CA1112238A - Cephem compounds and processes for preparation thereof - Google Patents

Abstract

ABSTRACT

A process is provided for preparing a 7-substituted-3-cephem-4-carboxylic acid derivative of the formula:

(VI) wherein R1 is amino or protected amino, R2 is hydrogen, halogen or hydroxy, R3 is carboxy or functionally modified carboxy, and A2 is lower alkylene substituted with a group of the formula : ?-O-R4 in which R4 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or cycloalkyl, and its nontoxic, pharmaceutically acceptable salts, which comprises reacting a compound of the formula.

Description

h~

This invention relates to new cephern compounds and their preparation. More particularly, it relat~s to new 7-substituted-3-cephem-4-carboxylic acids, pharrnaceutically acceptable salts and pharmaceutically acceptable biopre-cursors thereof and a process for their preparation; the new compounds have antimicrobial activities and can be used in the prophylactic and therapeutic treatment of infectious diseases in human beings and animals.
Accordingly, the objects of this invention are to provide-_ new 7-substituted-3-cephem-4-carboxylic acids, pharmaceutically acceptable salts and pharmaceutically acceptable bioprecurso`^s thereof, which exhibit excellent antimicrobial activities against a wide variety of pathogenic microorganisms including Gram negative and Gram positive bacteria, processes for preparation of the same, pharmaceutical composition comprising one of the same as an active ingredient, and a method of using the same prophylactically and therapeutically for treatment of infectious diseases caused by pathogenic microorganisms in human beings and animals.
According to one aspect of the invention there is provided cephem compounds of the formula (VI):-L

,"

or tautomers thereof, wherein Rl is arnino or protected a~lino, A is lower alkylene substituted with a group of the formula:
=N--oR4 in which R4 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or cycloalkyl, R is hydrogen, halogen or hydroxy, and R3 is carboxy or functionally modified carboxy, and non-toxic pharmaceutically acceptable salts and bioprecursors thereof.
m e cephem compounds ~VI) are useful as anti-micro-bial agents.
In another aspect of the invention there is provided a process for preparing a compound of formula (VI), as defined above, comprising reacting a compound of the formula ~Id'):

(Id ) R
, ~.

wherein Rl, R2 and R3 are each as defined above, and A4 is I
lower alkylene substituted with oxo, or a salt thereof, with a compound of the formula:

wherein R4 is as defined above, and when desired converting a free acid or base of formula (VI) obtained, or a tautomer thereof, to a corresponding non-toxic, pharmaceutically acceptable salt, and when desired converting a compound of

- 2 -r~
I
. .

formula (VI) or a salt thereof to a non~toxi~, pharmaceutically acceptable bioprecl1rsor thereof.
In particular the process of the invention may be applied to the preparation of syn isomers of the compound of formual (VI).
The terms and definitions described in this specification are illustrated as follows.
As is well known, the 2-amino- or 2-protected amino-thiazolyl group lies in tautomeric relation with the correspond-ing 2-imino- or 2-protected imino-thiazolinyl group. The tautomerism between the said thiazolyl and thiazolinyl groups can be illustrated by the following equilibrium:

R`l~ S ~ = R~

wherein Rl is amino or protected amino, and Rl is imino or protected imino.
Accordingly, it is to be understood that both of the said groups are substantially the s me, and the V

tautomers consisting of such groups are regarded as the same compounds, especially in the manufacturing chemistry Therefore, both of the tautomeric forms of the compounds having such groups in their molecule are included in the scope of this invention and de-signated inclusively with one expression '!2-am~no-~r protected amino- ~hiazolyl" and represented by the ; formula: Rl ~ (wherein Rl is as defined above) for the convenient sake throughout this specification.
A~d urther, it is well known tha~ the 3-hydroxy-

3-cephem compound having the partial structure of the ` formula:
: ' ' ,S~
~ 15 ~ ~ OH
r R~
lies in a tautomeric relation with the 3-oxo-cephem compound of the formula:
S ~
~ ~0 '~' O
R
- 25 each of which is referred to as the enol- or keto-tautomer, and that the enol-tautomer~is usually the stabilized one.
Accordingly, both of the compounds having such tautomeric structures are included within the same -30 scope of the compound, and therefore, the structure and nomenclature o~ such tautomers are expressed inclusively with one expression of the stabilized enol tautomer, i.e. "3-hydroxy-3-cephem" compound, throughout this specification.
In the above and subsequent dcscriptions of this .
.

i3 specification, suitable examples and illustration ~f the various definitions which this inverltion .intends to include within the scope thereof are explained in detail as follows.
~ Lower alkylene`' moiety in the definition of A
may be straight or branched bivalent hydrocarbon residue such as methylene, ethylene, trimethylene, propylene, ethylethylene, tetramethylene, pentamethylene, l-methyl-pentamethylene, 2-methylpentamethylene, 3-methylpenta-methylene, hexamethylene and the like and more preferablyone may be alkylene of 1 to 4 carbon atoms and the most preferable o~e is methylene.
`'Lower alkylene substituted with oxo" in the definition of A4 may be referred to as "oxo(lower)alkylene", and particularly it may be oxomethylene, oxoethylene, l-oxotrimethylene, 2-oxotrimethylene, 2-oxotetramethylene, 3-oxopentamethylene, and the like, and more preferably has 1 to 4 carbon atoms and is most preferably oxomethylene (namely, carbonyl). ' ~ - 5 -"Protective group" in the l'protected a~ino" for R1 may be a conventional N-protective group, for example, substituted or ungubstituted ar(lower)alkyl (e.g. benzyl, benzhydryl, trityl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, etc.), halo(lower)alkyl (e.g. trichloromethyl, tri-chloroethyl, trifluoromethyl, etc.), tetrahydropyranyl, substituted phenylthio, substituted alkylidene, sub-stituted aralkylidene, substituted cycloalkylidene, acyl, or the like.
Suitable acyl for the protective group may be sub-stituted or unsubstituted lower alkanoyl (e.g. formyl, acetyl! chloroacetyl, trifluoroacetyl, etc.), sub-stituted or un~ubstituted ar(lower)alkanoyl (e.g phenyl-acetyl, phenylpropionyl, etc.), substituted or unsub-stituted lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, l-cyclopropylethoxy-carbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, trichloroethoxycarbonyl, 2-pyridyl-methoxycarbonyl, etc.), substituted or unsubstituted ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, ~ ' .

benzhydryloxycarbonyl9 4-nitrobenzyloxycarbonyl~ etc.), lower cycloalkoxycarbonyl ~e.g. cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, etc.), 8-quinolyloxycarbonyl, succinyl, phthaloyl, or the like.
And further, the reaction produc~ of a silan-boron-,aluminium-or phosphorus-compo~nd with the amino g~oup may also be included in the protective group.
i Suitable exampIes of such compounds may be trimethyl-silyl chloride, trimethoxysilyl chloride, boron tri-chloride, butoxyboron dichloride, aluminum trichloride 7 diethoxy aluminum chloride, phosphorus dibromide, phenylphosphorus dibromide, or ~he like.
"Halogen" for R2 may be chlorine, bromine, iodine or fluorine, and preferred one is chlorine or bromine.
"Functionally modified carboxy" for R3 ~ay be an ester amide or the like, and preferably an ester.
Suitable examples of the ester may be alkyl ester (e.g. methyl es~er, ethyl ester~
p~opyl ester9 isoprupyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl este~, t-pentyl ester, hexyl ester, heptyl esterj octyl ester, l-cyclopropyl-ethyl ester, etc.); alkenyl es~er (e.g. vinyl ester7 allyl ester, etc.); alkynyl es*er (e.g. ethynyl ester, propynyl ester, etc.); alkoxyalkyl ester (e.g.
~5 methoxymethyl ester, ethoxymethyl ester, isopropoxy-methyl ester, l-methoxyethyl esber, l-ethoxyethyl es~er, .etc.); alkylthioalkyl ester te.g. methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl esteT, isopropylthiomethyl ester, etc.); haloalkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); alkanoyloxyalkyl ester ~e.g. acetoxymethyl ester9 propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, palmitoyloxymethyl ester,etc~

.

.

~7~
alkanesulfonylalkyl ester (e.g~ mesylmethyl ester, 2-mesylethyl ester, etc.); substituted or unsubstituted aralkyl ester (e.g. benzyl ester, ~-methoxybenzyl ester,

4-nitrobenzyl ester, phenethy~ ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.), substituted or unsubstituted aryl ester (e.g. phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, salicyl ester, etc.); an ester with a silyl compound such as trialkylsilyl compound, dialkylalkoxysilyl compound or trialkoxysilyl compound, for example, trialkylsilyl ester(e.g. trimethylsilyl ester, triethylsilyl ester, ètc.), dialkylalkoxysilyl ester (e.g. dimethylmethoxy-silyl ester, dimethylethoxysilyl ester, diethylmethoxy-silyl ester, etc.) or trialkoxysilyl ester (e.g.
trimethoxysilyl ester, triethoxysilyl ester, etc.) or the like.
With regard to the terms "protected amino" and "functionally modified carboxy" in the above, it is to be understood that these groups bear the meaning not only with reference to the synthetic manufacture of the object com~ound by chemical process(es), but also with reference to the physio-logical and pharm~ceutical properties of the object compound per se. That is, in the meaning of the synthetic manufacture, free amino group and/or fxee carboxy group may be transformed into the "protected amino" and~or `'functionally modified carboxy" as mentioned above before conducting the process(es) for preventing any possible undesired side reaction(s), and the "protected amino" and/or "functionally modified carboxy" group in the resultant compound may be transformed into free amino and/or carhoxy group after the reaction is conducted.

C ~ - 8 ~
_ .

.,.

f;'~ 3 This Will be apparent from the explanation o~ the processes in the following.
On the other hand, in the meaning of the physio logical and pharmaceutical properties of the object compound, the compound bearing the "protected amino" and/or "functlonally modified carboxy" group is optionally used for improving the properties such as solubility, stability, absorbability, toxicity of the particularly active object compound bearing the free amino and/or carboxy group.
Suitable "pharmaceutically acceptable salts" of the object compound (VI) are the conventional non-toxic salts, and may include a salt with an inorganic base or acid, for example, a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), ammonium salt, an inorganic acid salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, carbonate, bicarbonate, etc.), a salt with an organic base or acid, for example, an amine salt (e.g. tri-methylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N;N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris-(hydroxymethylamino)methane salt, phenethylbenzylamine salt etc.), an organic carboxylic or sulfonic acid salt (e.g. acetate, maleate, lactate, tartrate, mesyl-ate, benzenesulfonate, tosylate, etc.), a basic or acidic amino acid salt (e.g. arginine salt, aspartic acid salt, glutamic acid salt, lysine salt, serine salt, etc.) and the like.

.

It i~ well known in the pharmaceutical field that the active drug, when it has any undesired physioloyical and/or pharmaceutical property such as solubility, stability, absorbability, etc., is suitably converted into a modified derivative thereof for improving such undesired properties, and then said derivative, upon adrninistration to a patient, ; exhibits the active efficacy by being converted to the parent drug in the body. In this meaning, the term "pharmaceutically acceptable bioprecursor~' used through-out this specification is intended to fundamentally mean all of the modified derivatives, which have structural formulae different from those of the active compounds of this invention, but are converted in the body to the active compounds of this invention upon administration, and also to mean the derivatives which are sometimes derived physiologically from the compounds of this invention in the body and exhibit antimicrobial efficacy.

~; - 10 -The object compounds (VI~ and pharmaceUtlCally acceptable salts and bioprecursors thereof exhibit high antimicrobial activities inhibiting the growth of a wide variety of pathogenic microorganisms including Gram-positive and Gram-negative bacteria and are useful as antimicrobial agents.
In order to demonstrate the utility, test data of some representative compounds related to the compounds (VI) are shown in the following.
.' 10 In vitro antibacterial activity:
Test Method In vitro antibacterial activity was determined by the two-fold agar-plate dilution method as described below.
One loopful of an overnight culture of each test strain in Trypticase-soy broth (10 viable cells per ,.
. .

C

ml.) was streaked on heart infusion agar tHI-agar~ con-taining graded concentra~ions of antibiotics, and the minimal inhibitory concentration (MIC~ was expressed in terms of ~g/ml. after incubation at 37C for 20 hours.
. ~ ~ , .

~ COCONH~
COOH

No. 2 H2NJ~
OOH

N~ CHCONH S
NoO 3 H2N-~ S~ NH2 o ~ ~
COOH
HCOOH salt No. 4 H2N~ ~ HF ~ ~

COOH

. 30 .

., ~ ;

Test Results MIC (~q/ml ?
_ - Compound No. 1 2 3 4 -_ ' .. ....
: Salmonella enteTitidis 1.~6 1.56 3.13 3.13 _ _ - .. _. _ _ _ . Escherichia -~ coli 32~ 1.56 1.56 0.78 1.56 .. . --Klebsiella ;
aerogenes 417 0.1 0.2 0.39 0.78 .. ~ .__ _ ._ Proteus mirabilis 5ZO 0.78 0.39 0.78. 1.56 Proteus .
vulgaris 6l6 12.5 6.25 1.56 12.5 ; For prophylactic and/or therapeutic administration the active compounds are used in the form of a conventional pharmaceutical preparation which contains said compound, as an active ingredient, in admixture wi~h pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration. The pharmaceutical preparations may be in solid form such as capsules, tablet, dragee, ointment or suppository, or in liquid form such as solution, suspension, or emulsion. If needed, there may be included in the above preparations auxiliary sub-stances, stabilizing agents, wetting or emulsifying agents, buffers and the other commonly used additives.

~ hile the dosage of the compoun~ may vary from and also depend upon the age and conditions of the patient, a kind of disease and a degree of the infection, and further the particular active compound (VI) to be appl.ied, C

2~S.3 etc., an average single dose of about 50 mg~, 100 rng., 250 my "
and 500 mg. of the active compound (VI) is su~ficient for treating infectious diseases caused by pathoyenic bacteria.
In general, the active compound (VI) can be administered in an amount between 1 mg/kg and 100 mg~kg, preferably

5 mg/kg and 50 mg/kg.
It is to be noted that, the cephalo,sporin compound of the formula (VI) and non-toxic, pharmaceutically acceptable salts and bioprecursors thereof are particularly active as compared with related derivatives.
As indicated above the compound (VI) and its salts can be prepared by reacting a compound (Id') or its salt with a compound (VII) or its salt as illustrated by the following scheme:

Rl~A4-CONH~L R2 tId' ) R

R4 - ONH2 (VII) R1~ ~ A2-CONH ~ ~ tVI~

,:
wherein Rl, R , R3, R and A aré each as defir,ed above, and A is lower alkylene substituted with oxo.

The suitable example of the compound (VII) may be hydroxylamine, lower alkoxyarnine (e.g. methoxyamine, ethoxyamine, propoxyamine, butoxyamine, etc.), lower alkenyl-oxyamine (e.g. vinyloxyamine, allyloxyarnine, propenyloxyarnine, C

butenyloxyamine, etc.), lower alkynyloxyamine (e.g. ethynyloxy-amlne, propynyloxyamine, hutynyloxy~nine, etc.) or cyclo-alkoxyamlne (e.g. cyclobutoxyamine, cyclopentyloxyamine, cyclo-hexyloxyamine, etc.).
The salt of the compound (VII) may be acid salt such as hydrochloride, hydrobromide, sulfate or the like.
This reaction is usually conducted in a solvent such as water, alcohol or any other solvent which does not adversely influence the reaction, within a temperature range from cooling to heating.
When a salt of the compound (VII) is used, the reaction is preferably conducted in the presence of a base.
Suitable bases include, for example, an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e~g. magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkaline earth metal phosphate (e.gO magnesium phosphate, calcium phosphate, etc.), alkali metal hydroyen phosphate (e.g. disodium hydrogen phosphate, dipotassium hydrogen phos-phate, etc.), or the like, and an organic base such as alkali metal acetate (e.g. sodium acetate, potassium acetate, etc.), trialkylamine (e.g~ trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4,3,0]-5-nonene, 1,4-diazabicyclo~2,2,2]-octane, 1,5-diazabicyclo~5,4,0~-7-undeceneanion exchanye re~in or the like.

The partial structure of the formula: -C~C0-of the compound (VI) i8 intended to mean both of the geo-metric formula:
C-CO- and -C~CO~
N-O-R R -O-N
(S) (A) The geometry of the formula (S) is referred to as "syn"
and another formula (A) is referred to as "anti". From the view point of structure-activity relationship, it is to be noted that the syn isomer of the compound IVI ) tends to be of much higher antimicrobial activity than the corresponding anti isomer, and accordingly the syn isomer of the compound (VI3 is more preferable antimicrobial agent than the corresponding anti isomer in the prophylactic and therapeutic value. -~
Following examples are given only for explaining this invention in more detail.

~ .

~ ~?~

Example 1 A solution of 7-~2-(2^amino-4-thiazblyl)glyoxyloyl-amino]-3-cephe'm-4-carboxylic acid hydrochIoride (1.78 g) in water (100 ml) was adjusted to pH 6.0 with sodium bica~bonate under ice-cooling with stirring. Sodium acetate (0.38 g) and methoxylamine ~ydrochloride (1.37 g) were added to the solution adjusted to pH 7.0 with sodium bicarbonate and then s~irred at 48C for an hour.
The resultant solution was washed with ethyl acetate ~200 ml) and diethyl ether (100 ml) in turn, and then nitTogen gas was bubbled into the solution to remove diethyl ether. The aqueous solution was adjusted to pH 3.5 with 10~ hydrochloric acid under ice-cooling with stirring. The precipitates were collected by fil-tration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2-amino-4-thiazoiyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 120 mg). The mother liquor was subjected to column ch~omatography on macroporous, nonionic adsorption resin"Diaion HP-20l' tTrademark: manufactured by Mitsubishi Chemical Indust-ries Ltd.) and eluted with 40~ aqueous acetone. The elu~te was concentrated under reduced pressure, lyo-philized, and then dried over phosphorus pentoxide to give the same object compound (~50 mg). Total y~eld1070 mg.

I.R~ v NuJol : 3460, 32gO, 3150J 1780, 1655 1623 cm N.M.R. ~(DMS0-d6, ppm) : 3.60 (2H, broad s), 3.84 (3H, s), 5.12 (lH, d, J=SHz) 5.84 (lH,d,d~ J=5Hz~r8Hz)~ 6~52 (lH~ t~,

6.76 (lH, s), 7.26 (2H, broad s), 9.65 (lH, d, J=8Hz) ~ 1,"
~, Example 2 The following compounds may be prepared in similar manner to that of Example l.
(1) 7-[2-(2-aminothiazol-4-yl~-2-hydroxyimino-S acetamido]-3-cephem-4-carboxylic acid (syn isomer) I R. v NuJol : 3350-3200, 1770, 1670, 1630 cm 1 .
N.M.R. ~DMSO-d6, ppm) : 3.60 .(2H, broad s), 5.10 (lH, d, J~5Hz), 5.83 (lH, dd, J=SHz, 8Hz~, 6.47 (lH9 t, J=4Hz)~ 6.67 (lH9 s), 9~47 ~lH, d~ Jc8Hz~
(2) 7-[2-(2-aminothiazol-4-yl~-2-ethoxyiminoacet-.
~ amido]-3-cephem-4 carboxylic acid (syn isomer) : . 15 I. R. v Nma~l : 3500, 3300, 3200, 1785, 162SJ
1600 cm N.M.R. ô(DMSO-d6, PPm): 1.20 (3H, ~c, J=7HZ), 3.S7 (2H, m)-, 4.08 (2H, q, J=7Hz), 5.08 (lH, d, J=SHz), 5.83 (lH, dd, J~SHz, 8Hz), 6.47 (lH, m), 6~73 (lH, 5)9

7.20 (2H, m~, 9.58 (lH, d, J=8Hz) - (3) 7-[2--(2-aminothiazol-4-yl)-2-propoxyimino-acetamido]-3-cephem-4-carboxylic acid (syn isomer) ~5 I. R. v Naxl : 3250, 1770, 1650, 1660, 1620 cm 1 N,M.R. ~ (DMSO-d6, ppm~ : 0.93 t3H, ~, J=7Hz), 1.67 (2H, sextet, J=7Hz~, 3.60 (2H, m), 4.03 (2H, t, J=7Hz~, 5.13 (lH, dJ~J=5Hz), 5.83 (lH, dd, J=5Hz, BHzj, 6.48 ~2H, t, J-4Hz), 6.70 (lH, s), 7.18 (2H, m), 9.53 (lH, d, J=8Hz) (4) 7-~2-(2-aminothiazol-4-yl)-2~butoxyiminoaoet-- amido]-3-cephem-4-carboxylic acid ~syn isomer~

~ ~.

Z~;3r~

NU~ O1 33 20, 1 7 75 , 16 60 Cm N.M.R. ~ (DMSO-d6, PPm) : 0. ~8 (3H, t, J=7HZ), 1.1-1.9 (4H, m), 3.58 (~H, brOad S), 4.05 t2H, t9 J-7HZ), 5.08 (IH, d, J=5Hz), 5.80 (lH, dd, J-5Hz, 8Hz~, 6.44 (lH~
broad s), 7.18 (2H, s), 9~Sl (lH, d, - J=8HZ) (5) 7-[2-~2-aminothiazol-4-yl)-2-pentyloxyimino-acetamido]-3-cephem-4-carboxylic acid (syn isomer~.

I. R. v Nu~ol 33007 1775, 1650) 1540 cm 1 N.M.R. ~ ~DMSO-d6, ppm) : 0.6-2.0 ~9H, m), 3.56 (2H, d, J=2Hz), 4.03 (2H, t, J=6Hz3, 5-08 tl~, d, J=5Hz~, 5.81 (lH, dd, Ja5Hz, 8Hz), 6.46 (lH, t, J=4Hz), ~:
6.~9 (lH, s), 7.20 (2H, s), ~.15 (lH, - d, J~8Hz) ~6) 7-[2-(2-aminoathiazol-4-yl)-2-hexyloxyimino-acetamido~-3-cephem-4-carboxylic acid (syn isomer). : .

Nu~ol : 3~50, 1760, 1640, 1600 c N.M.R. ~(DMSO-d6, ppm~ : 1.88 (3H, m~, 1.1 -1.9 (8H, m), 3.60 (2H, m), 4.06 (2H, t, f ;
J=6Hz), 5.10 ~lH, t, J=5Hz), 5.82 (lHp dd, J=5Hz, 8Hz), 6.46 (lH, m), 6.70 (lH, s), 7.26 ~2H, m), 9.56 (lH, d, J~8Hz) t7) 7-~2-(2-aminothiazol-4-yl~-2-allyloxyimino-ace*amido]-3-cephem-4-carboxylic acid (syn isomer3.
Nu~ol 3300, 1780, 166~, 163 N.M.R. ~(DMSO-d6, ppm~ : 3.67 ~2~-l, d, J~Hz), .

-~ 19 -~a .

.` 3 4.67 (2H, m), 5.17 (lH, d~ J=SHz), S.25 (lH~ m), 5.50 (lH, m~ 7 5.90 (lH~
dd, J=5Hz, 8Hz), 6.03 (lH, m), 6.55 (lH, m), 6.80 (IH, s), 7.50 (2H, m;, 9.68 (lH, d, J=8Hz)

(8) 7-[2-(2-amino~hia~ol-4-yl)-2 propargyloxyimino-acetamido]-3-cephem-4-carboxylic acid (syn isomer).

I. R. v Nu~ol 3500, 3300, 1780, 1720, 1660, 1630 ~m~l N.M.R. ~DMSO-d6, ppm) : 3.48 (lH, m), 3.67 ~2H, m), 4.80 (2H, d, J=2Hz), 5.17 (lH, d, J=5Hz), 5.88 (lH, dd, J=SHz, 8Hz), 6.55 ~lH, m~, 6~85 (lH, s~, 7.33 (2H, m)

9.~3 ~lH, d, J-8Hz) (9) 7-[2-(2-aminothia701-4-yl)-2-çyclohexyloxyimino-acetamido~-3-cephem-4-car~oxylic acid (syn isomer3 I. R. v Nu~ol : 3350, 17i5, 1665, 1620, 1540 cm 1 N.M.R. ~ tDMSO-d6, ppm) : 0.8-2.2 (lOH, m), 3.60 12H, broad s), 4.04 (lH, m), 5.09 (lH~
d, J=5Hz), 5.83 (lH, dd, J=5Hz, 9Hz) a . . 6.45 (lH, t, J=4Hz~, 6.67 (lH, s) 9 7.19 ` ~2H, s), 9.48 ~lH, d, J=9Hz) The following examples serve to illustrate the preparation of compounds related to the compounds of the invention, as well as the preparation of starting mate-rials of formula (Id') for the process of the invention.

. . ~
r ~bDd Example 3 ~I) 4-Nitrobenzyl 7-amino-3-cephem-4-carboxylate hydrochloride (9 g), trime~hylsilylacetamide (24.~1 g) and b;s~trimethylsilyl)acetamide (9 ml) were added to dry ethyl acetate ~100 ml) and stirred at 45~C for an hour.
On the other hand, phosphoryl chloride (8.4 ml) was added dropwise to a stirred mixture of dimethyl-fo~mamide (4.0 ml~ and dry ethyl acetate (16.0 ml~

10 under ice cooling, and stirred for a while. To the solution were added ethyl acetate (240 ml) and 2-(2-fo~mamido-4-thiazolyl)glyoxylic acid (5.35 g) gradual-ly at -3C, and the mixture was stirred at the same temperature for-15 minutes. The solution was added dropwise to the solution containing the cephalosporin compound prepared above at -i50C and stirred at the same temperature for 30 minutes. Water (50 ml~ was added to the resultant solution, and the precipitates were collected by filtratio~, washed with water ~nd dried ov~r phosphorus pentoxide under reduced pr~ssure to give 4-nitrobenzyl 7-C.2-formamido-4-thiazolyl)-glyoxyloylamino]-3-cephem-4-ca~boxylate (7.124 g).
The ethyl acetate layer was separated from the filt-rate, ~ashed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and -concentTated under reduced pressure to give the same object comp~und as above (1.03 g). Total yield 8.154 .g- *
. I.R. vNU~l : 1775, 1725, 1650 cm 1 N.M.R. ~(DMSO-d6, ppm) : 3.66 (2H, m), 5.17 (lH, - d, J=5.2Hz), 5.42 (ZH, s~, 5.90 (lH, dd, J=5.2Hz, 7.8Hz), 6.66 (lH, t, J= .
. 5.0Hz), 7~67 (2H, d, J=9Hz), 8.22 (2H) d, J=9Hz), 8.39 ~lH, s), 8.55 tlH, 5), * trademark J
J'O

9.87 (lH, d, J=7~8Hz) ~23 A mixture of 4-nitrobenzyi 7-[2-~2-formamido-4-- thiazolyl)glyoxyloylamino]-3-cephem-4~carboxylate (3.0 g) methanol (60 ml) and tetrahydrofuran (80 ml) was added to a mixture of 10% palladium-carbon (1.5 g), acetic acid (10 ml) and methanol (10 ml) in an atmos-phere df nitrogen gas, and then subjected to catalytic ~eduction at room temperature under ordinary pressure for 4 hours. The resultant mixture was filtered, and the filtrate was concentrated under reduced p~essure.
The precipitates were collected by filtration, washed with diiso~ropyl ethe~ t50 ml) and d~ied to give powder (I>34 g). A mixture of water ~100 ml) and ethyl acetate tlO0 ml) was added to the powder adjusted to pH 6.0 with sodium bicarbonate and the a~ueous layer was separated~
washed with ethyl acetate and diethyl ether. The re-maining ether was removed off by bubbling with nitrogen gas, and the aqueous solution was adjusted to pH 2.0 with 10% hydrochloric acid. The resultant precipitates were collected by filtration and dried over phosphorus pentoxide to give 7-[2-~2-formamido-4-thiazolyl)glyoxy-loylamino]-3-cephem-4-carboxylic acid (0.4~.g). The above filtrate was concentrated under reduced pressure, and the residue was pulverized with a mixtuTe of diethyl ether and petToleum ether. The precipitates were col-lected by filtration, washed with diethyl ether and petroleum ether and dried under reduced pressure to give the same objective compound (l~l g~. Total yield 1.57 g.
I ~ ~ Nu]ol 1780, 1670 cm 1 N.M.R. ~(DMSO-d6, ppm~ : 3.63 (2H, m, J-4Hz~, 5.17 (lH, d, J~5.2Hz), 5~87 (lH, dd, J=5.2Hz, 8.2Hz~, 6.53 (lH, t, J=4Hæ~g 8.42 (lH, s), 8.59 {lH, s), 9.83 (lH9 .

d~ J=8.ZHz) (3) A mixture of conc.hydrochIoric acid (2.44 g) and methanol ~10 m~ was added to a mixture of 7-[2-(2-formamido-4-thiazolyl?glyoxyloylaminoj-3-cephem-4-carboxylic acid (2.44 g) in methanol (40 ml) under ice-cooling, stirred at 20 to 22C for S hours and fil-tered. The filtrate was concentrated under reduced pressure, and water (100 ml) was added to the Tesidue adjusted to pH 6.5 with sodium bicarbonate with stiTring and filtered. The filtrate was washed with ethyl ~! aceta~e, and adjusted to pH 3.5 with 10% hydrochloric acid. The resultant precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-~Z-amino-4-thiazolyl)glyoxyloylamino~-3-cephem-4-carboxylic acid (0.492 g~ The filtrate and washings were subjected to , column chTomatography on macroporous, non-ionic adsorp-tion resin "Diaion HP-20" (Trademark9 manufactured by Mitsubishi Chemical Industries Ltd.), washed with water and eluted with 15% isopropyl alcohol. The isopropyl alcohol was distilled of under reduced pressure and the remaining solution was lyophilized to give the same object compound ~1.561 g). Total yield 2.053 g.

I.R. ~ mUa~ol : 1780, 1668 cm l ; N.M.R. ~(D20`, ppm) : 3.57 (2H7 m), 5.17 (lH, d, ~ . J=4,8Hz), 5.78 (lH,d) J=4.~Hz), 6.33 ~lH, m), 8.26 ~lH, 5) Bxample 4 (1~ Phosphoryl chloride (0.7 g) was added to N,N-dimethylformamide (10 ml) at 20C and stirred at 40C
for 30 minutes. 2-(2-Formamidothiazol-4-yl)glyoxylic acid (0.4 g) was added to the solution at 0 to 5C and - sti~red for 40 minutes. The solution was added to a solution of 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem-~t 4-carboxylate (0.7 g~, trimethylsilylacetamide (1.85 g) and bis~trimethylsilyl)acetamide (1.62 g~ in ethyl acetate (20 ml) at -Z0C and stirred at -20C for an hour. After adding water (20 ml~ to the resultant solution, the ethyl acetate layer was separated, washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo.
The residue was triturated with diethyl ether ~o give 4-nitrobenzyl-7-[2-~2-formamidothiazol-4-yl)glyoxyloyl-amino]-3-hydroxy-3-cephem-4-carboxylate (0.85 g).
` 10 .
. I.R. v Na~l : 3150, 1770, 1660, 1600 cm 1 N.M.R. ~(DMSO-d6, ppm) : 3;;58 (2H,As_q, J=18Hz), 5.48 (2H, s~, 5.25-5.83 (3H, m), 7O75 (2H, d, J=9Hz), 8.32 (2H, d, J=9Hz), 8.58 (lH) s~, 8.63 (lH, s), 9.92 (lH, J=8Hz) ~2) A mixture of 4-nitrobenzyl 7-[2-(2-formamido-thiazol-4-yl)glyoxyloylamino]-3-hydroxy-3-cephem-4-carboxylate (0.7 g) and conc.hydrochloric acid (0.23 g) in methanol (10 ml) was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo and the residue was triturated with diisopropyl ether.
- The precipitates were collected by iltration and washed with diisopropyl ether to give 4-nitrobenzyl 7-C2-(2-aminothiazol-4-yl)glyoxyloylamino]-3-hydroxy-3-cephem-4-carboxylate hydrochloride (0.6 g).

I.R. vNUxol : 3300, 1770, 1660, 1630, 1600, 1510 cm 1 N.M.R. ~(DMSO-d6, ppm) : 3.52 t2H, broad s), 5.40 ~2H, s), 5.18-5.57 (3H, m), 7.70 (2H, d, J=9Hz), 8.25 ~2H, d, J=9Hz), 8.27 (lH, s), 9.97 tlH; t, J=9Hz) .

~ i - 2~ --Example 5 N,N-Dimethylformamide (88 mg) and phosphorus oxy-chloride (184 mg) were mixed to prepare Vilsmeier re-agent in a conventional manner, and the resultant Vilsmeier reagent was suspended in dry *etrahydrofuran ~10 ml). To the suspension was add~d Z-(2-fo~mamido-thiazol-4-yl~glyoxylic acid (0.2 g) under ice-cooling with stirring9 and the solution was stirred at the same temperature for 30 minutes to prepare the acti-vated acid solu~ion. 4-Nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate (0.4 g) was dissolved in a solution of trimethylsilylacetamide ~1.0 g) in ethyl acetate (100 ml~. To the solution was added the activated acid solution obtained above all at once at -20CJ and the solution was stirred at -20 to -5C for 1.5 hours. After water and ethyl acetate (50 ml3 were added to the resultant solution at -20C, the insoluble substance was separated by filtration, washed with water and acetone in turn and then dried to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)glyoxyloyl-amino]-3-chloro-3-cephem-4-carboxylate (0.1 g).

I.R. ~ NaU~ol : 3350, 1780a 173OJ 1650, 1600, 1520 cm N-M-R- ~(DMS0-d6, ppm) : 3.96 (2H, q, J=18Hz), 5.50 (2H, s~, 5.92 tlH, dd, J-5.8Hz~, 7.74 (2H, d, J~9Hz~, 8.28 (2H, d, J=9H~), 8.48 (lH, s), 8.60 (lH, s), 10.00 (lH, d, J=8Hz), 12.63 (lH, broad s) Example 6 ~1) 7-Amino-3-cephem-4-carboxylic acid (2.54 g) was dissolved in a solution of trimethylsilylacetamide (11.7 g) and bis(trimethylsilyl)acetamide (15 ml) in dried ethyl acetate (5G ml). A solution of bromine (2.43 g) in dried methylene chloride (10 ml) was added I

~ 3 dropwise to a solu~ion of diketene (1.2B g~ in dried methylene chloride (25 ml) at -30C over 10 minutes and stirred at the same temperature for 1.5 hours. The solution was added to the above solution containing 7-amino-3-cephem-4-carboxylic acid at -15C over 10 minu-tes, and stirred at -15 to-10C for 1.5 hours.
~ater ~50 ml) was added to the resultant solution. The ethyl acetate layer was separated, and extracted with aqueous solution of sodium bicarbonate The aqueous extract was adjusted to pH 2 0 with io% hydrochloric acid and extracted with ethyl ace~ate. The ethyl acetate extract was washed with water, dried over mag-nesium sulfate and concentrated under reduced pressure to give 7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-ca~boxylic acid (2.82 g).

I.R. v NmUa~ol : 1760, 1660 cm 1 N.M.R. ~(DMS0-d6, ppm) : 3 58 ~2H, d~ J=4Hz), 3.65 (2H, s), 4.40 (2H, s~, 5.06 (lH, d, Ja5Hz), 5.73 (lH, dd, J=8Hz, 5Hz), 6.50 (lH, t, J-4Hz~, 9~08 (lH,.d, J-8Hz) (2) Thiourea (663 mg), sodium bicarbonate (732 mg) and water (20 ml) were added to a s~irred solution of 7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-carboxylic acid (2.11 g) in tetrahydrofuran (20 ml~ under ice-cooling and stirred at the same temperature for an hour.
After the resultant solu~ion was adjusted to pH 4.0 with dilute hydrochloric acid~ the precipitates were - 30 collected by filtration, washed with water and dried oYer phosphorus pentoxide under reduced pressure to give ~7-~2-(2-amino-4-thiazolyl~acetamido]-3-cephem-4-carboxylic acid (1.01 g).

~' , *~ 3 I.R. v maUJ~l : 3550~ 3330, 175b, 1670, 16Z0 cm 1 N-M-R- ~ (DMS0-d6, ppm) : 3.42 (2H, s), 3.60 (2H, d, J=4Hz), 5.08 (lH, d, J=5Hz), 5.77 (lH, dd, J=8Hz, 5Hz), 6.30 (lH, s); 6.52 (lH, t, J=4Hz), 8 . 87 (iH, d, J=8Hz~
Exa.mple 7 (l) 4-Nitr~benzyl 7-amino-3-cephem-4-carboxylate (5 g) was dissol~ed in a solution of trimethylsilyl-acetamide (1308 g) and bis(trimethylsilyl)acetamide (10 ml~ in dry ethyl acetate (50 ml~ and stirred at 45C for 1.5 hours. A solution of bromine (2.88 g) in methylene chloride (7 ml) was added dropwise to a solu-lS tion of diketene (l.S g) in methylene chloride (7 ml) at -40C over 20 minutes and stirred at -30C for 1 hour. The solution obtained thus was added to drop-wise to the above solution of 4-nitr~benzyl 7-amino 3-cephem-4-carboxylate under cooling at -15C and then ; 20 stirred at the same temperature for 30.minutes. Water (50 ml) was added to the resultant solution and ex-tracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure ~o give oily 4-nitrobenzyl 7-[2-(2-bromoacetyl)acetamido~-3-cephem-4-caTboxylate (6.iS g~.

. I.R. v NmUa~ol : 1780, 1740, 1630 cm 1 N.M.R. ~(DMS0-d6, ppm) : 3.62 (2H~ broad s~, 4.37 (2H, s), 5.08 (lH,- d, J=5Hz), 5.40 (2H, s~, 5.77-6.05 (m), 6.67 ~lH, t, J=5Hz), 7.68, 8.04 (4H, m), J=9Hz3, 9.07 (lH, d~ J=8Hz) 3S (2) Thiourea (1.13 g), sodium bicarbonate (1.24 g) , . , . .. , . , . , . . .. , , _ . . . .. , . _ _ _ .. . .. . . . .................. . . .. . .

~ 3 and water (20 ml) were added to a solution o~ 4-nitTobenzyl 7-[2-(2-bromoacetyl~acetamido]-3-cephem-4-carboxylate (6.15 g) in tetrahydrofuran (60 ml) 7 and stirred at room temperature for an hour. After con-`5 centrating the resultant solution under reduced pres-sure9 the residue was extracted with ethyl ace~ate.
The extract was washed with water, dried OVeT magnesium sulfate and concentra~ed under reduced pressure. The oily residue was subjected to column chromatography on silica gel, and eluted with benzene, a mixture of benzene (1 part) and ethyl acetate (1 part) and then ethyl acetate in turn. The ethyl acetate fractions were collected and concentrated under reduced pTesSUre to give 4 nitrobenzyl 7-[Z-t2-amino-4-thiazolyl)-15 acetamido~-3-cephem-4-carboxylate (1.5 g).

I.R. ~ NUa~o~ : 3350, 1780, 1740, 1680, 1610 cm 1 N.M.R. ~(DMSO-d6, ppm) : 3.40 (2H, broad s)~
3.68 ~2H, broad s), 5.12 (lH, d, J~5Hz), 5.43 (2H, s), 5.84 (lH, dd, J=8Hz, 5Hz), 6.30 ~lH, s), 6.70 (lH, broad s), 7.72 (2H, d, J=9Hz), 8.27 ~2H, d, J=9Hz), 8.93 (lH, d, J-8Hz) (3) A solution of 4-nitrobenzyl 7-~2-(2-amino-4--thiazolyl)acetamido]-3-cephem-4-carboxylate (1.4 g) in a mixture of methanol (25 ml) and tetrahydrofuran (60 ml)-was added to a mixture of 10% palladium -on-carbon - (1.7 g), glacial acetic acid (7 ml) and methanol (20 ml) in an atmosphere of nitrogen. Hydrogen gas was introduced into the mixture and shaken for 8.5 hours at room temperature. After removing the insoluble substance by filtratio~, the filtrate was concentrated under reduced pressure. The residue ~as pulverized with diethyl ether, and the resultant substance was , ~ 28 -r~

dissolved in an aqueous solution o~ sodium bicarbonate, washed with ethyl acetate and diethyl éther in turn and then the remaining ether was removed by bubbling with nitrogen gas. The resultant solution was adjusted to pH 4.5 with dilute hydrochloric acid, subjected to column chromatography on macroporous non-ionic adsorpt-ion resin "Diaion HP-20" (Tradema'rk, manufactured by Mitsubishi Chemical Industries Ltd.), and eluted with 20~ isopropyl alcohol. Isopropyl alcohol was distilled off under reduced pressure and t'he remaining solution w~s lyophilized to give 7-[2-(2-arnino-4-thiazolyl)-acetamido]-3-cephem-4-carboxylic acid (185 mg).

I.R. vmUa~l : 3550, 3330, 1750, 1670, 1620 cm 1 N.M.R. i~(DMSO d6, ppm) 3.42 (2H, s), 3 60 (2H, d, J=4Hz), 5.08 (lH, d, J=5Hz~, 5~77 (lH, dd, J=8Hz~ 5Hz), 6~30 ~lHl s), 6.52 ~lH, t, J-4Hz), 8.87 (lH, d, J-8Hz) Example 8 (1) 7-Amino-3-cephem-4-carboxylic acid (1.7 g) and sodium bicarbonate (2.84 g) were dissolved in a mixture of wateT (35 ml) and acetone (35 ml). On the other hand, phosphorus oxychloride (1.95 ml) was added drop-wise to a suspension o~ 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid tsyn-isomer: 3.42 g) in dry ethyl'acetate (34 ml~ over 10 minutes at 0 to 6C, and the mixture was stirred at the same temperature for 30 minutes. To the solution was added dropwise a solution of t~imethylsilylacetamide ~2.39 g) in ethyl acetate (5 ml) at 0 to 6C over 20 minutes, and the mixture was stirred for 20 minutes. After phosphorus oxychloride ~1.95 ml) was added dropwise to the mixture at t'he above temperature over lG minu~es, khe mixture obtained thus was stirred for 30 minutes. And further, .

-- 2g -- ~

.~ ~ .;, 3'~
dime~hylf~rmamide (1.29 ml~ was~added d~opwis~ to ~he mixture over 10 minutes at the same tempe~a~ure and stirred for one hour ~o give a clear solution. The - solution was added dropwise to the solution of 7-amino-S 3-ceph~m-4-carboxylic acid at -5 to 5C, over 30 minutes, at pH 6~5 to 7.5, and the reaction mixture was stirred for one hour at the same temperature.
~thyl acetate (200 ml) was addcd to the resultant solution, and ~he aqueous layer was separated9 washed with methylene chloride, bubbled with nitrogen gas and adjusted topH 4 with acetic acid. The solution was sub-jected to column chroma~ography on macroporous, non~
ionic adsorption resin "Diaion HP-20" (Trade mark:
manufactured by Mitsubishi Chemical Industries Ltd.) lS and eluted with 20% aqueous solution of isopropyl alcohol. The eluate was concen~rated under reduced pressure and lyophilized to give 7-[2-~2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer: 2 . 0 g~
I. R. ~ NmUa~ol : 3470, 3280, 3200, 1780, 1695 1655, 1622 cm~
N.M.R. ~(DMSO-d6, ppm) : 3.60 (2H, broad s), 3.84 (3H, s), 5.12 (lH, dd, J=5Hz), 5.B4 (1~, dd, J=5.8Hz), 6.52 ~lH, broad t), 6. 76 (lH, s), 7 . 26 (2H, broad s), ~.65 (lH, d, J-8Hz) (2) Z;nc powder (4.5 g) was added ~o a stirred solution of 7- [~- (2-amino-4-thiazolyl)-2-methoxyimino-acetamido~-3-cephem-4-carboxylic acid (syn i~omer :
3 g) in 90% formic acid (150 ml) under ice-cooling over 5 minutes, and stirred at the same temperature for 15 minutes. Af~er the resultant solution was filtered and washed wi~h formic acid, the filtrate ... . . . .. . . . . . . . . . . .. . .
-- 30 ~

`

s/~

and th~ washings were combined and concentrated under reduced pressure to a volume of about Z0 ml The concentrate was dissolved in water (150 ml) and bu~bled - with hydrogen sulfide gas for 20 minutes under ice-: 5 cooling. The precipitating zinc sulfide was filtered off, and the filtrate was treated with activated charcoal and lyophilized to give 7- ~2- (2-amino-4-.*h~azo.lyl).glyc.inamido]-3-cephem-4-carboxylic acid . formate (2. 9 g), pale yellow powder,. mp~.240C.
I.R. v ma~~ : 3330~ 3200, 3100, 1770, 1690 cm 1 N-M-R- ~(D2O: pp~) 3.42-3.61 (2H, m), 5.03-5.16 (lH, m~, 5.19 (lH, s), 5.60 (1/2H, d~ J ~5Hz), 5. 79 (1/2H, d, J~5Hz), 6.36 -6.50 ~lH, m? . 8.32 (lH3 s) Example 5 To a stirred solution of 7-[2-~2-amino-4-thiazolyl)glyoxyloylamino~-3-cephem-4-carboxylic acid (520 mg) in methanol (15 ml) was added sodium boro-hydride (100 mg) under ice-cooling, and stirred at the same temperature for 3 hours. Methanol was-distilled . off under reduced pressure from the reaction mix*ure, and the residue was dissolved in water (3 ml) and adjusted to pH 3 with 6N-hydrochloric acid. The pre-cipitates were collected by filtration9 washed with water and dried over phosphorus pentoxide to give 7-12-(2-amino-4-thiazolyl)-2-hydroxyacetamido~-3-c~phem-4-carboxylic acid (290 mg).
I. R. v mU~ol : 1775, 1630 cm 1 N.M.R. ~ (D~O+DMSO-d6, ppm) : 5.03 (lH, s), 5.07 (lH, d, J=4.6Hz), 5.72 (lH, d, J=4.6Hz), 6.49 ~lH, m, J=3.2Hz), 6.67 ~lH, s) .

~ - 31 - .
. . , In this disclosure the expression 'Isuch as" is to be understood as meaning "for example"~

~' ' ~1 . ~ , . .~ ::.................. . . .

Claims (34)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A process for preparing a compound of the formula (VI):

(VI) or a tautomer thereof, wherein R1 is amino or protected amino, R2 is hydrogen, halogen or hydroxy, R3 is carboxy or functionally modified carboxy, and A2 is lower alkylene substituted with a group of the formula: ?-O-R4 in which R4 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or cycloalkyl, or a nontoxic, pharmaceutically acceptable salt or bioprecursor thereof, which comprises reacting a compound of the formula (Id'):

(Id') wherein R1, R2 and R3 are each as defined above, and A4 is lower alkylene substituted with oxo, or a salt thereof, with a compound of the formula:

wherein R4 is as defined above, and when desired converting a free acid or base of formula (VI) obtained, or a tautomer thereof, to a corresponding non-toxic, pharmaceutically acceptable salt, and when desired converting a compound of formula (VI) or a salt thereof to a non-toxic, pharmaceutically acceptable bioprecursor thereof,

2. A process for preparing a syn compound of the formula (VI'):

(VI') or a tautomer thereof, wherein R1 is amino or protected amino, R2 is hydrogen, R3 is carboxy or functionally modified carboxy, and R4 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or cycloalkyl, or a nontoxic, pharmaceutically acceptable salt or bioprecursor thereof, which comprises reacting a compound of the formula (Id"):

(Id") wherein R1, R2 and R3 are each as defined above, or a salt thereof, with a compound of the formula:

wherein R4 is as defined above, and when desired converting a free acid or base of formula (VI') obtained, or a tautomer thereof, to a corresponding non-toxic, pharma-ceutically acceptable salt, and when desired converting a compound of formula (VI') or a salt thereof, to a non-toxic, pharmaceutically acceptable bioprecursor thereof.

3. A process of claim 2, wherein R1 is amino or acylamino, R2 is hydrogen, R3 is carboxy or esterified carboxy, and R4 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or cycloalkyl.

4. A process of claim 3, wherein R1 is amino, R2 is hydrogen, R3 is carboxy, and R4 is hydrogen.

5. A process of claim 3, wherein R1 is amino, R2 is hydrogen, R3 is carboxy and R4 is lower alkyl.

6. A process of claim 5, wherein R4 is methyl.

7. A process of claim 5, wherein R4 is ethyl.

8. A process of claim 5, wherein R4 is propyl.

9. A process of claim 5, wherein R4 is butyl.

10. A process of claim 5, wherein R4 is pentyl.

11. A process of claim 5, wherein R4 is hexyl.

12. A process of claim 3, wherein R1 is amino, R2 is hydrogen, R3 is carboxy and R4 is lower alkenyl.

13. A process of claim 12, wherein R4 is allyl.

14. A process of claim 3, wherein R1 is amino, R2 is hydrogen, R3 is carboxy and R4 is lower alkynyl.

15. A process of claim 14, wherein R4 is propargyl.

16. A process of claim 3, wherein R1 is amino, R2 is hydrogen, R3 is carboxy and R4 is cycloalkyl.

17. A process of claim 16, wherein R4 is cyclohexyl.

18. A compound of the formula (VI):

(VI) or a tautomer thereof, wherein R1, R2, R3, R4 and A2 are each as defined in claim 1, or a non-toxic, pharmaceutically acceptable salt or bioprecursor thereof, whenever prepared by the process of claim 1, or by an obvious chemical equivalent thereof.

19. A compound of the formula (VI'):

(VI') or a tautomer thereof, wherein R1, R2, R3 and R4 are each as defined in claim 2, or a non-toxic, pharmaceutically acceptable salt or bioprecursor thereof, whenever prepared by the process of claim 2, or by an obvious chemical equivalent thereof.

20. A compound of the formula (VI'), as defined in claim 2, wherein R1, R2, R3 and R4 are each as defined in claim 3, or a non-toxic, pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 3, or by an obvious chemical equivalent thereof.

21. 7-[2-(2-Aminothiazol-4-yl)-2-hydroxyimino-acetamido]-3-cephem-4-carboxylic acid, syn isomer, or a non-toxic, pharmaceutically acceptable salt or bioprecursor thereof, whenever prepared by the process of claim 4, or by an obvious chemical equivalent thereof.

22. A compound of the formula (VI'), as defined in claim 2, wherein R1, R2, R3 and R4 are each as defined in claim 5, or a non-toxic, pharmaceutically acceptable salt or bioprecursor thereof, whenever prepared by the process of claim 5, or by an obvious chemical equivalent thereof.

23. 7-[2-(2-Aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-cephem-4-carboxylic acid, syn isomer, or a non-toxic, pharmaceutically acceptable salt or biopre-cursor thereof, whenever prepared by the process of claim 6, or by an obvious chemical equivalent thereof.

24. 7-[2-(2-Aminothiazol-4-yl)-2-ethoxyimino-acetamido]-3-cephem 4-carboxylic acid, syn isomer, or a non-toxic, pharmaceutically acceptable salt or bioprecursor thereof, whenever prepared by the process of claim 7, or by an obvious chemical equivalent thereof.

25. 7-[2-(2-Aminothiazol-4-yl)-2 propoxyimino-acetamido]-3-cephem-4-carboxylic acid, syn isomer, or a non-toxic pharmaceutically acceptable salt or bioprecursor thereof, whenever prepared by the process of claim 8, or by an obvious chemical equivalent thereof.

26. 7-[2-(2-Aminothiazol-4-yl)-2-butoxyimino-acetamido]-3-cephem-4-carboxylic acid, syn isomer, or a non-toxic, pharmaceutically acceptable salt or bioprecursor thereof, whenever prepared by the process of claim 9, or by an obvious chemical equivalent thereof.

27. 7-[2-(2-Aminothiazol-4-yl)-2-pentyloxyimino-acetamido]-3-cephem-4-carboxylic acid, syn isomer, or a non-toxic, pharmaceutically acceptable salt or biopre-cursor thereof, whenever prepared by the process of claim 10, or by an obvious chemical equivalent thereof.

28. 7-[2-(2-Aminothiazol-4-yl)-2-hexyloxyimino-acetamido]-3-cephem-4-carboxylic acid, syn isomer, or a non-toxic, pharmaceutically acceptable salt or biopre-cursor thereof whenever prepared by the process of claim 11, or by an obvious chemical equivalent thereof.

29. A compound of the formula (VI'), as defined in claim 2, wherein R1, R2, R3 and R4 are each as defined in claim 12, or a non-toxic, pharmaceutically acceptable salt or bioprecursor thereof, whenever prepared by the process of claim 12, or by an obvious chemical equivalent thereof.

30. 7-[2-(2-Aminothiazol-4-yl)-2-allyloxyimino-acetamido]-3-cephem-4-carboxylic acid, syn isomer, or a non-toxic, pharmaceutically acceptable salt or biopre-cursor thereof, whenever prepared by the process of claim 13, or by an obvious chemical equivalent thereof.

31. A compound of the formula (VI'), as defined in claim 2, wherein R1, R2, R3 and R4 are each as defined in claim 14, or a non-toxic, pharmaceutically acceptable salt or bioprecursor thereof, whenever prepared by the process of claim 14, or by an obvious chemical equivalent thereof.

32. 7-[2-(2-Aminothiazol-4-yl)-2-propargyloxyimino-acetamido]-3-cephem-4-carboxylic acid, syn isomer, or a non-toxic, pharmaceutically acceptable salt or biopre-cursor thereof, whenever prepared by the process of claim 15, or by an obvious chemical equivalent thereof,

33. A compound of the formula (VII), as defined in claim 2, wherein R1, R2, R3 and R4 are each as defined in claim 16, or a non-toxic, pharmaceutically acceptable salt or bioprecursor thereof, whenever prepared by the process of claim 16, or by an obvious chemical equivalent thereof.

34. 7-[2-(2-Aminothiazol-4-yl)-2-cyclohexyloxyimino-acetamido]-3-cephem-4-carboxylic acid, syn isomer, or a non-toxic, pharmaceutically acceptable salt or biopre-cursor thereof, whenever prepared by the process of claim 17, or by an obvious chemical equivalent thereof.