used in the ester saponification step described below, e.g. as p-nitrobenzyl esters.

The deprotection of the esters VI according to embodiment is effected using agents compatible with the ester protecting group utilized. As ester protecting groups R one may utilize an ester form which can be easily converted into a free carboxyl group under mild conditions, 'o the ester protecting group being exemplified by, for example, t-butyl, p-nitrobenzyl, benzhydryl, allyl, etc.

Also the residue of the readily hydrolyzable esters mentioned above as end products may be employed. For example the following reagents and their corresponding compatible esters are utilized: p-nitrobenzyl removed by hydrolysis in the presence of sodium sulfide at about or below 0 C to room temperature in a solvent, such as dimethylformamide (aqueous); t-butyl and benzhydryl romoved by reaction with trifluoroacetic acid, optionally in the presence of :hisole, at about 0 C to room temperature with or without a co-solvent such as methylene chloride; or allyl removed by a palladium catalyzed transallylation reaction in the presence of sodium or potassium salt of 2-ethyl hexanoic acid, see for example J. Org. Chem. 1982, 47, 587.

The reduction of the sulfoxides VII according to embodiment is effected utilizing one of a variety of reactions, for example, treatment with phosphorus trichloride in dimethylforn'amide or trifluoroacetic J- 1 33 anhydride in the' presence of sodium iodide in acetone/ methylene chloride. Both of the above reactions can be carried out ait about OC to -20°C with about 0OC preferred.

The oxidation of the compounds VIII according to embodiment isomerizes any A2 isomer VIII to the corresponding A3 isomer of formula I wherein n is 1 or 2.

The oxidation is carried out by treatment with an orqanic or inorganic oxidizing agent. Various compounds which readily yield oxygen can be used as the oxidizing agent; for example, organic peroxides such as monosubstituted organic Iperoxides C -C 4 alKyl- or alKanoylhydroperoxides such as t-butylhydroperoxide), performic acid and peracetic acid, as well as phenyl-substituted derivatives of these S, 15 hydroperoxides such as cumenehydroperoxide and perbenzoic acid. The phenyl substituent can, if desired, carry a further lower group a C 1 -C alkyl or alkoxy 0 ogroup), a halogen atom or a carboxy group 4-methylperbenzoic acid, 4-methoxy-perbenzoic acid, 3-chloroper- 20 benzoic 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 t, sodium, potassium or ammonium hypochlorite, peroxymonosulphuric and peroxydisulphuric acid. The use of 3-chloroperbenzoic acid is preferred. The oxidation is advantageously carried out in an inert solvent, for example, Iin an aprotic inert solvent such as tetrahydrofuran, dioxan, methylene chloride, chloroform, ethyl acetate or acetone or 30 in a protic solvent such as water, a lower alkanol (e.g.

methanol or ethanol) or a lower alkanecarboxylic acid which may be halogenated (eg. formic acid, acetic acid or trifluoroacetic acid). The oxidation is generally carried out at a temperature in the range of-20 0 C to +50 0

C.

When the oxidizing agent is used in equimolar amounts or L S-34 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, The cleavage of the amino-protecting group in the substituent R 3 0 of a compound IX (or an ester or salt S: 15 thereof) according to embodiment gives qorresponding compounds of formula I (and esters an salts thereof) carrying a free amino group. Possible amino-protecting groups are those employed in peptide chemistry, such as an alkoxycarbonyl group, t-butoxycarbonyl, etc., a 20 substituted alkoxycarbonyl group, trichloroethoxycarbonyl etc., a substituted aralkyloxycarbonyl group, e.g., p-nitrobenzyloxycarbonyl, an aralkyl group such as trityl or benzhydryl or a halogen-alkanoyl group such as chloroacetyl, bromoacetyl, iodoacetyl or trifluoroacetyl.

Preferred protecting groups are t-butoxycarbonyl (t-BOC) and trityl.

The amino protecting groups may be cleaved off by acid 30 hydrolysis the t-butoxycarbonyl or trityl group), e.g.

aqueous formic acid, or by basic hydrolysis the trifluoroacetyl group). The chloroacetyl, bromoacetyl and iodoacetyl groups are cleaved off by treatment with thiourea.

Amino-protecting groups which are cleavable by acid hydrolysis are preferably removed with the aid or a lower 4 r alkanecarboxylic acid which may be halog particular, formic acid or trifluoroacet acid hydrolysis is generally carried out temperature, although it can be carried Shigher or slightly lower temperature (e.

the range of about 0°C to +40 0 Protec are cleavable under basic conditions are hydrolyzed with dilute aqueous caustic a 0 C. The chloroacetyl, bromoacetyl and protecting groups can be cleaved off usi acidic, neutral or alkaline medium at ab enated. In ic acid is used. The at room out at a slightly g. a temperature in ting groups which generally lkali at 0°C to iodoacetyl ng thiourea in out 0°C-30 0

C.

0 44 4 4 40 4 44 4 4 In order to manufacture a readily hydrolyzable ester of the carboxylic acids of formula I in accordance with embodiment of the process provided by the present invention, a carboxylic acid of formula I is preferably reacted with a corresponding halide, preferably an iodide, containing the desired ester group. The reaction can be accelerated with the aid of a base such as an alkali metal hydroxide, an alkali metal carbonate or an organic amine such as triethylamine. The esterification is preferably carried out in an inert organic solvent such as dimethylacetamide, hexamethylposphocic acid triamide, dimethyl sulfoxide or, especially, dimethylformamide. The reaction is preferably carried out at a temperature in the range of about 0-400C.

The manufacture of the salts and hydrates of the compounds of formula I or the hydratee of said salts in 30 accordance with embodiment of the process provided by the present invention can be carried out in a manner known per se; for example, by reacting a carboxylic acid of formula I or a salt thereof with an equivalent amount of the desirtd base, conveniently in a solvent such as water or an organic solvent ethanol, methanol, acetone and the like). Correspondingly, salt formation is brought about by the addition of an organic or inorganic salt. The 4 t 36 temperature at which the salt formation is carried out is not critical. The salt formation is generally carried out at room temperature, but it can be carried out at a temperature slightly above or below room temperature, for example in the range of OC to +50 0

C.

The manufacture of th hydrates usually takes 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 at about +10'C to +40 0

C).

15 Exemplary of the process for obtaining products in oo accordance with the invention are the following reaction schemes, S0 o The compound of formula IV, referred to in the schemes.

0 4, 20 is a substituted piperazine of the formula 04 4

N

CH3 in which the piperazine nucleus may be substituted with one or more lower alkyl groups of 8, preferably 1-4 carbon atoms. It shall be understood that in these reaction schemes substituted piperazines of the struature L i i_ 1 -37- Io Va 110 similarly be used as starting materials in place of IV, I In the following reaction sequences, R' represents an easily removable amine-.protecting group, such as t-butoxy- 4 1 2 15 carbonyl: R, Rl and R are a previously defined, Where a substituent group is present which may be attacked during 1 the reaction it should be in protected form, utilizing well I known protecting groups, For excample, amino groups may be protected with easily removable protective groups employed 1 20 in peptide chemistry, such as an aJlkoxycarbonyl group, e,g.o I t-butoxyoarbonyl, and the like, a substituted alkoxycarbonyl group, eqg., trichloroethoxycarbony' and the like, a I substituted alkylcarbonyl, monochloromethylcarbonyl, a I ',substituted aralkyloxycarbonyl group, p-nltrobenZyloxycarbonyl, or an aralkyl group, e~g. ttiphenylinethyl.

A preferred protecting group is t-butoxycarbonyl (t-BOC) Ior triphenylmethyl, As carboxylic acid protecting groups one may utilize an ester form which can be easily converted Into a fe carboxyl group under mild conditions.. The ester protecting group can be, for example, t-butyl, p-nitrobenzyl.

benzhydryl, aJllyl, etc. Also suitable are trimethylsilyl Oster groups.

-38 The compounds of formulas X and IIla, whc starting materials for Schemes IV and V, are KnowEA, and c~in be made by established procedures; some are items or commerce, e.g., 7-aminocephalosphoranic acid. See Gordon, and Sykes, R.B. in "Chemistry and Biology of 13-Lactam Antibiotics,'! Volume Morin, R.B. and Gorman, Editors; Academic Press: New YorX, 1982; Chapter 3, and references therein, and Ponsford, R.J, et al. in "Recent Advances in the Chemistry of 13-Lactam Antibiotics, Proceedings of the Third international Symposium,"[ Brown A,G. and Roberts, S.M., Editors; Royal Society of Chemistry, Burlington Hjouse: London, 2.985; Chapter 3, and references therein, Compounds of formula I with m;;O can be conve±tted, it desired, into compounds in wtvich mn is I. or 2 by oxidation CIO according to general methods known in the bV reaction with m-chloroperbenzoio acid, 4 110 0 39 Scheme I

&N~R

2 N- CH 3 C-07H 0 Mia 1) MSTFA 2) ISIMe3 0 N N C0 2 H CHj I 3) IV MSTFA 4) It

I

I QO.d t It II I I V 1I fR 3

NH

COD- N.) Id 1 II 2L_ ~u I -u l r ij Si 'i 1 I1 4,, B B

I'

40 Scheme I The compound of formula Ilia is initially protected by reaction with a trimethylsilylating agent such as N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) in an inert solvent such as chloroform or methylene chloride. The resulting trimethylsily, ester, in which all potentially reactive sites, such as amino, hydroxy, and Carboxylic acid functions, are protected by trimethylsilyl groups, is then subjected to a reaction with iodotrimethylsilane at about 0°C to room temperature, over a period of about twenty minutes to about two hours. The reaction mixture is then concentrated to dryness under reduced pressure, and the residue is dissolved in a suitable non-hydroxylic solvent 15 such as acetonitrile. A small amount of tetrahydrofuran (THF) is introduced to decompose any residual traces of iodotrimethylsilane. The resulting protected iodo intermediate is then further reacted in situ with a protected form of the piperazine derivative IV which is obtained from IV by treatment with a trimethylsilylating agent such as MSTFA in a compatible solvent such as acetonitrile. The quaternization reaction is conducted at about room temperature over a period of about 30 minutes .o 24 hours, preferably about 2 hours. Addition of a hydroxylic solvent such as methanol, with ice-cooling, then causes solvolysis of the trimethylsilyl protecting groups, and the quaternary iodide of formula Ic precipitates.

Further treatment under aqueous conditions with a base such as sodium bicarbonate or sodium hydroxide, or with sodium phosphate buffer, converts Ic to the zwitterionic form Id, in which, depending upon the amount of base added, or the pH of the buffer, other acidic functions in the R and Q substituents can be converted to salts.

i.

41

H

2

N

o0 0o CH"

CO

2 H 0 x 1) MSTFA 2) ISM 3 3) IV MSTFA 4) Acylation 3

R.

2 R3N H IO

CH

MeOH rrrrrr eIa 1 4 U a aa a o a a ro o a o 00 i So f ft a a a a a 1) Deprotection if necessary 2) Aqueous base or buffer

R

2

S

S N)N CO CH COr CH3 Scheme II Starting material of structure X is subjected initially to reaction with a trimethylsilylating agent such as MSTFA in an inert solvent such as acetonitrile under anhydrous conditions at room temperature for a period of about minutes to two hours, preferably about 30 minutes.

Iodotrimetylsilane is then added and allowed to react for from 15 minutes to three hours, preferably about 30 minutes, at room temperature. A small amount of THF is then added to decompose any residual iodotrimethylsilane. The quaternization step is then carried out by adding a protected form of the piperazine derivative of IV which is obtained from a compound of formula IV by treatment with a trimethylsilylating agent such as MSTFA in a suitable solvent such acetonitrile. The quaternization reaction is allowed to 42 proceed for about 30 minutes to 24 hours, preferably about two to four hours, and most preferably at room temperature.

Then, an acylating agent consisting of an activated form of a carboxylic acid, for example, a thio ester such as

CO

N

NO

H N S S n is added. The reaction mixture is then stirred for a period of from 2 to 24 hours. The mixture is then concentrated to dryness under reduced pressure, and the residue is redissolved in acetonitrile. Addition of methanol hen 15 solvolyzes the trimethylsilyl protecting groups and S°precipitates the quaternary iodide of formula Ic. In the case where other protecting groups are present, for example, o in the substituent R 3 those protecting groups are then Sr removed by methods known in the art. For example, if a t-butyl ester is present, it is cleaved by treatment with trifluoroacetic acid-anisole. Finally, as in Scheme I, the product of formula Id is obtained after aqueous reaction with a base such as sodium bicarbonate or sodium phosphate S' buffer.

43 Scheme II*Lj

R

3 NH

FF

C0 2

R

II lb 1) Deprotection If necessary 2) Aqueous base or buffer IV MSTFA RINHj'

S

0

N,)

C0RCH 3

A

I

44444 4 4 4 4 4 444 44 4 4 44 4 44 44 4 4 44 4 44 44 4 4 4444 4 4 4 4' 4 4 44 4 4 4 4 44 44 44 4 Cc 2 CH3 44 Scheme III Compounds of formula IIIb which are starting materials for this scheme are prepared by the procedures described in U.S. Patent No. 4,266,049 Bonjouklian, May 5, 1981). In this sequence, the piperazine derivative of formula IV is converted to a protected form by reaction with a trimethylsilylating agent such as MSTFA in a suitable solvent, such as acetonitrile, under anhydrous conditions, Alternatively, conventional protecting groups which are readily removable under mild conditions can be used to protect reactive functionalities in the piperazine derivative of formula IV.

For example, a carboxylic acid can be protected as a t-butyl or p-nitrobenzyl ester. The reaction of IIIb with the S 15 protected form of IV in an inert solvent such as acetonitrile provides the quaternary iodide Ic. Further treatment as necessary removes the protecting groups: for example, when R is t-butyl, the ester is cleaved with S trifluoroacetic acid-anisole. Subsequent treatment with 20 aqueous sodium bicarbonate or sodium phosphate buffer gives a compound of formula I, in which other carboxylic acid functions in R 3 and Q may be converted to salts, depending upon the pH.

4 4 45 Scheme IV C0 2 H 0 x

H

2 N s N OH C0 2

H

RNH S N OH C0 2

R

xiII v4 0 Do 0 0 0 a4 0 4 4 a N OH 002

XII

-46- Scheme IV (cont'd) RN S

R'NH

C02R 0 0O 2 R 0 R2 2

H

2 N

H

R

3 NH s 0 N. 0 C02 0 T i COC02 0 H 0 Ila Id 47- Scheme IV X 4 XIII The compound of formula X is hydrolyzed under controlled conditions at -5 to +5 0 C with aqueous sodium hydroxide to produce compound XI, which is not isolated, but is subjected to further reaction to introduce a readily removable protecting group R' onto the amino nitrogen. For example, reaction with di-t-butyl dicarbonate over a period of from one to four days gives the compound of formula XII, in which R' is t-butoxycarbonyl. Esterification by methods known in i the art provides compound XIII, in which R is a protecting group which is readily removable under mild conditions. For 15 example, reaction of compound XII with diphenyldiazomethane VE gives compound XIII in which R is diphenylmethyl.

S" XIII XV Reaction of compound XIII with phosgene in the presence of a base such as N,N-diisopropylethylamine or triethylamine in an inert solvent such as methylene chloride or chloroform at a temperature of about 0 C to about 30 0 C gives the intermediate chloroformate ester of formula XIV, with is not isolated, but used in situ. Reaction of compound XIV with a substituted piperazine of the formula 3N N-Q o HN or a substituted pyrrolidineamine of the formula HzN^. a

L-

-48 or a substituted pyrrodinylmethylamine of the formula HNCH2-C N-Q where the piperazine or pyrrolidine nucleus may be optionally substituted with one or more lower alkyl groups, and where Q represents a substituted quinolinyl or naphthyridinyl group in which any carboxylic acid function is suitably protected as an ester, e.g. as a p-nitrobenzyl ester which can be easily converted to the free acid by hydrogenolysis, gives the carbamate of formula XV.

Alternatively, any carboxylic acid functions in the Q group can be protected as t~imethylsilyl esters, and the amino o 15 functions of the piperazine, pyrrolidineamine, or pyrrolidinylmethylamine can be trimethylsilylated before reaction with XIV to obtain XV.

R, and any other protecting groups in R are then removed by appropriate methods known in the art. More than '4 one reaction may be necessary for this deprotection procedure, depending upon the nature and diversity of protecting groups involved. For example, if R is diphenylmethyl and R' is t-butoxycarbonyl, these groups are removed by reaction with trifluoroacetic acid-anisole at temperature of from 0°C to about room temperature in solvents such as methylene chloride or chloroform. If R 1 0 contains, for example, a p-nitrobenzyl ester group, this can be removed by hydrogenolysis in a separate step, preferably prior to removal of R and R'.

IIa 4 Id In the final step of Scheme IV the amino group in the compound of formula IIa is acylated by reaction with an I- 49 activated carboxylic acid, according to methods known in the art and as described above, in order to introduce R 3 and to obtain compound Id. For example, utilizing suitable solvents such as aqueous acetone or aqueous tetrahydrofuran, compound Ila is subjected to reaction with an acylating agent such as an acid chloride, or a thio ester such as, for example, NOCH S

H

2 N S 0 in the presence of a base, such as sodium bicarbonate or S...triethylamine, Reactions are carried out at about 0 0 C to about 30°C for about 2 to 24 hours. If R itself is introduced in a form which contains protected functionalities, the protecting groups ace subsequently removed by appropriate methods known in the art.

a .A UW, 50 Scheme V

R

2 R+ s C0 2 H 0 P'kH R s N OH 0 Co 2

R

Va R2

OH

0 co 2

H

xvi 0 2

R

xvii 9 9r 99 9 99 9 9 09 9 9 9 4 9e A1 2 CO 2 R 0 N I "ylo C02R 0 2 0 C0 2 H 0 VIa 51 Scheme V liIa XVI A compound of formula IIla is hydrolyzed to a compound of formula XVI either with aqueous sodium hydroxide, or enzymatically, by reaction with an esterase such as citrus acetylesterase, or an esterase from Bacterium subtilis, or wheat bran, according to known procedures: See, for example, the following: H. Peter and H. Bickel, Helvetica Chimica Acta, 57, 2044 (1974); and U.S. Patent 4,406,899. For example, a compound 2 3 of formula lia in which R is H and R 3 is phenylacetyl is hydrolyzed in an aqueous mixture with acetylesterase from orange peel, purchased from Sigma Chemical Company, over a Si period of about 18 to 72 hours, at room teilperature, XVI Va S 20 The compound of formula XVI is esterified to obtain compound Va by methods known in the art, eg, by reaction with diphenyldiazomethane to prepare the diphenylmethyl ester Also, if group R 3 should coA.tain reactive *i functionalities, such as an amino group, a suitable protecting group should be introduced before the subsequent step, L Va 4Via Lj Reaction of the compound of formula Va with phosgene in the presence of a base such as NN-diisopropylethylamine or triethylamine in an inert solvent such as chloroform, methylene chloride, dioxane, or acetonitrile, at a tempera.

ture of about 0 to about 30 0 C, yields the intermediate chloroformate ester of formula XVII, which is not isolated but utilized in situ. Reaction of compound XVit with a substituted piperazine of the formula

U~

52 HN Nq N" :Q 0

HN

or a substituted pyrrolidineamine of the formula i or a substitute pyrrodinylmethylamlne of the tormula 0 00 '00 00 HNH where the piperazine or pyrrolidine nucleus may be optionally substituted with one. or more lower alkyl groups# and where Q repreoents a substituted quinolinyl or naphthyridlnyl group in which any carboxyl function is protected as an ester, as a p-nitrobeonyl ester which can be readily converted to the froe acid, gives the carbamate of formula Vla. Alternatively, a carboxylic acid C, function in the Q group can be protected as a trimothylsilyl ester, and the amino function of the piperazine, pyrro idineamine or pyrrolidinylmethylamine can be t r imethylsilyla tell betore reacting with compound XVII to obtain compound Vla, VIa 4 Id In the final step of Scheme V, deprotecton procodutrd known in the art are applied to remove U and any other protcting groups In R0and For, oxample, a L _i i r 53 p-nitrobeazyl ester group is removed by hydrolysis, a t-butyl or diphenylmetfyl ester grou~p by reaction with trif luoroacetic acid-anisole. and an N-triphenylmethyl (trityl) group by acid hydrolysis, e.g. zeaction with aqueous f)rnic acid. Lie~ compound of formula~ id is obtained.

Compounds of formula I containing the groupings 10130 1010 R -CO--C-O-N=C-CO- .23 il1 and

NOR

2 -0-COpreferably exist, as syn-fotms. Such syn-forms can be obtained by utili ,ing starting materials -,ontaining this groupipg pre-ftorme~d in the syn-foru. Alternativel~y, a imllvsyn/anti 'mixture obtained can be separated into the cotrespondling sy', and anti forms in usual manner, e.g. by recrysta1llizat.in or by chromatographic methiods using suitable solvonts or solvent mixtures, The compounds of formula 1, their pharmaceutically a-zceptzable salts and esters and hydrates of these compounds possess antibiotic, in patrticular bactericidal, activity and can be Used as agents to combat bacterial infections F7 -54 (including urinary tract infections and respiratory infections) in mammalian species, for example, dogs, cats, horses, etc., and humans. These compounds 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 (MIC) in micrograms/ml utilizing the Broth Dilution Method against a variety of Gram-positive and Gram-negative organism's is as follows: Compound A: 0 00 C 0 0 0 0 0 00 0 0 000 00 0 0 0 0 0 00 40 0 o 00 0 00 00 00 0 0 0 0 0 0 0 00 0 0 0 0 00 2Q Compound B,, [6R-[6cL,713(Z) I ((2-amino-4thiazolyl)(methoxyimino)acetyl)amino]-2-carboxy- 8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en.3y1> methylJ-4-3carboxy-68-diflorol...(2flUoroethyl)-l,4-iyr--x-7qioiy)l methylpiperazinium iodide C6R-tranis)-4-(3-carboxy-l-(2-fluoroethyl)6,8difluoro-l, 4-dihydro-4-oxoquinoli.n-7-yl-- 12 l-methy)4-piperazinium iodide imino Iacety..j amino] (2-f luoroethyl).-6, 8-dif luoro-1, 4-dihydro-4oxoquiLnolin-7-y1 -l2methylpiperazinlum hydroxide inner salt Monosodium salt (6R-f6ct, 1 3(Z) I thiazolyl)(me oxyimino)acetyl]amino32-carboxy.

8-oxco-5-thia..-azabicyclo(4. 2.OJ-oct-.2-en-3--ylj 0 0 0000 @0 00 00 4 O 0 Compound C: Compound D: dihydro-4-oxo-7-quinolinyl)-l-methylpiperazinium iodide Compound E: (6R-tans)-4-[3-carboxy-6,8-difluoro-1-(2fluoroethyl)-l,4-dihydro-7-quinolinyljl-[2-.

carboxy-7-(formylamino)--oxo-S-thia-lazabicyclo[4.2.Ooct-2-en-3-yllmethyl>-l methylpiperazinium trifluoroacetate Table 1 In Vitro MIC (ug/ml). Broth Dilution Method Compounds Culture A B C 1) E 0 D E. coli ATCC 25922 0.25 0.5 0.25 0.5 E. coli TEM 1 0.25 0.5 0.5 0.5 E. cloacae 5699 0.5 0.5 0. 5 1 E. E. cloacae P99 0.5 0.5 2 1 S. marcescens 1071 0.5 0.5 0.5 0.5 1 P. aeruginoa. 8710 8 8 8 8 8 P. aeruginosa 18 S/H 8 4 8 32 8 09 E. faecalis ATCC 29212 64 32 32 32 32 S. pneumoniae 6301 0.063 0.25 1 0.063 1 S. aureus 1059B 2 0.5 8 2 S. aureus 95 4 1 4 4 1 S. aureus ATCC 29213 4 0.5 4 4 The in vitro activity of the compounds of the present invention as measured by the Minimum Inhibitory Concentration (MIC) in micrograms/ml utilizing the Agar Dilution Method against a variety oiQ Gram-positive and Gram-negative organisms, is as follows: L _i;L'1 b 56 Compound F: (methoxyimino)acetyljamino]-3-C C C[4-(3--carboxy- 1-ethyl--6-fluoro-1. 4-dihydro-4-oxo-7-quinolinyl)-1--piperazinyljcarbonyloxymethyl-8.oxo- 5-thia-1-azabicyclo[4. 2.Ojoct-2-ene-2-carboxylic acid disodium salt.

[6R-[6z. 713(Z).] C(2-amino--4--thiazolyl) (methoxyimino)acetyllamino]-3-C[4-(3-carboxy.

1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7quinolinyl).--piperazinyllcarbonyl joxylmethylI -8-oxo--5-thia-1-azabicyclo[4.2 .Ojoct-2-ene-2" carboxylic acid disodiun salt.

Compound G: Table 2 in Vitro MIC (ug/ml). Agar Dilution Method I I If fI f I I 41 II, 4 Compounds F Culture E.coli 257 E.coli ATCC 25922 E.Coli TEM-.

Cit. freundli BS-16 K. pneumoniae A Enter. cloacae 5699 Enter. cloacae P99 Ser. marcescens SM Ser. marcescens 1071 Prot. vulgaris ATCC 6380 Prot. vulgaris 1028 BC Prot. mirabilis 90 Ps, aeruginosa ATCC 27853 Ps. aeruginosa 5712 Ps. aeruginosa 8780 Ps. aeruginosa 765 Ps. aeruginosa 18SH- 0.25 0.25 0.25 0.5 0.5 0.5 0.5 0.25 0.5 0. 0625 0. 125 0.25 8 16 4 8 4 0.0625 3062 0.0625 0.125 0.0625 0.125 0.0313 0. 125 0.25 0.0625 0. 0625 0.25 1 4 2 1 1.

-57- Staph. aureus Smith 1 Staph. aureus ATCC 29213 2 1 Staph. aureus 10598 2 1 i Staph. aureus 67 4 2 Staph. aureus 753 4 1 I Str. pneumoniae 6301 0.0157 0.0157 Str. pyogenes 4 0.0157 0.0157 i Str. faecalis ATCC 29212 0.5 0.25 i 10 For combatting bacterial infections in mammals a i compound of this invention (more precisely, a compound of i formula I or a corresponding readily hydjiolyzable ester or pharmaceutically acceptable salt or hydrate) can be administered to a mammal 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 S55 mg/kg/day.

'I I Modes of administration Which have been used in the past to deliver penicillins and cephalosporins to the site of the i infection are also contemplated for use with the compounds J of the present invention. By way of illustration, such methods of administration include parenteral, e.g.

intravenous or intramuscular, and enteral, as a i 25 suppository.

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 association with a compatible pharmaceutical carrier material. This carrier material can be an organic or inorganic inert carrier material which is suitable for enteral or parenteral administration such as, for example, water, gelatin, gum arabic, lactose, starch, magnes.:"m stearate, talc, vegetable oils, polyalkyleneglycols, petroleum jelly etc. The pharmaceutical preparations can be made up in solid form as tablets, dragees, I---Lli- ll l' -L-l;i L.Li~L r^i~-i I-~YLIY'II i 3 58 suppositories or capsules) or in liquid form 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 for varying the osmotic pressure, anaesthetics or buffers. The pharmaceutical preparations can also contain other therapeutically valuable substances. The carboxylic acids of formula I as well as te'ir salts and hydrates are especially suitable for parenteral administration and for this purpose they are preferably made up in the form of lyophilisates or dry powders for dilution with customary agents such as water of isotonic sodium chloride solution as well as solvent aids such as propylene glycol. The readily hydrolyzable esters of formula I are also suitable for enteral administration.

o C Oy Ca C 20 Ca Ct tr 1 59 EXAMPLE 1 Preparation of f6R-trans -4-r3-carboxy-l-(2-fluoroethyl)- 6.8-difluoro-1.4-dihydro-4-oxoquinolin-7-ylI-1-f[2-carboxy- 8-oxo-7-[(Cphenoxyacetyl)ami no 1-5-thia-l-azabicyc Ior 4. 2.01oct-2-en-3-yllmethyll-l-methylpiperazinium iodide 0 F CO 2

H

io Q NH N N N N OC029H F N Under an argon atmosphere, a mixture of 406 mg (1 mmol) of [6R-trans]-3-(acetyloxy)methyl]-8-oxo--7-t(phenoxy- 44 4 acetyl amino] -5-thia-l-azabic)clo[ 4.2.0] -oct-2-en-2-carboxylic acid, 2 ml of dry methylene chloride and 0.60 ml (3 mmol) of (MSTFA) was stirred for one hour; 0.28 ml (2 mmol) of iodotrimethylsilane was then add ed, and the mixture stirred for 2 hours. The solution was then concentrated to dryness under reduced pressure, and the residual oil dissolved in 2 ml of acetonitrile. Five drops of anhydrous tetrahydrofuran (THF) were added, and the mixture was stirred for 5-10 minutes. A solution prepared from 111 mg (0.3 mmol) of 6,8-difluoo-l-(2-fluoroethyl) -4dhr74mty l-piperazinyl)-4-oXo-3-quinolinecarboxylic acid, 0.11 ml (0.6 mmol) of MSTFA and 1 ml of acetonitrile was added, and stirririg was continued for 2 hours. The mixture was chilled in ic6, and approximately 100 mg of methanol were added.

The solid which precipitated was filtered, "i'ed with acetonitrile. and dried under reduced pressure to obtain the title compound: NMR (Me2SO-d 6 6 3.15 3H, NCH 3 3.45-3.85 9H. 4 x NCHR and CH of SCR 2 3.95 1H.

J gem 16.5 Hz, CH of SCH2 4.39 and 4.77 (AB, 2H, J gem 13Hz. NCR 2 4.61 and 4.64 (AB. 2H. J gem 15 Hz, OC 2CO). 4.83-5.07 4H, NC CH 5.24 IH. J CH), 3.82 (dd, 1H. J 5 and 7 Hz. CR), 6.95 2H. J 8 Hz. Ar), 6.97 1H. J 8 Hz. Ar). 7.29 2H, J 8 Hz), 7.96 1 H, J 12 Hz, Ar). 8.91 1H, 9.18 1H, J 7 Hz, NH); IR (KBr) 3400, 1788. 1728, 1700, -1 1612. cm mass spectrum m/z 716 (cation).

EXAMPLE 2 Preparation of [U'-[6ci..73(Z)11--tr7- r (2-amino- 4-thiazolyl)r1-(1-carboxy-1-methyl)eth oxylliminolacetyl aminol-2-carboXY-8 OXO-5-thia-l-az~abicYclo[4.2.Ooct2-eri-3.

v11methyl1-4-[3-carboy-1-(2-fluoroethyl )-68-dif luoro.-1,4 dihvdro-4-oxociuinolin-7-Yll-1-methylpiperaz inium hydroxide inner salt monosodium salt 0 NO CONa' F

CO

2

H

H H N S

N

N NH: I N 54 H 2 I I 0 N- N 0 I c

CH

3

F

Under an argon atmosphere, a mixture of 5.12 g (8 mmol) of [6R-[6 ,7i3(Z)]3-3-[(acetyloxy)methylj -7-([(2-amino- 4-thiazolyl)1-(1-carboxy-1-methyl)ethocxyjiminoacetyljami noj-8-oxo-5-thia-1-azabicyclor4.2 .0]oct-2-ene--carboxylic acid trifluoroacetic acid salt, 48 ml of dry acetonitrile, and 12 ml (64 mmol) of MSTFA was stirred for 30 minutes; ml (14 mmol) of iodotrimethylsilane was added dropwise, and, the mixture was stirred for 30 minutes. With momentary cooling in Ice, 1.12 ml (14 mmol) of dry T-IF was added.

c. 1 _i 1 1 61 After 10 minutes, a solution prepared from 2.27 g (6 mmol) of 6,8-difluoro-l-(2-fluoroethyl)-l,4-dihydro-7- (4-methyl-l-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, 24 ml of acetonitrile, and 1.28 ml (7.2 mmol) of MSTFA was added, and the mixture stirred for 1.5 hours. The mixture was concentrated under reduced pressure, and the residual oil was dissolved in 40 ml of acetonitrile. With ice-cooling, 4 ml of methanol were added, resulting in a thick precipitate. After settling for a few minutes, the precipitate was filtered and washed with four 10 ml portions of acetonitrile. After drying the solid was triturated with ml of methanol, filtered and washed with four 10 ml portions of methanol. The solid (5.7 g) thus obtained, was suspended in water, and aqueous sodium bicarbonate was added to bring the pH to 7. The solution of crude product was purified by C 18 reverse phase HPLC (High Pressure Liquid Chromatography) in three steps First a column of 50 g of Waters C8 -silica was used with water followed by acetonitrile in water as eluant. Then, using a 0.025 molar pH 7 buffer-acetonitrile gradient, the product was further i purified by HPLC on a Waters Prep 500 with C 18 columns.

Finally, the product was desalted on a flash column of 60 g of C 18 silica with water and 20% acetonitrile in water as eluants. After concentrating under reduced pressure to eliminate the organic solvent, and freeze-drying, 1.0 g of the title compound was obtained: NMR (Me SO-d6-D 2 0) 6 1.37 3H, CH3), 1.44 3H, CH 3 3.10 3H, NCH 3.39 and 3.88 (AB, 2H, J gem 16.5 Hz, SCH 2 3.40-3.70 8H, 4 x NCH 2 4.12 and 5.17 (AB, 2H, J gem 12.5 Hz, NCH 4.62-4.94 4H, NCH CH 2F), 5.15 (d, 1H, J 5Hz, CH), 5.73 1H, J 5Hz, CH) 6.74 1H, Ar), 7.83 1H, J 12 Hz, Ar), 8.47 (brs, lH, IR -1 (KBr) 3400, 1772, 1618, 1595 cm 1 mass spectrum m/z 859 (M H) -62- EXAMPLE 3 PreParation of [6R-F6a.,713(Z)11--[[7-[f(2-amino-4tLiazoly-)methoxyimino)acetyl ]laminol-2-carbox-8-oxo-5-thial1-azabicyclo[4.2 .Q1-oct-2-en-3-yllmethyll-4-(3-carboxy-l..

ethyl-6-fluoro-1,4-dihdro-4-oxo-7-juinolinl)-l-methyl.

Piperazinium iodide 0 NOCH3 F C0 2

H

NH H JNH

S

NN NN 0

I

CO

2 H CH, I' Under an argon atmosphere, a mixture of 273 mg (0.6 mmo6) of (6R-61.7B(Z) I 1-3- (acetyloxy)methyl] amino-4.- thiazolyl)(methoxyimino)acetyl l-azabicyclo[4.2.0O]oct-2-ene-2-carboxylic acid, 2 ml of dry methylene chloride, and 0.45 ml (2.4 mmol) of MSTFA was stirred for 2 hours; 0.17 ml (1.2 mmol) of iodotrlmethylsi ane was added, and stirring Was continued for another 2 hours. The mixture was concentrated under reduced pressure, and the residual oil was dissolved in 2 ml A 4" of dry acetonitrile. A few drops of dry THF were added and the mixture stirred for 15 minutes A solution prepared from 60 mg (0.18 mmol) of l-ethyl-6-fluoro-l,4-dihydro- 7-(4-methyl-l-piperazinyl)-4-oxo-3-quinoli necarboxylic acid, 1 il of dry acetonitrile, and 0.07 ml (0.36 mmol) of MSTFA was added, and stirring was continued for 2 hours. Dropwise addition of 125 mg of mthanol caused the product to precipitate. The solid was filtered, washed with four 1-mi portions of acetonitril'a and dried under reduced pressure4 Afte4 trituration with methanol and drying under redUced pressure the title compound was obtained: NMR (Me 2 SO-d6) e 63 6 1.45 (brt. 3H, CH3 of NEt), 3.15 3H, NCH 3.50-3.95 9H, 4 x NCH 2 and CH of SCH 2 3.85 3H, OCk 3 3.99 1H, J gem 16.5 Hz, CEI of SCH 2 4.43 and 4.70 (AB, 2H, J gem 14 Hz, NCH 4.61 (brq, 2H, CH of NEt). 5.31 1H, J 5 Hz, CH), 5.94 (dd, 1H, J and 8 Hz. CH), 6.76 1H. Ar). 7.30 (br. 2H, NH2) A 7.31 1H. J 6.5 HZ, Ar), 8.03 1H. J 12.5 Hz, Ar), 9.03 1H, 9.62 1H, J 8 Hz, NH); IR (KBr) 1785. 1720, 1680, 1628. cm -1 mass spectrum m/z 729 (cation).

EXAMi4? 4 Preparation of r6R-r6o,7B(Z1-1-f 7-r[[(2-amino-4thiazolyl)(methoxyimino)acety1amino-2-carboxY-8-oxo- -thia- 1~az bicyclor4.2.0O1oct-2-en-3-Vlmethyl -4-[3-carbo),v-6.8-ditluoro-1- 2-fluoroethyl)-1, 4-dihdro--4-oxo-7-cuinolinYI~ methylpiperazinium iodide NOCH 3 F C 02H H

H

N S"eP/N

H

2 NN J N s SS 0 LI CO 2 H CH I F A mixture of 84.6 mg (0.186 mmol) of (6R-C6d,78(Z)3)- 3 (tactyl oxy methyl -7-[[(2-amino-4-thiaolyl) (mnethoxyimino)- 3si ace ty j,1: aino i 1 Xo-5 -thia- i-azabic iyclo(4.2-Olo; j:t-2-e~ine-2- carC boxylic acid, 4 ml of dry methylene chloride, and 0.148 ml (O.R mmOl) of MSTFA was stirred for one hour. To the -64 resulting solution was added 0.0625 ml (0.46 mmol) of iodotrimethylsilane. The mixture was stirred for 2 hours, and concentrated to dryness undeL reduced pressure. The residue was dissolved in 2 ml of dry acetonitrile, and a few drops of dry TI-F were added. The mixture was stirred for 3 minutes. and then a solution prepared from 36.9 mg (0.10 mmol) of 6,8-difluro--l-(2-fluoroethyl)-l,4-dihydro-7-(4methyl-l--piperazinyl)-4-oxo-3-quinoline carboxylic acid, 0.040 ml (0.215 mmol) of MSTFA, and 2.0 ml of dry acetonitrile was added. The mixture was stirred for 3 hours. After addition of 0.50 ml of methanol, a precipitate formed. The solid was filtered, washed repeatedly with acetonitrile, and dried to obtain 87.5 "ag of the title compund NMR(MeSO-d6) 6 3.15 38. NCH 3 3.50-.3.90 (in. 9H, 4 X NC-I 2 and CH of SCH 2 3,86 3H.

OCH

3 3.96 (do l1H. J gemu 17 Hz, CR of SCH 4.42 and 4.73 (AB, 2H, J gem 14 Hz, NCH 2 4.85-5.10 (in, 4H, 2C CHF), 5.29 18I, J =5 Hz, CH), 5.93 (dd. 1H. J V 0 0 05 and 7 Hz, CR), 6.86 18, Ar), 7.24 28, NH 7.98 2 1I. J 12 Hz. Ar), 8.94 18 9.67 (do l1H, J 7Hz, NH); IR (KBr) 3420, 1775, 1720, 1675, 1618 cm EXAMIMLE 0 02 5 P r p a t o o f nolinvi 1-l-methylpiperazinium hydroxide inner salt monosodium salt 0 N0CH3 COZ' Na" H H N N N

H

2 N-<s C02 o I A suspension of 900 mg of the compound prepared in Example 4 in water was neutralized with 0.1 N aqueous sodium hydroxide, and the resulting solution was freeze-dried. The 0 residue was purified by C18 reverse phase HPLC on a Waters Prep 500R. eluting with a water-acetonitrile gradient Evaporation and lyophilization of the appropriate 0 00fractions afforded 344 mg of the title compound: NMR (Me SO-d6) 6 3.10 3H, NCH), 3.40-3.76 9H, 4 x NCH and OH of SCH 2 3.84 IH, J 16 Hz, CH of

SCH

2 3.84 3H. OCH 3 4.10 and 5.19 (AB, 2H, J gem ia 14Hz), 4.70-4.94 4H, NCH CH 5.13 1H, J 2 ,2 OH). 5.65 (dd. J 5 and 7Hz, CH), 6.74 LH, 25 Ar), 7.23 2H, NH 2 7.82 iH. J 12Hz, Ar), 8.55 LH, 9.58 1H, J 7Iz. NH): IR (KBr) 3410, 1 1772. 1665, 1618 cm mass spectrum i/z 787 (M H) EXAMPLE 6 Preparation of (6R-trans)-4-[3-carboxy-6,8-difltloro-l- (2-fluoroethyl 4-dihYdro-7-ciuinolinv l- 1 1dimethylethoxy)carbonyl- 7-(formylamino)-8-oxo-5-thia-lazabicyclo[4.2.01-oct-2-en-3-yllmethyl1-l-methylpiperazlnium iodide 66 0 0 F C0 2

H

H

I

HCNH S N N FN 0 A mixture of 0.67 g (2.35 mmol) of 6,8-difluoro-l-(2fluoroethyl)-l. 4-dihydro-7-(4-methyl-l-piperazinyl )-4-oxo-3quinolinecarhoxylic acid, 0.51 ml (2,6 mmol) of MSTFA and ml of dry acetonitrile was stirred for 30 minutes; 1.00 g of [6R(6c ,7I3-7-formylamino-3-iodomethyl-8-oxo-5-thia-l- 44 azabicyclo4.2.0]oct-2ene-2-carboxylic acid 1,1-dimethylethyl ester was added, and stirring was continued for 24 hours. The resulting precipitate was filtered and discarded. The mother liquor was absorbed onto a column of 5 g of C 1 8 -silica. After elution with water, 44 4 10%- and 20%- aqueous methanol the appropriate fractions 4 25 were combined and concentrated under reduced pressure to yield a precipitate. After filtration and drying 380 mg of the title compound was obtained: IR (KBr) 3440, 1785, 1720, 1610 cm mass spectrum m/z 666 (cation).

EXAMPLE 7 Preparation of (6R-trans)-4-r3-carzox-6. 8-difluorofluoroethyl)-.4-dihvdro-7-uinolinv1ll-4[ 2-carbxy-7- (formylamino)-.o-oxo-5-thia-l-azabicyclO[4.2.01oct-2-en-3-Yl1methyll-l-methylpiperazinlum trifluoroacetate salt 1 67 0 F C0 2

N

HCNH S SN Ni t C0 2 H CH3

F

CF

3 C0 2 A mixture of 200 mg of the compound from Example 6. 0.2 ml anisole. and 2.5 ml of trifluoroacetic acid was stirred for 3 hours at room temperature. After filtration of the insoluble portion, the solution was concentrated under reduced presaure. The residue was dissolved in 10 ml of acetonitrilo. and 200 ml of ether was added to precipitate the product. After filtration and drying, 135 mg of the title compound was obtained: N4R (Me 2 S0-d6) 6 3.14 (s, 3H, NCH 3.50-3.85 9H, 4 x NCH and CH of SCM 2 3 22 3.95 lH. J gem 16.5 Hz, CH of SCM 2 4.35 1H, J gem 13Hz, CH of NCM 4.82-5.05 5H, NCH CH F an MofNH),522 2 2 and CH of NCHl), 5.23 1H, J 5Hz, CH), 5.84 (dd, 1H, 0 0 25 J 5 and 7Hz, CH), 7.96 Cd, 1H, J 13Hz, Ar), 8.17 IH, NCMO)j 8.92 1Hi 9.11 lI, J m 7Hz, NH); IR -1 3400, 1780, 1720, 1685 cm mass spectrum m/z 610 (cation).

Example 8 Preparation of f6R-[6c,73(Z)1l-r[7- r(2-amino-4thiazolvl)-f[1.1-dimethyl-2-(1 1-dimethylethoxy)-2-oxoethoxyi iminolacetyllaminol-2-carboxy-8-oxo-5-thia-1-azabicYclo- 4 ylg 1 6.8-difluoro-1,4-di hdro-4-oxoquinolin-7-yl1-l-methylpiperazinium iodide c. 1 _I rrri-*WI1~~I1_1-rrr -_-~lllni-.i llllll lilL^ S- 68 0 SF C0 2

H

NO

H H N H S N N N H2 N N F

I

S 0 0 o CH3

F

CO

2 H

F

Under an argon atmosphere, a mixture of 272 mg (1 mmol) of 7-aminocephalosporanic acid, 0.67 ml (3.6 mmol) of MSTFA and 3 ml of dry acetonitrile ias stirred for 30 minutes: 0.25 ml (1.75 mmol) of iodotrimethylsilane was then added and stirring was continued for another 30 minutes. The 4 4mixture was cooled momentarily, and 0.14 ml (1.75 mmol) of anhydrous THF was added. After 10 minutes, a solution CI prepared from 277 mg (0.75 mmol) of 6,8-difluoro-1-(2fluoroethyl)-1,4-dihydro-7-(4-methyl-l-piperazinyl) oxo-3- 4 20 quinolinecarboxylic acid, 0.17 ml (0.9 mmol) of MSTFA and 3 ml of dry acetonitrile was added. Stirring at room temperfZuZre was continued for 2.5 hours: 478 mg (1 mmol) of 2-[[[i-(2-amino-4-thiazolyl)-2-[(2-benzothiazolyl)thiol-2- 0 oxoethylidenejamino]oxylmethylprOpanoic acid 1,1-dimethylethyl ester and 4 ml of dry acetonitrile were added, and the mixture was stirred overnight. After filtration to remove a small amount of insoluble solid, the mixture was concentrated to dryness under reduced pressure.

The residual oil was redissolied in 4 mi of acetonitile, and with ice cooling, 0.16 ml of methano:l was added. After stirring for one minute and standing for 3 minutes, the precipitated solid was filtered. After washing with three 3-ml portions of acetonitrile and drying under reduced pressure 530 mg of the title compound was obtained: NMR (Me 2 O-d6) 6 1.36 12H, t-B and C.H 3 1.40 C(s 3H, CH 3 3.12 3H, NCH 3 3.40-3.86 9H, 4 x ~1 ;i 1 69

NCH

2 and CH of SCH 2 3.96 1H, J gem 16Hz, CH of SCH 4.40-4.66 (AB, 2H, J gem 13H.,. NCH2), 4.62-5.06 4H, NCH2CH2F), 5.26 1H, J 5Hz. CH), 5.93 (dd, 1H, J 5 and 7Hz, CH), 6.68 IH, Ar), 7.25 2H,

NH

2 7.92 1H, J 12Hz, Ar), 8.88 IH, 9.44 1H, J 7Hz, NH).

Example 9 Alternate Synthesis of amino-4-thiazolyl)[l-(l-carboxy-l-methyl)ethoxylimino]acetyl amino]-8-oxo-5-thia-l-azabicyclo[4.2.Oloct-2-en-3-yllmethyll- 4-f3-carboxy-l-(2-fluoroethyl)-6,8-difluoro-1,4-dihvdro-4oxoquinolin-7-yll-l-methylpiperazinium hydroxide inner salt monosodium salt S, COZ' Na* NO FCOH NNH S 2 H0N-" I I

N-

CO-

CH

2 F A solution of 102 mg of the compound prepared in Example 8 in 0.4 ml of anisole, 1.5 ml of methylene chloride and ml of trifluoroacetic acid was kept overnight at O0C. After filtering, concentrating to dryness under reduced pressure, adding methylene chloride and again concentrating to dryness the residue was triturated with ether to obtain a solid.

The solid was dissolved in aqueous sodium phosphate buffer of pH 7 and purified by reverse phase HPLC to obtain the title compound having an NMR spectrum similar to that of the product obtained by the previously described route (Example 2).

K 1 70 EXAMPLE Preparation of (6R-trans)-3-hydroxymethyl-7-[[(l,1- [4,2,0]oct-2-ene-2-carboxylic acid

H

100 N SOH C0 2

H

A solution of 19.2 g (0.48 mol) of sodium hydroxide in dry-ice and acetone All at once, 54.4g (0.20 mol) of i 7-aminocephalosporanic acid was added. The reaction temperature was controlled at -5 to 0 0 C by raising and lowering the bath as necessary, until the initial heat of Sreaction was dissipated. Then the cold bath was replaced 25 with an ice bath and stirring was continued at 0-5 0 C for the remainder of a total reaction time of 30 minutes. The pH was adjusted to 9-9.5 by addition of approximately 2 ml of 6 N aqueous hydrochloric acid. Dioxane (700 ml) was added followed by a solution of 87.5 g (0.40 mol) of di-t-butyl dicarbonate in 200 ml of dioxane, added all at once. Sodium bicarbonate (33.6 g, 0.40 mol) was added, and the mixture stirred for 70 hours. Ethyl acetate (750 ml) was added, the layers were separated, and the organic phase was extracted with water (2 x 125 ml). The combined aqueous phase and extracts was washed with ethyl acetate (2 x 300 ml). Then the aqueous solution was layered with 750 ml of ethyl acetate, and 80 ml of 6 N aqueous HC1 was added to bring the 71 pH to 2.5. A precipitate formed which was removed by filtration through a bed of Hyflo. The aqueous phase was separated and extracted with 300 ml of ethyl acetate. The organic extracts were combined, washed with 300 ml of water, dried (Na 2

SO

4 and concentrated under reduced pressure to about 100 ml of volume. As the volume was reduced, solid material began to precipitate. The precipitate was filtered and washed with ether. The product was dried under reduced pressure; 24.1 g of the title compound was obtained.

This was used directly in the next Example.

EXAMPLE 11 Preparation of (6R-trans)-3-hydroxymethyl-7-[[(1,1- [4,2,01oct-2-ene-carboxylic acid diphenylmethyl ester o 0 0 0 0 0 0 S EN OH 0 4 4 20 4 44 C02CHPh 2 So ao 4, 4. 25 4 44 A suspension of 44.67 g (0.135 mol) of the product (hydroxy acid) from Example 10 in 270 ml of dry tetrahydrofuran (THF) was stirred mechanically. A solution of 32.51 g (0.167 mol) of diphenyldiazomethane in 390 ml of n-hexane was added, and the mixture wa,' stirred vigorously for 20 hours. The precipitate was filtered, washed with n-hexane, and dried under reduced pressure to obtain 45.74 g -72 of the title compound: 1H NMR (Me 2 SO-.d) 81.41 9H), 3.59 2H), 4.22 J=6Hz. 2H), 5.08 (d, 5.51 (dd. J=5 and 8 Hz, 1H), 6.88 1H), 7.26-7.51 (in. 10H), 8.03 J=8Hz, 1H).

EXAMPLE 12 Preparation of 1-ethyl-6-fluoro-1.4-dihydro-7-4-(1,1.

dimethylethoxy)carbonyl 1-l-piperazinyl-4-oxo-3-guinoline carboxylic acid 0 F C0 2

H

I

N

N

00 0 200 To a stirred suspension of 24.0 g (0.075 mol) of 1-ethyl -6-fluoro-1,4-dihydro-4-oxo-7-(l-piperazinyl)-3-quinolone- 0 25 carboxylic acid in 240 ml of dioxane were added 130 ml of water and 80 ml (0.080 mol) of 1N aqueous sodium hydroxide.

The mixture was heated at 1.000C for approximately 30 minutes until a clear solution resulted. The solution was cool~ed to 000. and a solution of 19.2 g (0.088 mol) of di-t-butyl dicarbonate in 50 ml of dioxane was added. The mixture was stirred at 0 0 C for 30 minutes and then for a further three hours at ambient temperature. The resulting precipitate was filtered and suspended in 520 ml of 10% aqueous acetic aciel. The mixture was heated to ].00 0 C briefly, and then allowed to cool before filtering the product. After drying under reduced pressure over P j0 5 27.0 g of the title compound Was obtained; H NMR (Me 2 SO) 61.39 73 (t,3H, J=7Hz), 1.40 9H), 3.25 4H), 3.48 4H), 4.54 (q,2H, J=7Hz), 7.08 1H, JHF7.5Hz), 7.91 1H, JHF= 14Hz), 8.94 (s,1H).

EXAMPLE 13 Preparation of 1-ethyl-6-fluoro-1.4-dihydro-7-f4-F(1,1dimethylethoxy)carbonyll-1-piperazinyll-4-oxo-3-quinolinecarboxylic acid (4-nitrophenyl)methyl ester 0 F" C0 2

CH

2

NO

2 N N 0O N

O

0 To a stirred suspension of 1.0 g (2.4 mmol) of the N-t-Boc product of the previous procedure (Example 12) in ml of water were added 2.5 ml (2.5 mmol) of iN aqueous sodium hydroxide. The mixture was warmed until complete solution occurred. The solution was filtered and cfreeze-dried to afford the sodium salt, which was dissolved in 10 ml of dimethylformamide (DMF) and stirred for 2 hours with 41 molecular sieves; 0.55 g (2.5 mmol) of 4-nitrobenzyl bromide was then added. The mixture was stirred for three days. The sieves were removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica gel, methylene chloride: ethyl acetate 1:2 as elutant) to afford 1.0 g of the title compound as a white solid: H NMR(CDCl 3 61.46 9H), 1.52 3H, J=7.5 Hz), 1.57 3H), 3.17 (va, 4H), 3.62 (mI, 4H), 4.18 2H, J=7.5 Hz), 74 5.46 2H), 6.74 1H. JHF= 7 Hz), 7.71 d. 2H.

8.12 1H. JHF=13Hz), 8.21 2H, 8.45 (s.1H).

EXAMPLE 14 Preparation of l-ethyl-6-fluoro-l,4-dihydro-oxo-7-(1piperazinyl )-3-quinolonecarboxylic acid (4-nitrophenyl)methyl ester

.C

2

CH

2 N NO 2 0 0 0" 0" n B 0 0 0ir 0 '0 0l 0 0O 0 O 0 r -K'y 0* 0 iD 0 PQ0Q0 A mixture of 10 g (0.018 mol) of the N-t-Boc (4-nitrophenyl)methyl ester prepared as in Example 13, 40 ml of anisole, and 40 ml of trifluoroacetic acid was stirred at 0 0 C for 3 hours. The mixture was concentrated to dryness under reduced pressure; the residue was triturated with ether (2 x 100 ml). The ether extract was washed with water (2 x 100 ml) and the water washings combined with the residue from the trituration. AqueouO IN NaOH was added to adjust the pH to 11, and the product was extracted with methylene chloride (7 x 100 ml). The combined organic extracts were dried (Na 2

SO

4 and concentrated to yield 7.70 g of the title compound: IH NMR (CDC1 3 61.57 3H, J=7.5 HZ), 3.11 (m,4H) 3.24 4.23 (q, 2H, J#7.5 Hz), 5.51 2H), 6.78 1H. JHF *7Hz) 7.75 2H, Jo8.5 Hz), 8.15 1H, HHF,14Hz, 8.26 2H,

HF-

Hz).8.49 1H).

EXAMPLE Preparation of (6R.trdns)-3-rCr4-E1-ethyl-6-fluoro-1,4dihvdro-3-[(4-nitrophenvl)methoxvcarbonyl1-4-oxo-7cuinolinyl1 -l-pperazinyl1carbonylloxyvmethyl1-7-f[(1,1dimethylethoxy)carbonylrlamino1-8-oxo 5-t hia-l-azabicyclor4.2.0]oct-2- ene-2-carboxylic acid di 4 1honyltaethyl ester 0 Fy N

N

0 S N COCHPh2 0 0 0 Oa 00 -o under an argon atmosphere, a solution of 2.00 ml (3.84 mmol) of 20% phosgene in toluene and 68 ml of dry methylene chloride was cooled to 3-4 0 C, A solution of 1.71 g (3.44 mmol) of (6R-trans)-3-hydroxymethyl,-7dC(l 3-dimethyle thyoxy;) ca rbo ny i 1 mi no iox 5 thh a ai"a zab b.CyClo t4 ,22 1 o jt-2-ene-2-carboxylic acid diphenylmethyl ester (Example 11) in 30 ml of methylene chloride was then added# along with 0.66 ml (3,85 mmol) of NO-diisopropylethylaiuine and ml of methylene chloride wash. The mixture was stirred cold for 15 minutes, and then for two hours at room temperature.

The resulting solution was added to a solution prepared from I.88 g (4.14 mmot) of e thyl-6-fluoro-,4-dihyd o-4 oXO.-7- (1-piperazinyl)-3-quinollnecarboxylic acid (4-nitrophenyl).

methyl ester (Example 14), 0,71 ml (4.15 mmo1) of NiN-diisopropylethyl-amine and 68 ml of methylene chloride, After stirring Under argon for 2 1/2 to 3 hours -76 the solution was concentrated under reduced pressure to a volume of approximately 20 ml and applied directly to a x 14 cm J.ilica column for chromatographic purification under pressure. The column was eluted first with 20 ml of methylene chloride, and then with ethyl acetate, collecting fractions of 20-25 ml each. Fractions 26-3Q, containing pure product, were combined and concentrated to dryness under reduced pressure to obtain a residue of 0.716 g.

Fractions 31-55 were re-chromatographed and the additional pure product obtained combined With the above residue to provide a total of 1.125 g (33.5% yield) of the title compound IR 1789, 1712, 1622 cm.

Anal. Calcd, for C H N 0 FS: C, 61,47; so 49 6 11% H# -15.060' N1,19160; S. 3,281- F, 1.94. P~ound: C, 61.23; H, 5,03; N, 8.50:- S, 3.35; F, 1.65.

EXAMPLE 16 Preparation o~f,,jR, trans r[rE4-(3-carboxv-1-eth _16 V fluoro-l,4. do4-oxo-7-ciuinolinyll-1-piperazinyl~lcarbonylI oxy-Imethvl1.-7-rF(1,1-dimethy/lethoxv)carbonyllamino--O~co-5- Ii thia-l-azabicvclof4.2.01oct-2-ene-2-carboxylic acid 1 diphenylmethyl ester 0 I F C0 2

H

L130 N N C0 2 CHPh 2 77 A mixture of 1.125 g (1.15 mmol) of the p-nitrobenzyl ester from Example 15, 1.54 g of 10% Pd on carbon catalyst and 115 mli of dry THF (distilled from sodium benzophenct ketyl) was stirred under hydrogen at atmospheric pressure for approximately three hours. After filtration of the catalyst the solvent was evaporated under reduced pressure.

The residue was purified chromatographically on a 2.2 x 11 cm silica column using ethyl acetate followed by EtoAc-acetone-MeOH-water (70:5:2,5:2.5) as eluant. The appropriate fractions were combined and concentrated to dryness under reduced pressure to obtain 0.817 g (86.3% yield) of the title compound: IR(KBr) 1785, 1715, 1625, 698 -1 cm EXAMPLE 17 Preparation of (6R,trans)i-7-amino-3-frFf4(3-( arboxy 1.

ethyl 6-fluoro1. 4-dihydro-4-oxo-7-quinolinl)-1 piperazinvi1 carbo iYl1oxymethyll-8-oxo 5-thia-l-azabicyclor4.2.01oct-2ene-2-carboxylic acid trifluoroacetic acid salt 0

FCO

2

H

CF3C02H

H

2

N

N4 N 2' 3 02H 0 A solution of 0.811 9 (0,963 mmol) of the diphoylmethyl ester prepared in Example 16 and 1.80 ml of anisole In 15 m1 of dry mothylene chloride was coolEd to 0OC under an atmosphere of argon: 11.8 m! of cold tifluoroacetic acid -78was then added and the mixture was stirred at 0 0 C for 2 hours. The mixture was then concentrated under reduced pressure at 0-5 0 C. Methylene chloride (5ml), ethyl acetate and ether (60 ml) were added to the residue. The mixture was stirred 5-10 minutes before filtering the solid and washing with ether. After drying under reduced pressure, 0.591 g (89.0% yield) of the title compound was obtained.

EXAMPLE 18 Preparation of, [6Rr6oL,7B(z)11-7-[f(2-amino-4-thiazolyl) (methixyimino)acetvllamino]-3-f[fr4-(3-carboxvl-l-ethyl-6fluora-J.4-dihydr o-4-oxo-7-Quinolinyll-1-piperazinvlicarbonllox] mthl]-8 -x-5-thia-l-azabicycloF4.2.0loct-2-ene- 2-carboxylic acid disodium salt 4 040 04C02 NOCH3

NN

4ec ~H 2 1 3 252 0 2Na* 4 Lm A mixture of 59.4 mg (0.086 mmol) of the trifluoroacetic acid salt prtepared in Example 17 and 1.5 ml of THFf was stirred and cooled ,,At 0-5 0 C. A solution of 26.0 mg (0.309 mmoj.) of, sodium bicarbonate in 2 ml of water was added, followed by a solution of 38.0 mg (0.108 mmol) of -2 -amino-u.(methoxylimi no) -4 -thiazo lee thanlethi i c acid S-2-benzothiazolyl oster in 0.75 ml of THF. The cooling bath was removed after 25 minuteg, and the reaction mixture 79 was stirred for 16.5 hours. Under reduced pressure the mixture was concentrated to remove THF. The remaining aqueous solution was washed with ethyl acetate and then adjusted to pH 7.55 by the addition of 0.025 molar aqueous sodium dihydrogen phosphate solution before chromatographing on a column of 1.75 g of C 18 -silica (from Waters). The product was eluted using a step-wise gradient of 0.025 molar sodium phosphate buffer-acetonitrile containing from 0 to of acetonitrile. The appropriate fractions were combined and partially evaporated under reduced pressure to remove acetonitrile. Acidification to pH 2 with IN aqueous HC1 gave a precipitate which was centrifuged, and twice washed with water, centrifuging each time. The precipitate was dissolved in water by adding sodium bicarbonate to bring the pH to 7.5. Adding acetone caused the sodium salt to precipitate. The product was isolated and washed with acetone by centrifuging. After drying under reduced pressure, 36.2 mg of the title compound was obtained: -1 IR(KBr) 3420, 1762, 1675, 1622 cm mass spectrum (FAB) m/z 803 (M+H) EXAMPLE 19 Preparation of l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl)-3-quinolinecarboxylic acid (4-nitrophenyl) methyl ester 0F LF

CO

2

CH

2 N02 N N HN. This compound was prepared from l-cyclopropyl-6-fluoro- 4-dihydro-4-oxo-7-(1-piperazinyl -3-qui nolin carboxylic acid using procedures similar to those above described (in Examples 12. 13. and 14) for the synthesis of 1-e thyl-6--fluoro-1. 4-dihydro-4-oxo-7-(l-piperazinyl-3quinolinecarboxylic acid (4-nitropenyl) methylester.

EXAMPLE Preparation of (6R, trans)- [7-(1,1-dimethylethoxy)carbonyllamino I -3-r r trr4-[ 1-cYcloPropyl-6-f luoro-1, 4-dihydro-3-[ (4nitrophenyl)methoxylcarbonyl1-4-oxo-7-uinolinyl1-lp_;pfE razinyl1carbonyl1oxvmehyl-8-oxo-5-thia-1-azabic clo- 14.2.01oct-2-ene-2-carboxylic acid diphenylmethyl ester COC 002 rr, H 200 i" C02CHPh2 0 4 1 tt~ Under an argon atmosphere, a soluti% .1 of 0.58 ml (1.12 mmol,) of 20% phosgene in toluene and 20 of methylene chloride was cooled at 0-5 0 C, A solution of 0.497 g (1 mmol) of (6R-trans)-3-hydroxymethyl-7.( (t,1-dimethylethoxy) carbonyl I amino]j-8-oxo-5-thia--azabicyclo 2. Ojoct- 2-ene-2-carboxylic acid diphenylmethy ester in 8 ml of methylene chloride was added along with 0.195 ml (1.14 mmol) of NN-diisopropylethylamine. The mixture was stirred for minutes at 0-50C before removing the ice bath. Stirring was continued for one hour and 40 minutes at ambient temperature. The resulting solution was added to a solution of 0.550 g (1.18 mmol) of l-cyclopropyl-6-fluoro-1.4.-dihydr- 7 -81 -4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (4-riitrophenyl)methyl ester and 0.205 ml (1.20 mmol) of NN-diisopropylethylamine in 17 ml of methylene chloride.

The mixture was stirred at room temperature under argon for three hours and five minutes. The mixture was then concentrated and purified by flash chromatography on 29 g of silica gel in a column approximately 2.2 cm in diameter.

The mixture was applied to the column as a solution in methylene chloride and was eluted with ethyl acetate-n-hexane and then ethyl acetate. The appropriate fractions were combined and concentrated to dryness under reduced pressure to provide 0.425 g of the title compound: IR (KBr) 1789, 1720. 1622, 1520, 1345. 702 cm mass spectrum (FAB) m/z 989 EXAMPLE 21 Preparation of (6R-trans)-3-rf[F4-(3-carboxy-l1-cyclopropyl-6fluoro-1, 4-dihydro-4-oxo-7-qvuinolinyl)-l-piperazinylicarbon- Y1 JoxYiitethyll-7-FF(1,1-dimtrhylethoycarbonyllamino1.-8-oxo- S-thia-l-azabicyclof4.2.Oloct-2-ene 2-earboxv.lic acid diphenylmethyl ester

O

F

CO

2

H

IF

OY N S N

N

0 0 N1

CO

2 CHPh 2

O

A mixture of 0.414 g (0.418 mmol) of the p-nitrobenzyl -82 ester (prepared in Example 20), 0.602 g of 10% Pd on carbon catalyst, and 40 ml of THF (distilled from sodium benzophenone ketyl) was hydrogenated at atmospheric pressure over a period of about 3.5 hours. After filtration of the catalyst the solvent was evaporated under reduced pressure.

The residue was chromatographically purified on a Chromatron Model 7924 preparative, centrifugally-accelerated, radial Thin Layer Chromatography (TLC) apparatus, using ethyl acetate followed by ethyl ace ta te-acetone-me thanol1-water (70:10:5:5) as eluant, to obtain 251.6 mg of the title compound: IR (KBr) 1788, 1720, 1628, 702 cm- 1 mass spectrum (FAB) m/z 854 (M K~) Alternate synthesis of (6R-trans)-3-rrrr4-(3--carboxy-lcyclopropvl--6-fluoro-1,4-dihydro-4-oxo-7-cguinolinyl)-lpipera inyllcarbonylloxylmethyl-7-fr(1. 1-dimethylethoxy)car banyl Iamino I-8-oxo-5- thia- 1-azabicyc 1of 4. 2. 0 1oct-2-ene-2carboxylic acid diphenylmethyl ester Under an atmosphere of argon, 124 mg (0.25 minol) of (6R-trans,)-3-hydroxymethyl-7-[[(l,1-dimethylethoxy)carbonyl]amino] -8-oxo-5-thia-1-azabicyclo[4 .2 .Ojoct-2-ene-2--carboxylic acid diphenylmethyl ester was dissolved in 3 ml of methylene chloride and stirred for 45 minutes with 4A molecular sieves. The solution was then cooled in ice and added simultaneously with 36 mug (0.28 mmol) of N,N-diisopropylethylamine to a cold solution of 0.14 ml of N0 phsoltine was tirreed at 1.5Cl of 30thmines anordeat 3The sltemperar foire 45050or3 minutes. Tesltowad the 0% oomtegenatuin torueneminute.5 mle ofometn chloride.

cooled again in ice and added at 0-5 0 C to an ice-cooled solution which had been prepared at room temperature by stirring 83 mug (0.25 mmol) of 1-cyclopropyl.-6-fluoro-1.4dihydro-4-oxo-7-(1-piperaziriyl)-3-quinolin(4carboxylic acid (previously dried under reduced pressure at 100 0 C) and 125 mug (0.62 mmol) of N-methyl-N-(trimethylsilyl)trifluoro- 83acetamide (MSTFA) with 3 ml of methylene chloride for minutes. After stirring for 30 minutes at 0-5 0 C and one hour at room temperature, the mixture was concentrated under reduced pressure. The residue was purified chromatographically to yield 63 mg of the title compound with spectral qualities similar to those of the product obtained above.

EXAMPLE 22 Preparation of (6R-trans)-7-amino-3-frfC4-(3-carboxy-lcxclopropyl-6-fluoro-1. 4-dihydro-4-oxo-7-guinolinyl)-lr4.2.Oloct-2-ene-2-carboxylic acid trif luoroa ,,etic acid salt a kit C0 2

H

CF

3

CO

2

H

Iii a i It i a It t a a A solution of 0.251 g (0.294 mmol) of the diphenylmethyl ester prepared in Example 21 and 0.55 ml ot anisole in ml of dry methylene chloride was cooled to 0 0 C. Cold trifluoroacetic aoid (3.6 ml) was added, and the mixture was stirred cold under argon for 1 hour and 45 minutes. The mixture was concentrated to dryness under reduced pressure.

The residue was treated with 1.5 ml of methylene chloride followed by 6 ml of ethyl acetate. The resultant gummy L" .J Ii tV LLIYJI acetate, and 80 ml of 6 N aqueous HCl was added to bring the -84precpitae gadualy olidified. Ether (23 ml) was then added, and the mixture was stirred cold for 10-15 minutes before filtering. The product was washed with ether and dried under reduced pressure, obtaining 186.2 mg of the title compound, with an additional 9.0 mg which adhered to the walls of the flask (total 93.3%).

EXAMPLE 23 Pr ep]a r at ion of 6R-[6 c, 78 (Z)I I- 7- r[r(2 -ami no- 4 -th ia z olyl1 (wethoxvimino) acetyl IaminoI- 3 -r r 4-3 -car boxy- cc lopropyl- 6-f luoro-1, 4-dihydro-4-oxo-7-guinolinyl)-l-piperazinyll.

carbonvlloxvlmethvll-8-oxo-5-thia-l-azabicyclor4 .2.0]oct-2- 1ene-2-carboxylic acid disodium salt

NOCH

3 F C0 2 Na Ni 22 Na S 0t The trifluoroacetic acid salt (183.7 mg. 0,262 mmol) prepared by the precedinig procedure (Example 22) was suspended in 4.5 ml of TfIF and cooled to 0 0 C. A solution of 79.9 mug (0.95 mmol) of sodium bicarbonate in 4.5 ml of water was added, followed by 1.5 ml of water wash. The mixture was stirred for 18 minutes. A solution of 93.9 mg (0.268 mmol) of (Z)-2-amino-ca-(methoxyimino)-4-thiazoleethanethioi.c acid S-2-benzothiazolyl ester in 1.5 ml of TH' was then added along with 0.7 ml of TH' wash. After minutes the cooling bath was removed, and the reaction 85 mixture was stirred at ambient temperature for 17 hours.

The mixture was concentrated under reduced pressure to remove the organic solvent. The remaining aqueous solution was extracted with ethyl acetate. The ethyl acetate was back-washed twice with water. The aqueous phase and water washes were combined. The pH of this solution was 8.70; 0.025 molar aqueous sodium dihydrogen phosphate solution was added to bring the pH to 7.80. The solution was concentrated slightly under reduced pressure to remove residual ethyl acetate before chromatography on a column containing 9 g of Cle-silica (from Waters). The column was washed with pH 7.8 aqueous sodium phosphate buffer and then eluted with a stepwise gradient of water-acetonitrile (from 0 to 30% acetonitrile) under pressure. Appropriate fractions were combined, concentrated and freeze dried to obtain 127.6 mg of the title compound. Of this material 52 mg were dissolved in 0.5 ml of water, and the pH was adjusted to 8.0 by addition of sodium bicarbonate. Cold ,t acetone (24 ml) was added to re-precipitate the product.

After centrifuging the supernatant liquid was removed; the residual solid was triturated with cold acetone, filtered and dried under reduced pressure over P20 to provide 39 mg of product: IR (KBr) 3410, 2540, 1762, 1672, 1622; mass spectrum (FAB) 837 (M Na) 815 (M H).

EXAMPLE 24 Preparation of (6R-trans)-3[[ [4-(3-carboxy-l-cyclopropyl- 6-fluoro-1.4-dihydro-4-oxo-7-quinolinyl)-l-piperazinyllcarbonyll oxy]methyll-8-oxo-7-[(phenoxyacetyl)aminol- 5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid .4 86 rI O c o 4CH o A suspension 'f 184 mg (0.262 mmol) of the trifluoroacetic acid salt, prepared as in Example 22, in 5 ml of THF was stirred at 0-5 0 C, and a solution of 101 mg (1.2 mmol) of sodium bicarbonate in 4.5 ml of water was added. A cold solution of 54 mg (0.314 mmol) of phenoxyacetyl chloride in 1.5 ml of THF was added dropwise. Stirring was continued at 0-5 0 C f6c twenty minutes and then for three hours at ambient temperature. The mixture was concentrated under reduced pressure to remove THF. 'The aqueous residue was diluted with water, washed with ethyl acetate, cooled in ice and acidified to pH 2.5 to precipitate the product. After filtration the solid was washed on the filter with water and ethyl acetate to obtain 130 mg of the title compound.

Further purification was accomplished by reverse-phase HPLC on C 1-silica using a pH 7.5 sodium phosphate buffer-acetonitrile gradient. The residue obtained after evaporation and freeze-drying of the appropriate fractions was dissolved in water. The solution was filtered, and then acidified to pH 2.5 to precipitate the product: mass spectrum (FAB) m/z 722 (M H)+ EXAMPLE Preparation of [6R-[6a,7B(Z)]]-7-[[(2-amino-4-thiazolyl)- [(l-carboxy-l-methyl-ethoxy)iminolacetyllaminol-3-[[[[4-(3carboxy-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- 1-azabicyclof4.2.0]oct-2-ene-2-carboxylic acid

'I

tI, I *t t :1 87 A02H r 0 COH NO H H C0 2 COa o0 A suspension of 552 mg (0.786 mmol) of the trifluoroacetic acid salt, prepared according to Example 22, in 14 ml of THF was cooled in ice. A solution of 240 mg (2.85 mmol) of sodium bicarbonate in 15 ml of water was added and the mixture stirred for 20 minutes. A solution of ,2 384 mg (0.804 mmol) of 2-[[[1-(2-amino-4-thiazolyl)-2-[(2benzothiazolyl)thio]-2-oxoethylidene]amino]oxy]methyl~ pgopanoic acid 1.,-dimethylethyl ester in 6 ml of THF was then added. The mixture was stirred for 15 minutes with ice cooling and then overright at room temperature. Under reduced pressure the mixture was concentrated to remove THF. The remaining aqueous solution was washed with ethyl acetate and acidified to pH 2.7. The solid precipitate was filtered, washed with water and dried under reduced pressure over calcium sulfate. The intermediate thus obtained (540 mg) was dissolved with cooling in 2,4 ml of anisole and 6 ml of trifluoroacetic acid and kept overnight at 0 0 C. The mixture was concentrated under reduced pressure. Methylene chloride (10 ml) was added and the mixture again evaporated under reduced pressure. On addition of 4 ml of methylene chloride and 16 ml of ethyl acetate, the residue solidified, After filtering, washing with ethyl acetate al 4 d air drying, 520 mg of product was obtained in the form of a trifluoroacetic acid salt. this product was dissolved along with four equivalents of sodium bicarbonate in 0.025 molar pH sodium phosphate buffer hand purified chromatographically on C18-silica, using pH 7.5 buffer-acetonitrile as eluant. The 88 appropriate fractions were combined and acidified to pH 3 to precipitate the title compound, which was filtered, washed with water, and dried under reduced pressure: IR 1782, 1703.

1628 cm 1 mass spectrum (FAB) m/z 843 (M EXAMPLE 26 Preparation of r6R-r6 ,7B(Z)11-7-[r(2-amino-4-thiazolyl)- [r(carboxymethoxy)iminolacetyllaminol-3-ff[[4-(3-carboxy-lcyclopropyl-6-fluoro--1,4-dihydro-4-oxo-7-quinolinyl)-....

piperazinyllcarbonylloxylmethyll-8-oxo-5-thia-1-azabicyclof4.2.0loct-2ene-2-carboxylic acid 02Hr 0

NO

11o2N- 0 OP 4, 4oS O I '4 using procedures similar to those in Example 25, but substituting the appropriate thio ester, the title compound -1: was prepared: IR 1780, 1698, 1628 cm mass spectrum (FAB) 815 (M Following t-he procedures set forth in the foregoing examples, there can be prepared the following additional compounds: S6R-C6aq73(Z) I 1 (2-amino-4 -thiazolyl) (methoxyimino)acetyljamino-3- C tl-(3-carboxy-l-ethyl-6-fluo o-l, 4 dihydro-4-oxo-.7=quinolinyl)-3-pyrrolidnyl aminojcalbony.>oxyjmethylj-8,-oxo-5-thia-l-azablcyclot44 .Ojoct-2-ene-2carboxylic acid 89

I

SC0 2

H

H2N--

S

C 6R- [6a. 713 (Z -7-C 2-amino-4,th a zoy I) (me thoxyiniino) acetyl]amino]-3-C[4-(3-carboxy-6-fuoro..N(4-fluoropheny).

1. 4-di-hydro-4--oxo-7-quinoliny]-l-piperazinyl]carbonylJoxy..

me thyl]-8-oxo--5-thi a -I-a zabicyc Io 2.0] oct"-2.ene- car boxylic acid0

NOCH

3 HHHIC2 is NS N 'N N C6 R- 6 a ,713 Z 7 2 a mio- 4- t h ia zo I y 1 (me th oxy im 1n o) act) mn 3-CC4 3-a oy ur-,4 d ihy dr o- 4 -o0x0- 1 8 -n ap h thy r d n 7 -y p ip e r a nyI ]c a r b o n vI o y]meth 1-8-oXo-5- 2 0 1o ct 2,*e ne 2 carboxylic acid c 2 t6R-(6ct,7B3(Z) 3 C (2-amuino-4-ttiazoly1.) (methoxyimino)actl]mn] 3 HI40Ccotpl6floo2 ,9tta hYdro-3 4-dioxoisothiazolo( 5#4-bjquinolin.-7-y.) -l-piperazinytjcarbonyljoxylmethyl)-8-oxo...s.thia-1-azabicyclot4.2.03- Oct#-2-ene-2-carboxyllc acid 90 [6R-[6 a,713(Z [(2-amino-4-thiazolyl) (me thoxyimii.o)acetyl]amino]-3-fCI(4-(9-cyclopropy--6-f2,uoro-2. 3,4,9tetrahYdro-3,4-diloxoisoxazoloI5,4-b]quiflin-7-yl)-l-piperazi,nyl]carbonyl3oxy~methy1]-8-oxo-5-thia-l-azabilcycJ.o(4,2.01oct-2--ene-2-carboxylic acid 01 0 V '1 o I I 0

N-

i u

CORH

aoetyllamintoj-3-[ ((1-(3-carboxy-8~chloro4l-cyopropy1-6carbonyljoxylrnethyl-8~oxo- -thia-azabicycloI4,2,0Ooct-2- 25 ene-2-carboxylic acid NC0% I HH H

=O

2

H

(6R-16&t,7$3(Z) I ((2-amino-4-thiazol~1) t (1-carboxy-Vmethylethoxy) imin03]acetyj amo)e-3- [J [4-(3-carboxy-thyl-Gf),uoro-., 4-dihydro-4-oxo-7.qUinolinl)-t-piperazil- 91 carbonyl]oxy)methyl3-8-oxo-5-thia-l-azabicyclo[4.2.O]oct-2ene-2-carboxylic acid ,XCC 8 ,CO 2

H

[6R-E6c73(Z) 11-7 -1[(2-amino-4-thiazoy (car boxymethoxy)dihydro-4-oxo-7-quinoliny)-.piperazinyl]carbonyl]oxy] metlhyl)]-oxo-5-thiia-1-azabicyclo14.2.0]Qct-2-ene-2-carboxylic acid (6R-t~ans)-3-t E4-(3-carboXy-1-ethyl-6-ftUoro-1, 4-dihydro-4oxo-7-'quinlinyl)--piperazirnylCatbonfl)xyTlethyl)-7-d (hydroxyphenylacetyl)amino]-B-oxo--ia-1-azabicyclo(4.2,0~oct- 2-ene.-2-carboxylic aci~d 0 1?C COH O-1 HCNH4 IK C yN oXb-7-gUiaolInyt)'1p Iper a zIny I I a bo I I0xy) met hy I J-8-oxo-7t(pherioxyacey)amino)Sthia-1-azabicyclot4.2.O)oc2-one-2r

F-

92 ca~lboxylic acid 0l [6R6a,73(l) j -3-C [C4-(3-.arboxy-l--thy-6f uoro.1, 4 dihyclro-4-oxo-7-qui no I iny,) -1-piperazinyl ]car bonyl oxy I rnethyl]-7-[((4-etthyl-23-dioxo-piperaz~iyl)carbonyl].

amino] phenylacetyl amnino) -8-oxo-S-thia- I-a zabicyco 4.2. O]oct- 2-ene-2-carboxylic acid

A.

'J a a .4 A A 4 A .4 [6R-6cL,78(Z) 117-C(2-oatiazo-4-hiz)( e thoxyimiio)- 25 a cetylJamio]-3-[ I L 4-(5-amio-~3-carboxcy..-cyclopropyl-6,8dcarbonyl Ioxy) me tyl I-EO-Qxo.5-thi a1- a zabicyolo[4 01oct-2ene-2-carboxylic acid ,C0 2

H

a 1-a Fl-- ~il -93- -14 A Examplg 97 Preparation of Diphenylniethy.l 6R.7R)-7-.(l-tert-butoxyformamido) -3-chlorocarbonvloxv-niethyli4-oxo-5-thia-l-azabicyclo[4.2 .0]oct A solution of 855 mig 0l.72mmol) of diphenylmethyl tert-buitoxyformamlido)-.3-(hiydr-oxymeth,.)-8-oxo-5-thia-l-azabicycloC4.2.0]oct-2 -ene-2-carboxylate in 15 mL of dry CH 2 C1 2 was added dropwise over a period of approximately one minute, to a cold solution (ice-bath) of 4 mL (7.72 mmol of phosgerne sol ution (1I.,93 M i n tol uene) wi th sti rri ng at 0C. At the same ti me, a sol ution of 0, 32 mL 1.87 mmol of

'I

0 dilsopropylethylamine in 10 mL of CH C11 was added also over a period 4-15 of five minutes, 'rhe clear reaction solution was stirred at 0 0 C for 2 h under argon. It was then taken into 50 mL of cold CH Cla ahdwt 2 ,wshdwt cold 3 x mL H 0, and dried over anhydrous Na so 4 at 0 0 C, After filtration, the CH C1 2 was evaporated at 0 0 C to S 0 C to yield Diphenyl (6R,7R)-7.(-tert-butoxyformamlido)-3-chilor~ocarbonyloxy-methyl -8oxo-5-thi a-l--azabi cyclo[4,2.0joct-2-ene-2-carboxyl ate as a yellowish solution in toluene. (NMR spectrum 18035-136) MX;. 559,042, Fr, I C 27 27 1

N

2 7

S

J.or-2[34.9-(9ahdr-34.

oxmetyil8-xQ-- ~-~bthi z QLy2oy--ee-crovic ci A sample of 1.4 mL (7.52 mmol) of N-methyl4J-(trimethylilyl) trifluoroacetamide (MSTFA) was added to a suspension of 600 mig (1 k I -93a (1.55 mmol) of 9-cyclopropyl-6--fluoro-2,3,4,9-tetrahydro-7-(lpilperazi nyl ilsoth azol 4bquinoone-3,4-dlone in 10 m dry CHM 2 C1 2 with stirring under argon at 230C. After 30 minutes, the clelt-r yellow solution was chilled in an ice-bath, and treated dropwise with a cold toluene solution (ca. 3 mL) of the chloroformate prepared in Example 2741 above. The resultant Qlear yellow solution was stirred at 000 under argon for 1,0 h. To the reaction mixture 0.25 mL of CH 3 OH was added and stirring was continued at O 0 C for 20 min. The resultant yellow precipitate was filtered, washed with 3 x 2 mL 5% CH 3 OH in CH 2 Cl 2 and dried under vacuo to give 175 mg of 9-cyclopropyl-6-fluoro-2)3,4,9tetrahydro-7-(l-piperazinyl) isothlazolo[5.4b~qulnollne-3,4-dione, To thle filtr.ate, 200 m of diethylether was added to precipitate the product. The solid was collected by filtration, washed with 3 x 5 mL ether, and dried in vacuo to give 809 mg (65% yield) of [6R-15ax,7P(Z)JJ-7-(l-tertbutoxyformamldo)-3-1[4-(9.-cyclopropyl-6-fluoro-2,3,4,9-tetrahiydro S-3,4-dioxoisothlazoloL5,4-blquinoline-7-yl)-l-piperazinyllcarbonylloxymethylI 4 44, -8-oXo--5-thia-1-azabicyclo[4,2.0]oct-2-ene-2-carboxylic acid diphenylmethyl eI Ister as a tan soli1d (NNR, UV, P024977) M,'LA 88Z. 995, E

C

44

H

4 FN 0 S 2 444 692 Mhp ara t ion of [6 R- 6L7--)U-.amn--14(-ylorpl6f~oo carbonylloxymethyl)-8 oxo-5-th ia- I-azab ic yc I o1., 0Qloct-2-e ne-2-carbox y Ii r acid, Q1:1) trifluoroap~ejs.dsalt A Mixture of 15 mL dry nitromethane, 20 mL trifluoroacetic acid, and 0.3 mL of anisole was cooled to 000, To this mixture, tinder an argon atmosphere, ,130 with stirring, Il#6g 01,81 mmol of [6R-[5ca,7f3Z)1--7- (l-tert-butoXyformamiido)-3-uj71-'(9-cyClopropyl-6-fluoro-2,3,4,9terlyr-,-ixiohaoo[,-lqioie7y--ieaiycroy -93b oxymethyl)-8-oxo--5-thia-l-azabicycloE4.2.0)act-2--ene-carboxylic acid diphenylmethyl ester, was added in portions. The resultant solution was stirred at 000 under argon for 3h. The reaction was stopped by adding first 30 mL hexane, followed by 160 mL diethyl ether. After 10 minutes at 0 0 C with vigorous stirring, the precipitate was filtered, washed with 3 x mL ether, and dri ed i n vacuo to gi ve 1l.1 6g (87, yi el d) of [6R-Hc, 7f(Z) J-7-am no-3-[ 4-(9-cyclopropyl -6-f Iuoro-2, 3, 4,9tetrahydro-3, 4-di oxoi sothi azolo-f25. 5-blqui nol in-7-yl -pi perazi nylJI carbonyl1Joxymethyl -8-oxo-5-th a-1 -azab cyc o14.2. 0 oct-2-e ne-2-car boxy 1i c aci d (lI:l1)tri fl1uoroaceti c aci d sal t as a pal e yell1ow sol id (NMR PC 249944), MXN: 730.676, C 26

H

25

FN

6 0 7

S

2

C

2

HF

3 0 2 Emple Preparation ofj6 x 7 f3QZ111- 7 E2-amino--thazoll)(iiethoxyiminoi) D--ee2crbxlcai disodlum salt tri hydrat, A solution of approximately 7 niL saturated NaHCO 3 was added to a mixture of 1 .53 q (2.09 mmol of E6R-6c, 7f3(Z)lJ1-7-ami no-3- MAE-(-cyclopropyl 6-flIuoro-2, 3,4, 9-tetrahydro-3,4-di oxoi sothi azolo(5,.4-blqui nol In-7-yl 0a0Q pi peraz-i nyl Icarbonyl 1oxymethyl )-8-oxo-5-thi a-l -azabi cycl 2 Oloct-2-ene- "025 2-carboxyl ic aci d (1I:1I) trl fl1uoroaceti c aci d sal t I n 60 mL of 1:1 tetrahydrof ural -water until1 the pH was 8.0 8. 5. It was stirred vigourously for 15 minutes and then cooled to 0 0 C. To this mixture, a solution of 0.91 g (2.6 mmol) of S-(2-benzothiazoyl)-2-amino-4thiazoleglyoxylate (E)-.0-methyloxime in 10 mL of THF was added over a period of 15 minutes. The reaction mixture was stirred at 0QC 5CC for and at 230C for, 1 .0 h, Acetone (800 mL Was then added and the resultant precipitate was collected by filtration, washed with acetone KW K: -93c- (4 x 20 mL) and dri-ed under vacuum to yield 1 .9 g of sol id. This material was tatken into 50 mL of 2.5% CH CN in water and treated with saturated sodium bicarbonate 20 mL) until the pH reached 9.5. After dilution with water (100 mL), the solution was passed through a 0 18 column (75 g of YMC-gel, 120 Elution with 15% to 20% CH 3CN in water gave fractions containing the product. The CH 3 CN was evaporated in vacuo and the aqueous solution was lyophilized to give [6R-F6x,7f(Z))-7-[2-amino-4-thiazolyl)(methoxyimino)acetyI ]amino] -3-EE t4-9-.cyclopropyl-6-fluoro-2,3,4,9-tetrahydro-3,4-dioxoisothiazoloE5,4blquinolin-7-yl)-l-piperazinyllcarbonylJoxylmethiyll-8-oxo-5-thia-l-azabicyclo [4.2.O1oct-2--ene-carboxylic acid disodium salt trihydrate as a white solid, Calcd, for CG 32 H 28 FN 9 0 9

S

3 2Na3H 2 0 (897.84); C42.8, H 3. 81 ,N 14.04, F 2 .11I, Na 5. 12, Found; C 42,8, H 3,46, N 13.71, F 2,17, Na5,04.in Vitro and In Vii..Q-a.Lz E6R-E6cx,7f(Z)3)1-7-[2-amino-4- thiazolyl)(methoxyimino)acetyllaminoJ-3- [LU(4-(9-cycloprQpyl-6-fluoro-2,3,4,9-tetrahydro-3,4-dioxoisothiazoloE5,4-bJquinollni-7-yD)-l-pipeazinylcarbonyloxylmethyl-8-oxo-5-thia-l-azabicylclo- [4,2,Oloct-2- one-carboxyl ic acid shows excellent in vitro antibacterial activity and also demonstrated impressive activity subcutaneously in the murine streptococcal pneumonia model with an ED 0 of 4. mg/kg as described below, MICa ED b Escherichia coll 257 0.0157 DCO 0.25 DC2 0.0313 Pseudomonas aeruglnosa 56 Staphylococcus aureus Smith 0.125 StreptococcuIS pneumonae 6301 0.0019 4.1 a MIC in >g/ml ED in mg/kg KWK: 93d The following Example illustrates pharmaceutical preparations containing the cephalosporin derivatives provided by the present invention: Example A Production of dry ampoules for intramuscular administration: A lyophilisate of 1 g of active ingredient is prepared in the usual manner and filled into an ampoule. The sterile water ampoule contains propylene glycol. Prior to the administration, the lyophilisate is treated with 2.5 ml of a 2% aqueous lidocaine hydrochloride solution.

As active ingredient can be used ore of the end products prepared according to the above Examples.

ii ao a a i/ a a TMS/275

Claims (7)

1. Acyl derivatives of the general formula T Mm 1. wherein R is a substituted N-heterocyclus of the formulas 1 i t i ii 0 A 0CH 3 3 (c) where R10 is one of the groups (cl) (c2) (c3) O k fe qu s4 -1HCH 2 171 (c4) Q represents a substituted quinolinyl or naphthyridinyl group and the N-heterocyclic nucleus may optionally be substituted with one or more lower alkyl groups: R2 is selected from the group consisting of hydrogen, lower 3, alkoxy, lower alkylthio and lower alkanoylamino: R is an acyl groups; m is zero, 1 or 2: and A is a 95 -pharmaceutically acceptable anion. and readily hydrolyzable esters and pharmaceutically acceptable salts of these compounds and hydrates of the compounds of formula I or of their esters or salts.

2. A compound as in claim 1, wherein R is one of group and

3. A compound as in claim 2 wherein m is zero and R2 is hydrogen.

4. A compound as in claim 2 or 3 wherein R is of the formula 0 3 3 R CH 2 i wherein Z represents R30-C or nitrogen; R 30 represents hydrogen, halogen or an oxymethylene (-CH 2 bridge to the piperazine nucleus to form a fused six-membered ring; R 31 represents hydrogen, lower alkyl, lower alkenyl, C 3 -C 7 cycloalkyl, 1 1 halo-lower alkyl or mono-, di- or tri-halophenyl; R 0 and R 3 when taken together represent a C3-C alkylene group, a C -C alkylene mono-oscy group, a 2 4 ci-C 2 alkylene dioxy group or a group of the formula -OCH 2 N(CH3)-, and 33 represents hydrogen or halogen. 30 A compound as in claim 4, wherein Z is R -C in which R 30 is hydrogen, bromine, chlorine or fluorine, 2 r i i- 96 31 R -is lower alkyl, halo-lower alkyl or C 3 -C 7 33 cycloalkyl, and R 33 is hydrogen, chlorine or fluorine.

6. A compound as in claim 5, wherein R 30 is hydrogen 31 or fluorine, R 31 is ethyl, fluoroethyl or cyclopropyl, and R 33 is hydrogen or fluorine.

7. A compound as in claim 2 or 3, wherein R 1 is of the formula 4 4 i S( I 4 t 8, A compound as in claim 2 or 3, wherein R' is of the formula

444- 4 4 44 r 9. A compound as in any one of claims 2-8 wherein R is an aliphatic acyl group of the formula R CO- 97 -whetein R 5 is selected from the group consisting of hydrogen.. lower alkyl. C 3 C 7 cycloalkyl. lower alkoxy. lower alkenyl. C 3-c7 cycloalkenyl or cyclohexadienyl. or lower alkyl or alkenyl substituted with one or more halogen, cyano. nitro, amino, mercapto. lower alkylthio. or cyanomethylthio groups. A compound as in any one of claims 2-8 wherein, R3 is an aromatic acyl group selected from the group consisting of 4 4 4 ;~4 f4 4 4 4 *4 CH- Co- R. 8 CH 2 Co-. -0-OH- Co- rI S -CH 2 CO- 7 R 8 CH- CO- c co- jj 7 R CM-'CO- .I 15 N I I 4 I 49 I so 2 M 6 7 8 wherein n is 0, 1. 2 or 3: R, R and R are independently selected from the group consisting of hydrogen, halogen. hydroxy, nito, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and aminomethyl: and R90 is selected from the group consisting of amino, acylamino, hydroxy, a carboxy salt, protected carboxy, formyloxy, azido and a sulfo salt, and M is a cation. 11. A compound as in any one of claims 2-8a wherein R is a heteroaromatic acyl group selected from the group consisting of R -(CHo 2 )n-CO- 99 101 R 101-CH-CO- R 9 0 101 R -O-CH -CO- 101 R 101-S-CH2-CO- and 101 R -C0- Co- wherein n is 0, 1, 2 or 3; R 90 is selected from the group consisting of amino, acylamino, hydroxy, a carboxy salt, protected carboxy, azido and a sulfo salt; and BR 101is a substituted or unsubstituted 5S, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, 12. A compound as in any one of claims 2-8 wherein R is a C(4-asubstituted-2,3 -dioxo-l-piperazinyl)carbonyl> amino~acetyi group of the formula 120- I 00 wherein R 111 is lower alkyl, hydroxy-lower alkyl or an aromatic group Of the formula 100 7 R 6 R8a 67 8 wherein R R, and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of I to 4 carbon atoms, amino- methyl. or a substituted or unsubstituted 6- or 7-membered heteocycliq ring containing 1, 2, 3 or 4 hetero atoms selected from the group consisting ,f 120 nitrogen, oxygen and sulfutr, and R is lowec alKyl or substitutedal (wherein the lower alkyl grcoup is substituted with one or more halogen, cyano, nitro, amino or mercapto groups). 13. A compound as in any one of claims 2-8 whe4an R 3 is an (acylamino)acetyl group of the formula 140 al -CO-Nt-CH-GCO- aromatic group of the formulaa AU 101 7 R 6 6 7 8 wherein R R and R are independently selected frqm the group consisting of hydrogen, halogen, hydroxy, nitro. amino, cyano, trifluoromethyl. alkyl or 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and aminomethyl. and a substituted or unsubstituted 6- or 7-membered heterocyclic Ling containing 1, 2, 3 or 4 hetero atoms selected from the group consisting of 140, nitrogen, oxygen and sulfur and R is )R 6 RO- n (C H2) 0o- a, (where R R 7 and are as previously defined and n is 0. 1, 2 or hydrogen, lower alky, substituted lower alkyl, amino, lower alkylamnino, dl-lower alkylamino, (cy' no-lower alkyl)amino, hydtazino, loweA alkyl-hydra ino, aryl-hydzazino or acyl-hydrazino. 14. A compound as in any one of claims 2-8 wherein R 3 is a (substituted oxyimino)acetyl group having the formula 102 R22 140 R -CO-C-O--N=C-CO- R23 ill wherein R ilis lower alkyl. hydroxy-lower alkyl or an aromatic group of~ the formula o ci ci 0 ii~ Q 0 0 48 ci 88 88 88 888 8 4 S 0088 8 88 88 8 8 88 88 8 4 88 wheei R6,R 7and R 8 are independen-tly selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl or 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and amino- methyl, or a substituted or unsubstItUted 6- or 7-membered heterocyclic ring cotitaining 1, 2, 3 or 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, and R 8- 88 8C. 103 6 7 8 -(wherein R R and R are as defined above and n is 0. 1, 2 or hydrogen, lower alkyl. substituted lower alkyl, amino, lower alkylamino. di-lower alkyl- amino. (cyano-lower alkyl) amino. hydrazino, lower alkyl-hydrazino, aryl-hydrazino and acyl-hydrazio and 22 23 R and R23 are independently selected from the group consisting of hydrogen and lower alkyl, or R 2 2 and R23 taken together with the carbon atom to which they are attached fori a C3-C7 carbocyclic ring. A compound as in any one of claims 2-8 wherein R 3 is a [C[3-substituted-2-oxo-l-imidazolidinyl]carbonyl]- amino]acetyl group of the fQzmula 4 a C RGAL- N-CO-NH-CH-CO- 20 C 2 H2il wherein R is lower alkyl, hydroxy-lower alkyl or an 4 4 4 4 25 aromatic group of the formula 44 4. ad4 4 9 4 30 R a I" RT 6 7 8 wherein R R and R are independently selected from the group consisting of hydtrogen, halogen, hydro. -104- -nitro, amino, cyano, trifluoromethyl, alkyl or 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, amino- methyl, or a substituted or unsubstituted 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 hetero atoms selected from the group consisting of 15 nitrogen, oxygen and sulfur, and R is hydrogen, lower alkylsulfonyl, arylmethyleneamino 111 111 -N=CHR wherein R is as defined above), R CO- (wherein R is hydrogen, lower alkyl or halogen substituted lower alkyl), aromatic group (as 111 defined by R above), lower alkyl or substituted lower alkyl (wherein the lower alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups). II 16. A compound as in any one of claims 2-8 wherein acyl 3. group R is of the formula 13R0 R -O-N=C-CO- I 20 I 101 wherein R is an unsubstituted or substituted 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur wherein the heterocyclic ring is substituted by halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, C 1 -C 4 alkyl or C -C 4 alkoxy and R 1 is hydrogen, lower alkyl, C3-C 7 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 R in claim 15), carboxy (including salts thereof), lower alkanoylamino, carbamoyl, lower alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxy-lower alkoxyphosphinyl, dihydroxyphosphinyl, 105 .hydroxy(phenylmethoxy)phosphinyl, di-lower-alkoxyphosphinyl substituents]. 17. A compound as in claim 16 wherein R is of the formula I wherein R2 is hydrogen or an amino protecting group, 130 and R is hydrogen, lower alkyl or a group of the formula I -COP I R 2 3 wherein R 2 2 and R 2 3 are selected from the group consisting of hydrogen and lower alkyl or taken together with the carbon atom to which they are attached form a C 3 -C 7 carbocyclic ring, and P is hydroxy or -NHR 1 9 where R 19 is hydrogen, lower alkyl, amino, lower alkyl-amino, arylamino or acylamino. 18. A compound as in claim 17 wherein R 2 0 is hydrogen and R is methyl or a group of the formula -106- C -COOR R 23 22 R wherein R 22and R 23are selected from the group consisting of hydrogen and methyl. 19. A compound as in any one of claims 14 and 16-18 which is in the syn-form or as a mixture in which the syn-form predominates. A compound as in claim 2, wherein R 1is group (a) and R 3is phenoxyacetyl. 21. A compound as in claim 2 selected from the group 0 0 consisting of 0( 6 R-trans)-4-[3-carboxy--(2.fluoroethyl)6.8.difluoro. acetyl)amino]-5-thia-1 aaiyco42o-c..en3.yljmethyl]. 1-methylpiperazinium iodide, carboxy-l-methyl)ethoxy] imino]acetyl ]amino] 2carh~xy-8- oxo-5-thia-1-azabicyclo(4.2.oloct-2en.3.ylJmethyl>4- E 3 -carboxy-l-(2-fluoroethyl)6,8difluoro1,4-dihydro-4- oxoquinolin-7-yl)-1-methylpiperazinium hydroxide inner salt monosodium salt and ~ffL' C 6 R-[ 6 a,78(Z)]3-1-LE7-[C(2-amino-4-thiazolyl)(methoxy- (420ot2e--lmty]4(-abx--ty--loo 1,4-iyr-- unlny)lmtypprznu iodide. 22. 6 R-C 6 G.,73(Z)]]-lE(E(2Amino.4thiazolyl)(methoxy- imino) acetyl ]aino] (420ot2e--lmty]--3croy-,-iloo 1' 1 -107 1-2flooty)14dhdo--x--unlnl--eh1 piperazinium iodide. )acetyl ]amino] -2-carboxy-8-oxo-5-thia--azabicyclo- [4.2.0]oct-2-en-3-yl]methyl)-4-[3-carboxy-6.8-difluoro- 1- (2-f luoroethyl 4-dihydro-4-oxo-7-quinolinyl]3-1-methyl- piperazinium hydroxide inner salt monosodium salt. 24. (6R-trans)-4-[3-Carboxy-6.8-difluoro---(2-fluoro- ethyl) 4-dihydro-4-oxo-7-quinolinyll C[2-carboxy-7- (formylamino) -8-oxo-5-thia-1-azabicyc 10 oct-2-en-3-yl 3- methyl]-1-methylpiperazinium trif luoroacetate. 15 25. [6R-[6at,713(Z) 3 E(2-,Amino-4-thiazolyl)[[1,1- dimethyl-2- 1-dimothylethoxy)-2-oxo-ethox>] liminojacetyl]- amino] -2 -car boxy-8-oxo-5- thia-Kl-azab icyc lo 2. 0j oct-2-en-3 ylj-methyl]-4-(3-carboxy-(2-fluoroethyl)-6,8-difluoro-l,4- dihydro-4-oxoquinolin-7-yl3-.l-methylpiperaziflium iodide. 26. A compound as in claim 1 wherein R 1 is group 27. A compound as in claim 26 wherein m is zero or 1. 28. A compound as in claim 26 or 27 wherein Q is #40440 4 0 I, #04 4, 4 o r N 108 -wherein Z represents R -C or nitrogen, X represents oxygen or sulfur, R 30 represents hydrogen, halogen or an oxymethylene (-CH20-) bridge to the piperazine nucleus to form a fused six-membered ring; !31 represents hydrogen, lower alkyl, lower alkenyl, C 3 -C 7 cycloalkyl, halo-lower alkyl or mono-, di- and tri-halophenyl; R 3 0 and R 3 1 when taken together represent a C 3 -C 5 alkylene group, a C2-C 4 alkylene mono-oxy group, a C-C2 alkylene dioxy -c- group or a group of the formula -OCH2N(CH 3 R is hydrogen or halogen; and R 34 is hydrogen or amino. 29. A compound as in claim 28, wherein Z is Swherein R 3 is hydrogen, chlorine, bromine or fluorine, 31 R is lower alkyl, halo-lower alkyl or C -C 337 cycloalkyl, and R 3 is hydrogen, chlorine or fluorine. A compound as in claim 29, wherein R 30 is hydrogen 31 or fluorine, R is ethyl, fluoroethyl or cyclopropyl, and 33 R is hydrogen or fluorine. 31. A compound as in claim 28, wherein R is of the formula o FC0 2 H N N -I i- lC- 109 -32. A compound as in clair 28 wherein R 1 is of the formula C0 2 H o 0 4o 0 0, 00U '4r~ 33. A compound as in any one of claims 26-32 wherein R is an aliphatic acyl group of the formula R CO- wherein R 5 is selected from the group consisting of hydrogen, lower alkyl, C 3 -C 7 cycloalkyl, lower alkoxy, lower alkenyl, C 3 -C 7 cycloalkenyl or cyclohexadienyl, or lower alkyl or alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, lower alkylthio, or cyanomethyithio groups. 34. A compound as in any R 3 is an aromatic acyl group consisting of one of claims 26-32 wherein selected from the group CO- vi CH 2 co- P CH-*CO- 4""'&NH F- 111 -wherein n is 0, 1, 2 or 3; R 6 R 7 and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and aminomethyl; and R is selected from the group consisting of amino, acylamino, hydroxy, a carboxy salt, protected carboxy, formyloxy, azido and a sulfo salt, and M is a cation. 35. A compound as in any one of claims 26-32 wherein R 3 is a heteroaromatic acyl group selected from the group consisting of R 10 1 (CH2)n-CO 101 I R -CH-CO- R 9 0 R -O-CH2 CO- 101 R 01S-CH2-CO and R 0 CO-CO- wherein n is 0, 1, 2 or 3; R 90 is selected from the group consisting of amino, acylamino, hydroxy, a carboxy salt, protected carboxy, azido and a sulfo salt: and R 1 0 1 is a substituted or unsubstituted 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur. 112 .36. A compound as any one of claims 26-32 wherein R3 is a [[(4-substituted-2,3-dioxo-l-piperazinyl)carbonyl]- aiino]-acetyl group of the formula o-p wherein R ilis lower alKyl, hydroxy-lower alkyl or an aromatic group of the formula 207 wherein R 6 R 7 ,and R8are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethiyl, alkyl of 1 to 4 carbon atoms. alKoxy of I. to 4 carbon atoms, amino- methyl, or a substituted or unsubstituted 6- or 7-membered heterocyclic ring containing 2, 3 or 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, and R 10Is lower alkyl or substituted alkyl (wherein the lower alkyl group is substituted with onie or more halogen, cyano, nitro, amino or mercapto groups). 113 -37. A compound as any one of claims 26-32 wherein R 3 is an (acylamino)acetyl group of the formula R wherein R l l is lower alkyl, hydroxy-lower alkyl or an aromatic group of the formula wherein R, R 7 and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl or 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and aminomethyl, and a substituted or unsubstituted 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, and R 140 is R 6 R8 (CH 2 n-0- i i_ L 1 114 6 R7 adR8 (where R R and R are as previously defined and n is 0. 1, 3 or hydrogen, lower alkyl. substituted lower alkyl, amino. lower alkylamino, di-lower alkyl- amino, (cyano-lower alkyl)amino hydrazino, lower alkyl-hydrazino, aryl-ydrazino or acyl-hydrazino. 3 38. A compound as any one of claims 26-32 wherein R is a (substituted oxyimino)acetyl group having the formula ,22 L4:0 RL -CO-C-0-N=C-CO- I I 23 111 wherein is 1 Lower alKyl, hydroxy-lower alkyl or an aromatic group of the formula J 7 6- 7 8 7 wherein R 6 R7 and R are independently sQlected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, triluornomethyl, alkyl or 1 to 4 carbon atoms, alkoXy of 1 to 4 carbon atoms and amino- methyl. or a aubstitUted or unsubstitted 5-0 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 hetero atome selected from the group consisting of nitrogen, oxygen and sulfur, and n 140 is 115 Ra (CH2 n 6 7 8 (i terejn R6 R and R are as defined above and r, is 0. 2 cr hydrogen, lowet alkyl, substituted lower alkyl, amino, lower alkylamino, di-lower alkylamino, (cyano-lower alkyl) amino, hydrazino, lower alkyl-hydrazino, aryl-hydrazino and acyl-hydrazino, and 22 23 R 22and R23 are independently selected from the group oonsisting of hydrogen and lower alky, or r22 and 3 taken together with the carbon atom to which they are attached form a C 3 -C 7 carboxylic ring. 39. A compound as any one of claims 26-32 wherein R3 is a C3 -substituted-2-oxo-1- imidazo lidiny1jcarbonyl- aminoaicetyl group of the formula 0 r",-Co-NH--C-CO- 02R111 wherein 11 is lower alkyl, hydroxy-lower alkyl or an aromatic group of the formula 116 R7 R6 R 8 6 7 8 wherein R R and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl or ]i to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, amino- methyl, or a substituted or unsubstituted 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, and R is hydrogen, i lower alkylsulfonyl, arylmethyleneamino -N=CHR wherein R is as defined above), SR CO- (Wherein R 16 is hydrogen, lower alkyl or Shaloqen substituted lower alkyl), aromatic group (as defined by I? above), lower alkyl or substituted lower alkyl (wherein the lower alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups). A compound as any one of claims 26-32 wh in acyl group R 3 is of the form'a R130--N:C-CO- 10 1 wherein R is an unsubstituted or substituted 6- or 7-membered heterocyclic ring containing 2, 3 or 4 hetero atoms selected from the group consisting of 117 -nitrogen, oxygen and sulfur wherein the heterocyclic ring is substituted by halogen, hydroxy, nitro, amiino, cyano, trifluoromethyl, C1-C alkyl or C1-C4 alkoxy and R1 30 is hydrogen, lower alkyl, C 3 -C 7 cycloalkyl, jarboxy-C 3 -C 7 -cycloalkyl or substituted lower alkyl [wherein the lower alkyl is substituted with one or more halogen, cyano, nitro, amino, mercapto, 111 lower alkylthio, aromatic group (as defined by R in claim 39), carboxy (including salts thereof), lower alkanoylamino, carbamoyl, lower alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxy-lower alkoxyphosphinyl, dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl, di-lower-alkoxyphoi- phinyl substituents]. 101 41. A compound as in claim 40 wherein R is of the formula S 0 N I* 22 41* S R29dH/KS wherein R20 is hydrogen or an amino protecting group, 130 and R is hydrogen, lower alkyl or a group of the formula 2 2 -COP 23 -wherein R 22and R 23are selected from the group consisting of hydrogen and lower alkyl or taken together with the carbon atom to which they are attached form a C -C7carboxylic ring, and P is hydroxy or -NHR 19 6 where R 9is hydrogen, lower alkyl, amino, lower alkyl-amino. arylamino or acylamino. 42. A compound as in claim 41. wherein R 20is hydrogdn or triphenylmethyl. 43. A compound as in any one of claims 38 and 40-42 which is in the syn form or as a mixture in which the syn form predominates. 44. A compound as in claim 26 selected from the grOUP consisting of fluoro-1. 4"dihydro-4-oxo-7-quinolinyl -l-piperaz inyl 1- 2-ene-2-carboxylic acid, acetyl ]amino) C( 4-(3croylccorpl6floo1 4- boxylic acid, (6R-trans)-3[[ C 3 croy--ylprpl6floo14- [4.2.0]oct-2-ene-2-carboxylic acid, methyl-ethoxy) imiflo~acetyl ]amino 3-[CC 4(3carboxyl-cyclo- propyl-6-fluoro-l. 4-dihydro-4-oxo-7-q,,uinolinyl) -1-pipera- oct-2-ene-2-carboxylic acid and [6-6L7()]7[(-mn--haoy)[croy methoxy) imino ]acl.tyl ]aminlo]-3-t CC( (3carboxyl-Cyclo- -119- propyl-6-fluoro--l *4-dihydro.-4-OXO-7-quiflolinyl piperazimy]]carbonyl ]oxyjmethyl cyclo[4.2.0]oct-2-ene-2-carboxylic acid, as well as salt6 of these compounds and hydrates of these and salts. Salts of the compounds accrding to claim 44 which are sodium salts. 46. Compounds of the formula TM R2HS wherein R 1 R 2 R 3 and m are as above aad R'is t-butyl. benzhydryl. p-nitrobenzyl or ally. 47. (6R-trans)-4-[3-carboxy-6,8.-difluoro-l-(2-fluoro- ethyl) 4-dhydro-4-oxo--7-quinolinyl 1 1-dimethyl- ethoxy) car bonyl-7 ormylamino) -8-oo- 5- thia-l-azabicyc lo- [4.2.0joct-2-en-.3-yl]methyl]-l-methylpiperazinium iodi.de. 48. Compounds of the formula A'H 0 120 wherein R 1 and Rare as above, R is hydrogen or a carboxylic acid protecting group and R' is hydrogen or a readily removable amino protecting group. 49. (6R-trans)-3-EE4-(3-carboxy-1-cyclopropyl-6-.fluoro- dihydro-4-oxo-7-quino-linyl)-l-piperazinyllcarbonyloxymethyl--7-[[(1,l- dimethylethoxy)carbonyllaminol-8-oxo-5-thia,-l-azabicycloC4.2.oloct-2- ene-2-carboxylic acid diphenylmethyl ester. Process for the manufacture of the compounds according to any one of claims 1-45, which proces5 comprises a) for the manufacture of a compound of formula I, in which m is zero, reacting a compound of the general formula H N- I 2 L CH RH 0jf 2. *COOH 4wherein R 1and R2are as above, or a readily hyvdrolyzable ester or salt thereof with a carboxylic acid of 44 3 the general formula R OH or a reactive derivative thereof, or 0 j" r 4 4475 U' _L-YIP~-li--LI_~ lim~yl_ 121 b) for the manufacture of a compound of formula I, in which m is zero and R 1 is one of the groups and reacting a compound of the formula R NH CH2X III iIo *I *1 II *t ,I 2 3 wherein R and R are as above and X is a leaving group, and amino, hydroxy and carboxy groups present may be protected, or a readily hydrolyzable ester or salt thereof with a compound of the formula CH 3 IVa wherein Q is as above and the nitrogen groups may be protected, or c) for the manufacture of a readily hydrolyzable ester of a carboxylic acid of formula I, in which m zero and R 1 is group reacting a compound of the formula 122 CH 2 OH *d 4 44 4 4 4 4 2 3 wherein R and R are as above and R1 is the residue of a readily hydrolyzable ester, in the presence of a base with phosgene an reacting the reaction product obtained with a compound of formula R 10 in which R0 i 0 r as above, except that amino, hydroxy and/or carboxy functions thereof may be protected, followed by cleavage of any protecting group present, or d) for the manufacture of a carboxylic acid of formula I converting an ester of the formula 'CH 1 1 2 3 wherein R 1 R R and m are as above, and R is a carboxylic acid protecting group, to the carboxylic acid of formula I, or e) for the manufacture of the compound of formula I, in which m is zero, or a readily hydrolyzable ester or salt thereof reducing a compound of the formula 123 VII' 1 CH* R 2 1 1 2 3 wherein R R and R are as above, or a readily hydrolyzable ester or salt thereof, or f) for the manufacture of a compound of formula I in which 15 m is 1 or 2; or a readily hydrolyzable ester or salt thereof oxidizing a compound of the formula a 4 I 4 1 VIII COOH wherein R R and R are as above and the dotted lines indicates the presence of a A2 or A3 double bond, 30 or a readily hydrolyzable ester of salt thereof, or 44 0 A) O g) for the manufacture of a compound of formula I, in which R 3 contains an amino substituent, or a readily hydrolyzable ester or salt thereof cleaving off an amino protecting group in the substituent R 30 of a compound of the formula ilr-r :~Un~lru~iri.WL^u.i 124 (0) R2 I m R 3 0 NE IX CH 2 COOH wherein R1, R 2 and m are as above and R 30 is an acyl group containing a protected amino substituent, or of a readily hydrolyzable ester or salt thereof, or h) 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 i) 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. 51. Process according to claim 50 which comprises carrying out process alternative 52. Process according to claim 50 which comprises carrying out process alternative or 53, End products according to any one of claims 1-45 whenever prepared according to the process claimed in claim 52 or by an obvious chemical equivalent thereof. 54, A compound as In any one of Claiiln 26-30, wherein Q is o o F A wherein X is oxygen or sulfur. 55. A compound as in Claim 54, wherein X is oxygen. 56. A compound as ii Claim 54, wherein X is sulfur. ",TIS L i I_ i -125 57. [6R-E6x, 7P3(ZIfl-7-EE(2-Ami no-4-thi azolIyI) (me thoxyimi no) acetylI Iam ino )-3-.EEE[4-(9-cyclIopropy I-6-flIuoro-2,3,4,9-tetrahydro -3,4-dioxoisothiazolo[5,4-bjquinolin-,7-yl)-1-piperazinylI carbonylloxylmethylJ-8-oxo-5-thia-l-azabicyclo[4.2.O]oct-2-ene-2- carboxylic acid as well as salts thereof and hydrates of this compound and of its salts, 58. I26-Hac,7p(Z) ])-7-I2(2-Ami no-4-thiazoyl)(me thoxyimi no) ace t yllamino)-3-1EEE4-(9-cyclopropyl-6-fluoro-2,3,4,9-tetr-ahydro-3,4-dioxoiso- thiazoloE5,4-blquinolin--7-yl)-l-piperaz-inyllcarhcnylloxy]-methyl)-8-oxo- 5-thia-l-azabicyclo[4.2.O]oct-2-ene-2-carboxylic acid as well as salts thereof and hydrates of this compound and of its salts, 59. Acyl derivatives of the formula I as set out in claim 1 substantially as hereinbefore de~cribed with reference to any one of the Examples. 15 60 \A pharmaceutical preparation for the treatment or prophylaxis of~jnfecflious disease comprising a compound according to any onR of claims 1 to 45 or any one of claims 53 to 59 together with a pharmaceutically acceptable carrier, diluent and/or excipient. 61, A method for the treatment or prophylaxis of~infectlous disease in a patient requiring said treatment or prophylaxis, which method comprises administering to said patient an effective amount of at least one compound according to any one of claims 1 to 45, or any one of claims 53 to 59, or of a composition according to claim 1 25 set 62o A process for preparing acyl derivatives of the formula I as st o t int claim 1 substantially as hereinhefore descrIbed with reference DATE.D this TWENTY"SEVENTH day of FEBRUARY 1992 Hoffmann-La Roche company Aktienigesellschaft Patent Attorneys for the Applicant SPRSON FERGUSON 04