DD240375A5 - PROCESS FOR THE PREPARATION OF CEPHALOSPORIN ANTIBIOTICS - Google Patents

Abstract

A cephalosporin antibiotic of formula I or a salt or ester thereof, wherein R is phenyl, substituted phenyl, cyclohexenyl, cyclohexadienyl, CH3CH (OH), CH3CH (OSO3H), CH3CH (OCH3) or an optionally substituted aromatic 5- or 6-membered heterocyclic group with 1, 2 or 3 heteroatoms, each independently selected from O, S and N; R2 is CH2OCOCH3, CH2OCONH2, Cl, F, OCH3, CH2N3 or a group of the formula wherein each R3 is independently H or C1C4 alkyl, m is 1 or 2, n is 3 or 4 and Het is an optionally substituted 5- or 6-membered heterocyclic group with up to 4 heteroatoms, selected from O, S and N, wherein the heterocyclic group optionally fused to an optionally substituted benzene ring or to another 5- or 6-membered heterocyclic group having up to 4 heteroatoms, selected from O, S and N. and R1 is a group of the formula CONR4R5 or COR6 wherein either (a) R4 and R5 are each independently H or C1C4 alkyl, (b) R4 is H or C1C4 alkyl and R5 is an optionally substituted 5- or 6-membered aromatic heterocyclic Is a group having 1 or 2 nitrogen atoms, or (c) R 4 and R 5 together with the nitrogen atom to which they are attached form an optionally substituted 5- or 6-membered heterocyclic group having 1 or 2 N atoms and R 6 optionally substituted phenyl or a substituted or unsubstituted, optionally benzo-fused 5- or 6-membered heterocyclic group or the group CH 2 NHC (NH) (4-pyridyl). Formula I and formula

Description

, -CH

2 ^ N

CH SO OH

is.

11. The method according to item 10, characterized in that it is used for the preparation of a compound of formula (I), wherein

(a) R = CH ₃ CH (OH) -, R ¹ = -CN - - £ t. And R = -

D O

CH COOH

2 1

(b) R and R are as in (a) and R

and (c) R = Ph, R ^{1 is} as in (a) and R ^{2 is} pyridiniummethyl.

• 12th Process according to claim 1, characterized in that a compound of formula (I) as claimed in item 1 or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, wherein R is other than CH ₃ CH (OSO ₃ H) - or CH ₃ CH (OCH ₃ ) - and wherein R ^{2 is} other than -CH ₂ N ₃ or -C ^ SHet when Het is the heterocyclic group fused to an optionally substituted benzene ring or to the other heterocyclic group.

Field of application of the invention

This invention relates to cephalosporin antibiotics, and more particularly to cephalosporins having a 7a-hydroxyamino substituent.

Characteristic of the known technical solutions

US Pat. No. 4,297,488 describes cephalosporin antibiotics of the formula

GQOH

wherein R ^{1 is} an acyl group, A is an organic radical or an organic group and R _{1 is} a hydrogen-replacing radical or group, and their derivatives, such as esters, amides and salts. R ₁ in the above formula may e.g. A "nitrogen-bonded group", for which a particular case is "-NR ₃ OH", where "R _{3 is} R ₂ (which is a straight-chain or branched C 1 -C 6 -alkyl group) or hydrogen." In this specification no compounds with R _{1 shown} as "- NR ₃ OH" as examples.

Aim and presentation of the essence of the invention

We have found a panel of 7α-hydrooxyamino-cephalosporins that have unexpectedly good antibacterial properties, especially towards Gram-negative organisms, and activity against β-lactamase producing bacterial strains.

Thus, the present invention provides cephalosporin antibiotics of the formula

NHOH

'Ξ ^ S.

R-CH-CONH m

m 'I -^(I)

": COOH

and their salts and esters, wherein R is phenyl, substituted phenyl, cyclohexenyl, cyclohexadienyl, CH ₃ -CH (OH) -, CH ₃ -CH (OSO ₃ H) -, CH ₃ -CH (OCH ₃ ) -or optionally substituted aromatic 5 or 6 membered heterocyclic group having 1, 2 or 3 heteroatoms each independently selected from 0, S and N;

R ^{2 is} -CH ₂ OCOCH ₃ , -CH ₂ OCONH ₂ , -Cl, -F, -OCH ₃ , -CH ₂ N ₃ or -a group of the formula

(R ³ ) m

 Ό

C ₁ -C ₁₄ -alkyl)

or -CH ₅ S.Het

is, '-.

wherein each R ^{3 is} independently H or C 1 -C 4 alkyl, m is 1 or 2; η is 3 or 4 and Het is an optionally substituted 5- or 6-membered heterocyclic group having up to 4 heteroatoms selected from O, S and N, said heterocyclic group optionally being an optionally substituted benzene ring or another 5- or 6-membered heterocyclic group having up to 4 heteroatoms selected from O, S and N, condensed; and R ^{1 is} a group of formula-CONR ⁴ R ⁵ or-COR ⁶ wherein either

(a) R ⁴ and R ^{5 are} each independently H or C ₁ -C ₄ alkyl,

(b) R ^{4 is} H or C ₁ -C ₄ alkyl and R ^{s is} an optionally substituted 5- or 6-membered aromatic heterocyclic group having 1 or 2 nitrogen atoms, or

(C) R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form an optionally substituted 5- or 6-membered heterocyclic group having 1 or 2 N atoms and

R ^{6 is} optionally substituted phenyl or a substituted or unsubstituted, optionally benzo-fused 5- or 6-membered heterocyclic group or the group -CH ₂ NH-Cf = NH) (4-pyridyl).

When R is substituted phenyl, it is preferably phenyl substituted by _1, 2 or 3 substituents, each independently selected from -OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, (C ₁ -C ₄ alkyl) ) CO-O-, halogen, CF ₃ , -NHSO ₂ (C ₁ -C ₄ -alkyl-NHCO (C ₁ -C ₄ -alkyl), -NH ₂ , -NH (C ₁ -C ₄ -alkyl) ₁ -N (-C ₄ -alkyl) ^ - COOH, -CONH _2, -CONH (C ₁ -C ₄ -alkyl), - CON (C ₁ -C ₄ -alkyl) _2, -COO (C ₁ -C ₄ AIlCyI ) and benzyloxycarbonyloxy.

Typical examples of R as substituted phenyl are 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3,4-diacetoxyphenyl, 3-chlorophenyl and 4-benzyloxycarbonyloxyphenyl.

When R is the optionally substituted aromatic 5- or 6-membered heterocyclic group, typical examples are 2- and 3-thienyl, 2-amino-4-thiazolyl and 5-amino-1,2,4-thiadiazol-3-yl.

Preferably R is phenyl, 3,4-dihydroxyphenyl, 4-hydroxyphenyl, 4-benzyloxycarbonyloxyphenyl, 2- or 3-thienyl, CH ₃ CH (OH) -CH ₃ CH (OCH ₃ ) or CH ₃ CH (OSO ₂ -OH ) -.

When R ^{1 is} -CONR ⁴ R ⁶ , it is preferably a group of the formula

C = O, NH "

C = O NH

or

wherein R ^{7 is} selected from (a) hydrogen, (b) cyclopropyl, (c) hydroxy, (d) C ₁ -C ₄ -alkoxy, (e) -SO ₂ NH ₂ , (f) -NHR ¹¹ , wherein R ¹¹ H, a C ₁ -C ₆ -alkyl group, optionally containing a double or triple bond, or C ₃ -C ₆ -cycloalkyl, (g) -NH-alk-R ¹² , wherein alk is a straight- or branched-chain C, - C ₄ -alkylene group and R _{12 is} -OH, -SH, -CN, -CONH ₂ , -SO ₂ NH ₂ , -COCH ₃ , NH ₂ , -NH- (C 1 -C ₄ -alkyl), -N (C _r C ₄ alkyl) _2, -NH-CHO, -NH-COCH _3, -NHCONH _2, CH ₃ SO ₂ NH-, -OCH _3, -OC ₂ H _5, -0-COCH ₃ _ _{S. CH3, -SO-CH3,} -SO ₂ -CH _3, -COOH or-COOCH _3,

(h) -NH ·

wherein η is O or 1 and R ¹³ and R ^{14 are} each independently H, halogen, -OH, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, -NHCO- (C ₁ -C ₄ -alkyl), -NHCONH ₂₇ -NHCONH (C ₁ -C ₄ -alkyl), NHCON (C ₁ -C ₄ -alkyl) _2, (CrC ₄ -alkyl) SO ₂ NH -, - CO (C ₁ -C ₄ -alkyl), -O-CO- (C ₁ -C ₄ -alkyl), - CONH ₂ , -CONH (C ₁ -C ₄ -alkyl), --CON (C ₁ -C ₄ -alkyl) ₂ , -NO ₂ , -CN , -S-CH ₃ -SOCH ₃ , -SO ₂ CH ₃ , -SO ₂ NH ₂ , -SO ₂ NH (C _r C ₄ alkyl) OdCr-SO ₂ N (C ₁ -C ₄ -AlkYl) ₂ mean and (i) -NH (CH ₂ ) _n -R ¹⁵ wherein η is O or 1 and R ^{15 is} a substituted or unsubstituted 5- or 6-membered heterocycle having 1 or 2 identical or different heteroatoms selected from O, Sund N ;

R ⁸ and R ^{9 are} each independently H or C ₁ -C ₄ alkyl, or together are (CH ₂ J ₃ -or- (CH ₂ ) ₄ -; and R ^{10 is} H ₁ C ₁ -C ₃ -alkyl - SO ₂ (C ₁ -C ₄ alkyl), phenyl, benzyl, -N = CH- (2-furyl), - N = CH- (3,4-dihydroxyphenyl) or - (CH ₂ J ₂ OH.

Preferred heterocyclic groups represented by R ₁₅ are thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl, all optionally substituted by ζ. For example, halogen, C _r C ₄ alkyl, nitro, cyano, amino, -NHCO (C ₁ C ₄ -alkyl), -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl ) _2, -OH, C ₁ -C ₄ -alkoxy, CrC ₄ alkylthio, d-Gi-alkylsulfinyl, -NHSO ₂ (C ₁ -C ₄ -alkyl), -CONH _2, COO (C ₁ -C ₄ - AIkYDi-Sp ₂ NH ^ -SO ₂ NH- (C ₁ -C ₄ -alkyl) or -SO ₂ -C ₄ -alkyl) ₂ .

R ⁶ is preferably either a phenyl group optionally substituted by 1 or 2 substituents, each selected from -OH and C ₁ -C ₄ -alkyl, or else a 5 or 6 membered heterocyclic group containing O or N, optionally benzo-fused and optionally substituted by -OH, C ₁ -C ₄ alkyl, -NH ₂ or oxo.

When R ^{1 is} -COR ⁶ , it is preferably a group of the formula ^;

C = O

or

When R ^{1 is} -CONR ⁴ R ⁵ , it is preferably a group of the formula

C = O NH ₂

o wherein RC ₁ -Co AIkVl or Io

Benzyl is,. ,

wherein R ^{10 is} H, C ₁ -Cg-alkyl,

Y or or LA "'' - (CH ₂ J ₂ OH is.

When R ^{2 is} -CH ₂ SHet, "Het" is preferably an optionally substituted triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyKTriazinyl, thiadiazolyl, benzoxazolyl, benzothiazolyl or tetrazolopyridazinyl group Preferred substituents are C ₁ -C ₄ -alkyl, -C ₄ -alkoxy, halogen, oxo or a group of formula - (CH ₂ iPr ^16, wherein ρ is 0,1,2 or 3 and R ¹⁶ is -COOH, _-OSO2 OH, -SO ₂ OH, -PO ₃ H ₂ or -OH, with the proviso that ρ is not O when Het is tetrazolyl With hydroxy and oxo substituents, of course, tautomerism can occur. "Halogen" means F, Cl, Broder J.

The more preferred "Het" groups are attached to the adjacent S atom via a carbon atom of the heterocyclic ring and are (i) thiadiazolyl optionally substituted by C ₁ -C ₄ alkyl or 2-hydroxyethyl, (ii) tetrazolyl optionally substituted by C ₁ -C ₄ -alkyl, carboxymethyl, sulfomethyl, 2-hydroxyethyl or 2- (hydroxysulfonyloxy) ethyl, (iii) thiazolyl optionally substituted by 1 or 2 substituents each selected from among Ci-C ₄ alkyl and carboxymethyl (iv ) Isothiazolyl, optionally substituted by 1 or 2 substituents, each selected from hydroxy and carboxy, (v) benzothiazolyl or benzoxazolyl, optionally substituted by hydroxy, C 1 -C ₄ -alkoxy or halogen, (vi), tetrazolopyridazinyl, optionally substituted by carboxy, (vii) triazinyl optionally substituted by C ₁ -C ₄ alkyl and / or by 1 or 2 oxo or hydroxy groups; and (viii) triazolyl optionally substituted by carboxymethyl.

The preferred single groups represented by "Het" are those given in the specific examples.

Apart _from-CH2 SHet, the preferred groups represented by R ^2-CH ₂ OCOCH _3, -CH ₂ OCONH ₂₁ -CH ₂ Ns and a group of formula

or

In the most preferred compounds of formula (I), the substituents are as follows:

(a) R is unsubstituted phenyl or CH ₃ CH (OH) -

(b) R ¹ is a group of the formula

C = O

where RC ₃ H ₅ is or

(c) R ² is a group of the formula

N N

CH COOH

N - N

JI I or -CH, N

is. ,

The preferred individual compounds of formula (1) have the following substituents:

r- > NN

1 '\ 2 Il H

(a) R = CH ₀ CH (OH) -, R = -CN N-Ec, and R = -CH ₀ S-JL ", ν!

³ i / ² "'

0 ^ O,. CH COOH

2 1 '\

(b) R and R are as in (a), and R = -C-N

Il V

⁰ ο

and (c) R = Ph, R ¹ is as in (a) and R ² is pyridiniummethyl.

The salts and esters (including in vivo hydrolysable esters) of the compounds of formula (I) are well known to those skilled in the art. These salts include not only salts with -COOH, but also with _-OSO2 OH and a-SO ₂ OH. The preferred salts are the sodium and potassium salts and the triethylammonium salts. Of course, some of the compounds may be in zwitterionic form. The preferred in vivo hydrolysable esters are those of the formula

-CH ₂ OCOtBu ₁ -CH ₂ OCOCH ₃ , -CH (CH ₃ ) OCOCH ₃₁ -CH (Ch ₃ )

OCOOE ₁

And

The preferred esters useful as intermediates are the t-butyl and benzylhydryl esters.

In general, the DL and D form at the carbon atom marked a star of the compounds of the formula (I) or when a threonine-derived side chain is present, the 2 R, 3S form is preferred.

The compounds of formula (I) are preferably prepared by replacing-S-CH ₃ at the 7a-position with -NHOH. This can be done on the 7a-methylthio-7ßacylamino compounds, ie after carrying out the acylation to introduce the group RCH (NHR ¹ ) CO-, or to compounds that have no acyl group in the ß-position. The desired 3-substituent may be introduced before or after the presence of the hydroxyamino substituent. Further, any O or carboxy protecting groups can be removed before or after the -NHOH group is in position.

Typically, the hydroxyamino substituent is prepared by reacting the appropriate methylthio compound with a mercury (II) salt, e.g. Mercuric ether trifluoroacetate, mercury (II) chloride or mercury (II) acetate, and preferably with mercury dioacetate, at low temperature, e.g. B. -50 ° C, in a suitable organic solvent, for. B.

Dimethylformamide (DMF) introduced. Hydroxylamine (preferably from hydroxylamine hydrochloride / triethylamine generated), it is again typically in DMF, is added and the solution was heated slowly from -2O ⁰ C to +20 ⁰ C. An acid addition salt of hydroxylamine, e.g. As the hydrochloride, can be used instead of hydroxylamine itself. The 7a-hydroxyamino product can then be isolated in a conventional manner. Ca-Cj-alkylthio, phenylthio or benzylthio derivatives can be used instead of the methylthio starting materials. Similarly, metal salts (eg, acetates) such as silver, thallium, lead, or copper salts can be used in place of mercury (II) salts.

The 7a-methylthio compounds are either known compounds or can be prepared in a conventional manner. Typical routes to the compounds of formula (I) are schematically illustrated as follows:

(A)

SMe

acylated

COC ¹¹ CBP "

(see US-PS 3976641)

NHOH

RCH (NHR

RCH (NHR

SMe

RCOO.CBP

+

i) Hg ii) NH OH

Splitting off the carbons

oxy-protecting group

RCH (NHR) C0N

COOH

RCOO.CBP

"CBP" = a carboxy-protecting group

Modification in the 3-position (e.g., -CH ₂ OAc to -CH ₂ SHet) may be made, if desired, before or after introduction of the hydroxyamino substituent.

SMe

(b) RCH (NHR ¹ ) CONH

OAc

COO.CBP

Cleaving the carboxy-protecting group

SMe

RCH (NHR ¹ ) CONH

ii)

NHCH

i) pyridine or HS.Het ii.) Kg ²⁺

NHOH

RCH (NHR) C0NH * v ±

COOH

COOH '

SCH.

S.CH (c) RCH (NHR ¹ ) CONH »JL ·" ^S

.sf ν RCH (NHR ¹ ) CO ίί

COOH

NHOH

RCH (NHR ¹ ) CO NH »^ Ξ

RCH (NHR ¹ ) CONH _- J

O = C = ₀ CL N.SO

, OCONH,

• COCH

COOH

2+

NHOH

i) Hg '/ NH_0H, = -S_Z_ } RCH (NHR) CONH ^ = -

ü) Acylation i i) Deprotection

COOH

(see for example GB-PS 1526793).

Compounds in which R ^{2 is} -CH ₂ N ₃ may be prepared by converting -CH ₂ OCOCH ₃ into -CH ₂ N ₃ using a

Alkali metal azides, e.g. B; Sodium azide.

Any hydroxy-protecting group, if present, may be cleaved again before or after introduction of the hydroxyamino group

become.

Apart from the introduction of the hydroxyamino group, all of the above steps are conventional (see, e.g.

UK Patentanmeldung2107307AoderUS-PS4297488). '. '

The acylation is typically carried out using an acid chloride or bromide of the acid RCH (NHR ¹ ) COOH or '

an O-protected derivative of it. Alternatives are naturally activated esters, mixed anhydrides. The reaction is typically carried out at a temperature (-10 ° to ⁰ ° C) in a suitable organic solvent, e.g. For example, dichloromethane. When an acid halide is used, the presence of an acid-binding agent such as pyridine or triethylamine,

prefers. '

Many conventional carboxy-protecting groups (CBP's) can be used, e.g. For example, t-butyl, benzhydryl, benzyl, p-methoxybenzyl and p-nitrobenzyl. These can all be split off according to conventional measures. The preferred ones

Protecting groups are t-butyl, which is typically cleaved with trifluoroacetic acid, and benzhydryl, which is typically cleaved with anisole / AICI ₃ or trifluoroacetic acid. Modifications take place in the 3-position of the cephalosporin ring

according to conventional methods, for. B.

(a) -CH ₂ OAc

pyridine

Sodium j ocüd-Kataly se '

(also for all compounds in which R ^{2 contains} a quaternary group)

CH ₂ OAC

Het SH

CH ₂ :

, Br

-> -CH ₂ S-Het

(or a salt (e.g., an alkali metal salt) thereof)

(other suitable leaving groups than -OAc, I or Br can be used).

The Cs-acetoxymethyl group can be reacted with the thiol in the presence of a Lewis acid, such as boron trifluoride, if desired (see J 55020724).

It should be noted that oxygen-protected derivatives of hydroxylamine instead of hydroxylamine can be used in the formation of the -NHOH group, such as derivatives including H ₂ N-OSiMe ₃ , H ₂ N-OSiMe ₂ tBu, H ₂ N-OSiPh ₂ IBu, H ₂ N-OSi (C ₁ -C ₄ -alkyl) ₃ , H ₂ NO-benzyl, H ₂ NO-COO-benzyl, H ₂ NO-COOtBu, H ₂ NO-COOCH ₂ CCI ₃ ,

H ₂ NO-COOCH ₂ CH = CH ₂ , H ₂ N

H ₂ NO-COOCH ₂

OCH ₃ or H ₂ NO-COOCH ₂ CH ₂ Si (CH ₃ ).

The O-protecting groups can be cleaved in a conventional manner.

If desired, the same O-protecting groups can be used to protect the hydroxy groups of CH ₃ CH (OH) - (see R) and any hydroxy or hydroxyalkyl substituents. The preferred Q-protecting groups are t-butyldiphenylsilyl and t-butyldimethylsilyl cleaved with aqueous hydrofluoric acid.

The salts and in vivo hydrolysable esters can be prepared in a conventional manner. An alternative method for the introduction of hydroxyamino can be represented as follows:

t-Bu

t-Bu

(known)

t-Bu

t-3u

OAc

COO. C3P HNH or O-protected derivative thereof

NHOH or NHO protecting group N Ξ

OAc

NHOH

CCO.CBP

.. ' . '__ COO. CBP

For administration to humans in the curative or prophylactic treatment of bacterial infections, parenteral dosages of the compounds are typically in the range of 100 mg to 8 g daily for an average adult patient (70 kg) and most usually from 1 g to 4 g daily. Thus, for a typical adult patient, individual parenteral formulations will contain from 0.5 to 2 g of active compound in a suitable pharmaceutically acceptable carrier. In practice, the physician will determine the actual dosage that will be most appropriate for a single patient and will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case, but of course there may be isolated cases where higher or lower dosage ranges are beneficial and such are within the scope of the invention. For human use, the compounds of formula (I) may be administered parenterally in admixture with a pharmaceutical diluent selected with regard to the intended route of administration and standard pharmaceutical practice. They can be injected intravenously, intramuscularly or subcutaneously. They are best used in the form of a sterile, aqueous solution which may contain other substances, e.g. Enough salts or glucose to render the solution isotonic with blood, and the solution may also contain an anesthetic such as lignocaine. Thus, in a further aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof or in vivo hydrolysable ester, together with a pharmaceutically acceptable diluent or carrier.

The compounds may also be administered in combination with other antibiotics and / or β-lactamase inhibitors, such as sulbactam.

The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for use in medicine, in particular for use as an antibiotic.

The invention also provides a method of treating a bacterial infection in a human subject comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.

The compounds of formula (I) and their pharmaceutically acceptable salts and in vivo hydrolysable esters are antibiotics which have unexpectedly high activity. In particular, they are active against Gram-negative organisms such as E. coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Proteus morganii, Providentia stuartii, Providentia rettgeri, Haemophilus

influenzae and bacteriodesfragilis.

The following Examples, in which all temperatures are in ⁰ C, illustrate the invention:

Embodiments.

Example 1 -

7β4D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonyamino) -2-phenylacetamido] -7α-hydroxyamino-3 - [{1,2,3-thiadiazol-5-yl) thiomethyl] ceph- 3-em-4-carboxylic acid

(Old-butyl-ys-amino-S-Ki ^ S-thiadiazole-S-y-thiomethyne-ceph-S-em ^ -carboxylate 7β-Amino-3- [1,2,3-thiadiazol-5-ylthio) methyl] ceph-3-em-4-carboxylic acid (2.0 g) was suspended in dry dichloromethane (50 ml) and treated with 0-t-butyl-N, N'-diisopropylisourea (4.0 g) in dichloromethane (20 ml) for 5 min. After 6 h, the solution was filtered and the filtrate washed with saturated sodium bicarbonate (50 mL). The organic phase was dried (over MgSO ₄ ) and evaporated in vacuo to give the title compound as a brown foam (1.6 g). IR (CH ₂ Cl ₂ ) 1785cm " ¹ .

NMR (CDCl ₃ ) δ = 1.53 (s, 9H), 3.45 and 3.68 (ABq, J = 16, 2H), 4.08 and 4.18 (ABq, J x = 12.2 H ), 4.95 (s, 1H), 5.32 (s, 1H), 8.52 (s, IH).

(b) t-Butyl-7β-phenylimino-3 - [(1,2,3-thiadiazol-5-yl) thiomethyl] ceph-3-em-4-carboxylate t-butyl-7β-amino-3 - [( 1,2,3-thiadiazol-5-yl) thiomethyl] -ceph-3-em-4-carboxylate (1.6g) was dissolved in methanol (50ml) and treated with benzaldehyde (0.44g) overnight. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate. This was washed with aqueous sodium metabisulfate, water, dried (over MgSO ₄ ) and evaporated to a brown foam (1.7 g).

NMR _(CDCl3) S = 1.53 (s, 9 H), 3.40 and 3.68 (ABq, J = 16,2H), 4,05und 4.22 (ABq, J = 13,2H), 5.16 (d, J = 4.1H), 5.44 (d, J = 4, 1H), 7.4-7.8 (m, 5H), 8.54 (s, 1H) , 8.63 (s, 1H)

(Clt-butyl VSS amino-ya-methylthio-S-ti ^ S-thiadiazol-S-S-yOthiomethyllceph-em ^ -carboxylate

t-Butyl-7β-phenylimino-3 - [(1,2,3-thiadiazol-5-yl) thiomethyl] -ceph-3-em-4-carboxylate (1.7 g) was dissolved in dry tetrahydrofuran (50 ml) and cooled to -70 ⁰ C under nitrogen. A solution of potassium t-butylate (400 mg) in tetrahydrofuran (20 ml) was added in one portion and stirred for 5 minutes. Methylthiomethansulfonat (CH ₃ SO ₂ SCH _3, 435 μΙ) was added and the mixture for 3 h at 0 ⁰ C heated. A pH 6.5 buffer solution (150 ml) was added and the whole was extracted with ethyl acetate (3 × 50 ml). The combined organic phases were dried (over MgSO ₄ ) and evaporated in vacuo to a brown oil which was chromatographed on silica gel (dichloromethane / ethyl acetate 3: 1) to give the 7a-methylthioimine (1.2 g). This was dissolved in ether (50 ml) and treated with a solution of p-toluenesulfonic acid in the minimum volume of acetone After 30 minutes at room temperature and 0 ^° C. for 30 minutes, the p-toluenesulfonic acid acid of the title compound was filtered off This salt was partitioned between saturated sodium bicarbonate distributed and Ethyiacetat and the organic phase was washed with water, dried (over MgSO ₄₎ and evaporated in vacuo zurTitelverbindung. ¹

NMR (DMSOd ₆ ) S = 1.40 (s, 9H), 2.12 (s, 3H), 2.95 (s, 2H), 3.5 and 3.72 (ABq, J = 15, 2H) , 4.18 (ABq, J = 6, 2H), 5.01 (s, 1H), 8.9 (s, 1H).

(D) t-butyl 7ß- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonyi-amino) -2-phenylacetamido] -7a-methylthio-3 - [(1,2,3 thiadiazol-5-yl) thiomethyl] ceph-3-em-4-carboxylate

t-Butyl ^ ß-amino ^ a-methylthio-S-KI ^^ - thiadiazol-S-yO-S-thiomethyljceph-em ^ -carboxylate (0.20 g) in dichloromethane (5ml) was cooled to -2O ⁰ C and treated dropwise with a solution of D-2- [4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino] -2-phenyl-acetyl chloride (0.17 g) in dichloromethane (2 ml) over one minute. Pyridine (40 μΙ) was added for 0.5 min. ¹ , the solution was allowed to warm to ⁰ ° C. over 2 h, washed with 1% hydrochloric acid (20 ml), saturated sodium bicarbonate (20 ml) and dried (over MgSO ₄ ). The solvent was evaporated in vacuo and the residue chromatographed (silica gel / dichloromethane: ethyl acetate 7: 3) to give the title compound (0.23g). ¹ '

NMR (CDCl ₃ ) O = 1.22 (t, J = 7.3H), 1.48 (s, 9H), 2.25 (s, 3H), 3.54-3.62 (m, 4H) , 3.95-4, 31 (m, 6H), 4.89 (s, 1H), 5.60 (d, J = 6.1H), 7.38-7.51 (m, 5H), 8.51 (s, 1H), 10.00 (d, J = 6.1H).

(e) -Butyl-7β- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3 - [(1,2,3-) thiadiazol-5-yl) thiomethyl] ceph-3-em-4-carboxylate

t-butyl 7ß- [D-2- (4-ethyl-2,3-dioxopiperazin-1-yicarbonyl-amino) -2-phenylacetamido] -7a-methylthio-3 - [(1,2,3-thiadiazol 5-yl) thiomethyl] ceph-3-em-4-carboxylate (0.23 g) (in dimethylformamide (DMF) 3 ml) was cooled under nitrogen to -50 ⁰ C, then treated sequentially with a solution of QuecksiJber (II) acetate (0.105g) in dimethylformamide (1ml) and hydroxylamine hydrochloride (0.03g) in dimethylformamide (1ml). The mixture was added over 1 h to ⁰ ° C and warmed to Ethyiacetat (50 ml). The solution was washed with water (5 x 30 ml), dried and evaporated in vacuo. The residue was purified by chromatography (silica-dichloromethane / ethyl acetate gradient) to give the title compound (0.20g). ... ·. ' ,

NMR (CDCl ₃ ) O = 1.15 (t, J = 6.3H), 1.5 (s, 9H), 2.95 and 3.08 (ABq, J = 15.2H), 3.59 (m, 4H), 3.92-4.2 (m, 4H), 5.23 (s, 1H), 5, S (d, J = 6.1H), 7.3-7.7 (m, 5H), 8.5 (s, 1H), 10.08 (d, J = 6.1H).

(f) γ-β-D-ethyl-Z-dioxopiperazin-1-ylcarbonylaminol-phenylacetamidol-Ta-hydroxyamino-S-filo-S-thiadiazol-S-yl-thiomethyl-lceph-S-em-carboxylic acid

t-butyl 7ß- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonyiamino) -2-phenylacetamido] -7a-hydroxyamino-3- [1,2,3-thiadiazol-5-ylJthiomethyllceph -S-em -carboxylate (0.20g) was dissolved in trifluoroacetic acid (3ml) and allowed to react for 10min before being evaporated in vacuo. The residue was taken up in ethyl acetate (20 ml) and extracted with saturated aqueous sodium bicarbonate solution (2 × 20 ml). The combined aqueous extracts were backwashed with ethyl acetate and acidified to pH 2 with hydrochloric acid. The acidified solution was extracted with ethyl acetate (3 × 30 ml), the combined organic phases were washed, dried (over MgSO ₄ ) and evaporated in vacuo to give the title compound (0.06 g). IR (KBr) 1780cm " ¹ .

NMR (DMSOd ₆ -D ₂ O) O = 1.08 (t, J = 6.3H), 3.2-3.6 (m, 6H), 3.8-4.0 (m, 2H), 4.10 and 4.23 (ABq, J = 13.2H), 5.05 (s, 1H), 5.65 (d, J = 7.1H), 7.2-7.5 (m, 5H ), 8.85 (s, 1H), 9.58 (s, 1H), 9.90 (d, J = 7.1H).

Example 2 '

7ß- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyaminocephalosphoransäure

(a) t-Butyl-7β- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthiocephalosporanate t-butyl-7β-7a-methylthiocephalosporanate (1, 86 g) in dichloromethane (25 ml) was cooled to -10 ° C. and treated dropwise over 1 minute with a solution of D-2- [4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino] -2-phenylacetyl chloride 1.86 g). treated in. 'Dichloromethane (5ml). Pyridine (440 μΙ) was added over 1 min and the solution stirred 30 min at -10 ⁰ C, then washed with 1% saline (50 ml), saturated sodium bicarbonate (50 ml) and dried (Na ₂ SO 4) dried. The solvent was removed in vacuo and the residue was chromatographed (silica gel, dichloromethane / ethyl acetate 1: 1) to give the title compound (3.1 g). IR (KBr) 1790cm " ^1. * 'NMR (CDCl ₃ ) δ = 1.16 (t, J = 7, 3H), 1.48 (s, 9H), 2.02 (s, 3H), 2 , 22 (s, 3H), 2.85-3.75 (m, 6H), 3.8-4.2 (m, 2H), 4.67 and 5.03 (ABq, J = 13.2H) , 4.84 (s, 1H), 5.72 (d, J = 7.1H), 7.1-7.6 (m, 5H), 7.66 (Brs, NH), 9.95 (d, J = 7, NH).

(b) t -butyl-7β- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyaminocephalosporanate t -butyl-7β- [D-2- ( 4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetämido] -7a-methylthiocephalosporanat (1.35 g) in dimethylformamide (8 ml) was cooled under nitrogen to -50 ⁰ C, then treated sequentially with a solution of Mercury (II) acetate (0.64g) in dimethylformamide (3ml), followed by a solution of hydroxylamine in dimethylformamide prepared from hydroxylamine hydrochloride (0.14g), triethylamine (278μΙ) and dimethylformamide (4ml). The mixture over 30 min at -20 ⁰ C. and added to ethyl acetate (100 ml). This solution was washed with water (3 × 50 ml). washed, dried and evaporated in vacuo. The crude product (1.05g) prepared was purified by chromatography (silica gel, dichloromethane / ethyl acetate gradient) to give the title compound (950mg), m.p. 147 ° (dec.).

NMR (CDCl ₃ δ = 1.20 (t, J = 7, 3H), 1.53 (s, 9H), 2.08 (s, 3H) 2.95 and 3.29 (ABq, J = 17 , 2H), 3,4-3,65 (m, 4H), 3,85-4,13 (m, 2H), 4,78 and 4,95 (ABq, J = 13,2H), 5,23 (s, 1H), 5.52 (d, J = 6.1H), 6.58 (d, J = 3.1H, exchange), 6.86 (brs.1H), exchange), 7.3-7.65 (m, 5H), 8.63 (brs, NH), 10.0 (d, J = 6, NH).

Found: C 52.37 H 5.54 N 12.40%.

for C ₂₉ H ₃₆ N ₆ O ₁₀ S calc .: C 52.72 H 5.45 N 12.72%

(c) 7β- [D-2- (4-ethyl-2,3-dioxopiperazine-T-ylcarbonylamino-2-phenylacetamido] -7a-hydroxy-amino-cephalosporic acid t-butyl-7β- [D-2- (4-ethyl-2 , 3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyaminocephalosporanate (660 mg) was dissolved in trifluoroacetic acid (3 ml) and allowed to react in vacuo for 5 min before evaporation.

Supervision indicated incomplete reaction and the reaction was repeated with fresh trifluoroacetic acid (3 ml). The residue was taken up in dichloromethane / carbon tetrachloride, 1: 1 and evaporated on a rotary evaporator.

This evaporation was repeated and finally the product was triturated with dry diethyl ether to give the.

To give the title compound as a near white solid (485 mg).

IR (KBr) 1780cm ~ ¹ .

NMR (DMSOd ₆ ) O = 1.1 (t, 3H, J = 6), 2.1 (s, 3H), 3.1-3.65 (m, 6H), 3.85-3, 98 (m, 2H), 4.62 and 4.90 (ABq, J = 12.2H), 5.04 (s, 1H), 5.72 (d, J = 7.1H), 6.52 (brs, 1H), 7.25-7.55 (m / 5H), 8.20 (s, 1H), 9.56 (s, NH), 9.84 (COOH), 9 , 88 (d, J = 7, NH).

Example 3 '

7ß- [DL-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2- (2-thienylacetamido] -7a-hydroxyamino-3 - [(1,2,3-thiadiazol-5-

ythiomethynceph-S-em -carboxylic acid,

(A) t-Buty -7ß- [DL-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2- (2-thienyl) acetamido] -7a-methylthio-3 - [(1 , 2,3-

thiadiazole B-ylthiomethyllceph-Srem ^ -carboxylate.

The 7a-methylthiocephem (from Example 1 (c)) (0.30g) was converted to the title compound (0.37g) by the method of Example T (d) using the appropriate acid chloride.

IR (CH ₂ Cl ₂ ) 1785cm- ¹ .

NMR (CDCl ₃ ) δ = 1.25 (t, J = 6, 3H); 1.50 (s, 9H), 2.25 and 2.33 (2s, 3H), 3.5-3.7 (m, 6H), 4.0 ^ -4.3 (m, 4H), 4 , 9 + 4.93 (2s, 1H), 5.9 (d, 1H, J = 6), 7.0-7.40 (m, 3H), 8.55 (s, 1H), 9.9 (d, J = 6.1H). ·

(B) t-butyl 7ß- [DL-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2 - [(2-thienyl) acetamido] -7a-hydroxyamino-3 - [(1 , 2,3-thiadiazol-ö-yllthiometriyflceph-S-carboxylate ^ ren

t-butyl 7ß- [DL-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2- (2-thienyl) acetamido] -7a-methylthio-3 - [(1,2,3 -thiadiazol-5-yl) thiomethyl] ceph-3-em-4-carboxylate (0.37g) was converted to the title compound by the method of Example 1 (e).

IR (CH ₂ Cl ₂ ) 1780cm " ¹ .

NMR (CDCl ₃ ) O = 1.24 (t, J = 6.3H), 1.42 (s, 9H), 3.2-3.8 (m, 6H), 3.9-4.4 ( m, 4H), 5.26 + 5.30 (2s, 1H), 5.61 (d, J = 6.1H), 6.9-7.3 (m, 3H), 8.50 (s, 1H), 10.02 (d, J = 6.1H).

yOthiomethyllceph-S-em-'l-carboxylic acid

t-Butyl-7 / 3- [DL-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonyl-amino) -2- (2-thienyl) acetamido] -7a-hydroxyamino-3 - [(1 2,3-Thiadiazole-S-methylthioethyl lceph-S-em ^ -carboxylate (0.25g) was converted to the title compound by the method of Example 1 (f) (0.05g)

¹

NMR (DIvISOd ₆ ) Cr = 1.06 (t, J = 6, 3H), 3.2-3.8 (m, 8H, 4.0-4.3 (m, 2H), 5.09 and 5 , 11 (2, s, 1H), 5.96 (d, J = 6.1H), 6.94-7.47 (m, 3H), 8.12 (1H), 8.87 and 8 , 89 (2s, 1H), 9.53 and 9.58 (2s, 1H), 9.8 (d, J = 6.1H). '

Example 4.

yl) thiomethyl] ceph-3-em-4-carboxylic acid

(A) t-Butyl-7i3- [D- {4-benzyl-2,3-dioxopiper3zin-1-ylcarbon-ylamino) -2-phenyl3cet3mido] -7a-methylthio-3 - [(1,2,3-thi3diazoi -5-yOthiomethynceph-S-em ^ -carboxylic

The 7a-methylthiocephem (from Example 1 (c)) (0.38g) was converted to the title compound (0.32g) by the method of Example 1 (d) using the appropriate acid chloride

¹

NMR (CDCl ₃ ) α = 1.47 (s, 9H), 2.25 (s, 3H), 3.38-3.6 (m, 4H), 3.8-4.4 (m, 4H) , 4.7 (s, 2H), 4.96 (s, 1H), 5.45 (d, J = 6.1 H), 7.29-7.50 (m, 1OH), 8.51 (s, 1H), 9.93 (d, J = 6.1H). -

S-yOthiomethynceph-S-em ^ carboxylate

t-Butyl-7 / 3- [D- (4-benzyl-2,3-dioxopiperazin-1-ylcarbonyl-amino) -2-phenylacetamido] -7a-methylthio-3 - [(1,2,3-thiadiazol 5-yl) thiomethyl] ceph-3-em4-carboxylate (0.32g) was converted to the title compound (0.21g) by the method of Example 1 (e). ·

¹ ~

NMR (CDCl ₃ ) CT = 1.42 (s, 9H), 2.85 and 2.95 (ABq, J = T3.2H), 3.42 (m, 2H), 3.8-4.3 (m, 4H), 4.65 and 4.73 (ABq, 2H, J = 14), 5.27 (s, 1H), 5.6 (d, J = 6, 1H), 7.29-7 , 6 (m, 1 OH), 8.49 (s, 1H), 8.72 (s, 1H), 10.1 (d, J = 6.1 H).

(C) 7 / 3- [P- (4-Benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3 - [(1,2,3-tiiiadiazol-5-r yOthiomethyllceph-S-em ^ -carboxylic

t-Butyl-7j8- [D- (4-benzyl-2,3-dioxopiperazin-1-ylcarbonyl-amino) -2rphenylacetamido] -7a-hydroxyamino-3 - [(1,2,3-thiadiazol-5-yl) thiomethyl] ceph-3-em4-carboxylate (0.21g) was treated with trifluoroacetic acid in the manner of Example 1 (f) to give the title compound (0.13g). '. ,

NMR (DMSO d ₆ / D ₂ O) d " = 3.2 and 3.5 (ABq, J = 13, 2H), 3.5 (s, 2H), 3.85 (br.s, 2H), 4.12 and 4.25 (ABq, 2H, J = 12), 4.55 (s, 2H), 5.07 (s, 1H), 5.7 (d, J = 6.1 H), 7.2-7.5 (m, 1 OH), 8.85 (s, 1H) 9.55 (s, 1H), 9.9 (d, J = 6.1H).

example

7ß- [DL-2- {4-methyl-2,3-dioxopiperazin-1-ylcarbonylamino] -2-phenylacetamido] -7a-hydroxyamino-3 - [(1,2,3-thiadiazol-5-yl) thiomethyl ] ceph-3-em-4-carboxylic acid

(A) t-Butyl-7 / 3- [DL-2- {4-methyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthio-3 - [(1,2,3 thiadiazol-5-yl) thiomethyl] ceph-3-em-carboxylate

t-butyl ^ / S-amino-α-methylthio-S-id ^^ thiadiazol-S-yD-thiomethyl-ceph-S-em ^ -carboxylate and D-2- [4-methyl-2,3-dioxopiperazine] 1-ylcarbonylamino] -2-phenylacetyl chloride (Australian Patent AU 518792: Oct. 22, 1981) were reacted together by the method of Example 1 (d); to make the title connection. IR (CH ₂ Cl ₂ ) WSOCm " ¹ .

NMR (CDCl ₃ ) CT = 1.46 (s, 9H) 2.02 and 2.24 (2xs, 3H, DL), 3.12 (s, 3H), 3.3- »3.7 (m , 4H), 4.0-4.3 (m, 4H), 4.85 and 4.87 (2xs, 1H, DL), 5.60 (d, 1H, J = 7.0), 7 , 35- »7.55 (m, 5H), 8.50 and 8.52 (2xs, 1H) 9.96 (d, 1H, J = 7.0).

(b) t -butyl-7jS- [DL-2- (4-methyl-2,3-dioxo-riperazin-1-ylcarbonyl-amino) -2-phenylacetamido] -7a-hydroxyamino-3 - [(1,2 _/ 3 thiadiazol-5-yl) thiomethyl] ceph-3-em-4-carboxylate

Reaction of the 7a-methylthio compound from part (a) with mercury (II) acetate and hydroxylamine hydrochloride by the method of Example 2 (b) gave the title compound

IR (CH ₂ Cl ₂ ) W ^ QCm " ¹ .

NMR (CDCl ₃ ) δ = 1.41 and 1.46 (2x s, 9H), 3.10 and 3.13 (2xs, 3H) 3.2-> 3.7 (m, 4H), 3.8 - ^ 4.2 (m, 4H), 5.23 and 5.27 (2xs, 1H), 5.60 (d, 1H, J = 7.0), 7.3-7.6 (m , 5H), 8.01 (s, 1H), 8.49 and 8.51 (2xs, 1H) 10.05 (d, 1H, J = 7.0).

(C) 7j8- [DL-2- (4-methyl-2,3-dioxopiperazin-1-ylcarbonylamino] -2-phenylacetamido) -7a-hydroxyamino-3 - [(1,2,3-th1adiazol-5-y -thiomethyll-ceph-S-em ^ -carboxylic

Deprotection of the cephem t-butyl ester from part (b) with trifluoroacetic acid by the method of Example 2 (c) gave the title compound.

IR (KBr) 1785cm " ¹ .

NMR (DMSOd ₆ ) O = 2.92 (s, 3H), 3.1-> 3.7 (m, 4H), 3.8 ^ 3.9 (m, 2H), 4.1- »4, 3 (m, 2H), 5.05 and 5.08 (2xs, 1H), 5.67 (m, 1H), 7.2- 7.5 (m, 5H), 8.30 (s, 1R ), 8.84 and 8.82 (2xs, 1H), 9.83 (m, 1H). '

Example 6

7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido / -7a-hydroxyamino-3 - [(1-methyl-1H-tetrazol-5-yl) -thiomethyl] ceph-3-em-4-carboxylic acid, sodium salt (a) 7/3 - [(D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a Metriylthiocephalosporanic acid. Dert-butyl ester (from Example 2 a) (1 g) was dissolved in trifluoroacetic acid (3 ml) After 5 min at room temperature, the trifluoroacetic acid was removed in vacuo TLC monitoring indicated incomplete reaction and the process was repeated Residue, after removal of trifluoroacetic acid, was dissolved in dichloromethane / carbon tetrachloride (1: 1 mixture, 20 ml) and evaporated. Final trituration with diethyl ether (10 ml) afforded the title compound as an off-white solid (825 mg).

IR (KBr) 1780cm " ¹ .

NMR (DMSOd ₆ ) O = 1.1 (t, J = 6.3H), 2.04 (s, 3H), 2.23 (s, 3H), 3.2-3.65 (m, 6H ), 3.8-4.0 (m, 2H), 4.65 and 4.97 (2H, ABq, J = 13), 5.1 (s, 1H) 5.67 (d, J = 7 , 1H), 7.25-7.55 (m, 5H), 9.69 (s, NH), 9.84 (d, J = 7, NH), 13.77 (brs, COOH).

methylthioceph-S-em ^ carboxylic acid

A solution of 7 / HD-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7- '

methylthiocephalosporanic acid (1.2 g) and 5-mercapto-i-methyltetrazole (0.45 g) in 1,2-dichloroethane (75 ml) was refluxed under nitrogen for 3 h. The mixture was cooled to room temperature and the title compound filtered and dried in vacuo (0.32g). ,

IR (KBr) 1780cm- ¹ . , , .

NIVIR (DMSO-D ₆ ) O = 1.10 (t, J = 6.3H) 2.23 (s, 3H), 3.3-3.8 (m, 8H) _/ 3.9 (s, 3H ), 4.18 and 4.40 (2H, ABq, J-13), 5.05 (s, 1H), 5.66 (d, J = 7.1H), 7.3-7.5 (m, 5H), 9.68 (s, NH), 9.83 (d, J = 7, NH). ;., .-- ^{/ V} '

ythiomethyl-ceph-S-erTM-carboxylic acid, sodium salt. '.

The 7a-methylthiocephem from part (b) above (0.29g) in dimethylformamide (20ml) was cooled to -60 ° C and a solution of mercuric acetate (137mg) in dimethylformamide (5ml) was added A suspension of hydroxylamine hydrochloride (30 mg) and triethylamine (120 μ, Ι) in dimethylformamide (5 ml) was added. The mixture was warmed to 20 ^° C. and stirred for 1 h. Ethyl acetate and saturated brine were added and the mixture was acidified to pH 2 with 2N hydrochloric acid and filtered through "Hyflo" (Registered Trade Mark) The organic layer was separated and washed thoroughly with brine, dried (over Na ₂ SO ₄ ) and in vacuo The residue was suspended in water and neutralized with aqueous sodium bicarbonate (pH 7.5), then lyophilized to give the title compound (56mg).

IR (KBr) 1765cm " ¹

NMR (D ₂ O) O = 1.21 (t, J = 7, 3H), 3.5-3.8 (m, 6H), 3.9-4.3 (m, 4H), 4.00 (s, 3H), 5.10 (s, 1H) 5.53 (s, 1H), 7.4-7.6 (m, 5H). ^r

Example 7

em-4-carboxylate.

(a) 7β- [D-2- {4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthio-3- (pyridinethymethyl) -ceph-3-em-4-carboxylate

7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthiocephalosporanic acid (Example 6a) (1.86 g) was dissolved in water (10 ml), containing sodium bicarbonate (250 mg), then potassium iodide (7.4 g) and pyridine (750 μ l) were added. The solution was heated to 70 ^° C. for 90 minutes, then cooled and concentrated in vacuo to 5 ml. This was diluted with acetone (50ml) and chromatographed on silica (75g) eluting with acetone / water (3: 1) to afford the crude title compound (1.2g). This material was dissolved in water (5 mL), filtered through "Hyflo" and lyophilized to afford the title compound (650 mg).

IR (KBr) 1780cm " ^1. '^'

NMR (DMSOd ₆ ) O = 1.08 (t, J = 7.5, 3H) 2.27 (s, 3H), 2.85 and 3.00 (Abq, J = 17, 2H, C (2) -CH ₂ ), 3,4 (q, J = 7,5, 2H), 3,5-4,0 (m, 4H), 4,95 (s, H), 5,13 and 5,56 (ABq, J = 12.5.2H), 5.65 (d, J = 8.5.1H), 7.2-7.5 (m _; 5H), 8.1-9.45 (m , 5H), 9.6 (s, NH), 9.8 (d, J = 8.5,

NH). · "'

(b) 7/3 [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonyl) -2-phenylacetamido] -7a-hydroxyamino-3- (pyridiniummethyl) -ceph-3-em-4- carboxylate

The product of Example 7a (640 mg) was dissolved in dry dimethylformamide (6ml) and cooled under nitrogen to ⁰ -5o C. A solution of mercuric (II) acetate (350 mg) in dimethylformamide (2 ml) was added, followed by a

Slurry of hydroxylamine hydrochloride (77mg) and triethylamine (153μ.Ι) * ίη dimethylformamide (1ml). The reaction was stirred for 30 min at -50 ⁰ C and stirred for 30 min at -20 ⁰ C, then treated with acetone (50 ml) and chromatographed on silica. Elution with acetone / water (3: 1) provided the crude product. After evaporation of the solvents, the product was redissolved in water (5 ml), filtered through "hyflo" and lyophilized to give the title compound (300 mg).

IR (KBr) 1780cm " ¹ .

NMR (DMSO d ₆ ) δ = 1.13 (t, 7.5.3H), 2.84 and 2.96 (ABq, J = 16, C- (2) -CH ₂ ), 3.3-4 , 0 (m, 6H), 5.0 (s, 1H, C (6) -H), 5.1 and 5.6 (ABq, J = 13.5z, 2H), 5.7 (d, J. = 8.5.1H, O-CH.-NH), 6.35 (s, 1H, exchange), 7.2-7.6 (m, 5H), 8.1-9.4 (m, 6H, pyridine + 1H, exchange), 9.55 (s, NH), 9.9 (d, J = 8.5, NH).

Examples'

3- (2,3-Cyclopentenopyridiniummethyl) 7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7ahydroxyaminoceph-3-em-4-carboxylate

(a) 3- (2,3-Cyclopentenopyridiniummethyl) -7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7amethylthio-ceph-3-em -4-carboxylate

The above compound was prepared from the product of 6 (a) by the method described in Example 7a using 2,3-cyclopentenopyridine instead of pyridine.

IR (KBr) 1775cm " ¹ .

NMR (DMSO-D ₆ ) O = 1.1 It, J = 7.1.3H), 2.28 (s, 3H), 2.8-4.0 (m, 14H), 4.92 (s , 1 H, C (6) -H), 5.25 and 5.36 (ABq, J = 14.4.2H), 5.66 (d, J = 7.2.1 H 0 -CH-NH), 7.1-7.7 (m, 5H, 7.8-9.2 (m, 3H), 9.67 (s, NH), 9.82 (d, J = 7.2, NH).

(b) 3- (2,3-Cyclopentenopyridiniummethyl) -7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7ahydroxyaminoceph-S-em ^ - carboxylate

The product from Example 8 (a) (140 mg) was dissolved in dry dimethylformamide (5ml) and cooled under nitrogen to-50 ⁰ C. A solution of mercury (II) acetate (72 mg) in dimethylformamide (0.5 ml) was added, followed by a slurry of hydroxylamine hydrochloride (14 mg) and triethylamine (29 μ, Ι) in dimethylformamide (1 ml). The reaction

was stirred for 30 min at -20 ° C, then diluted with diethyl ether (100 ml) and the crude product was filtered and washed with diethyl ether (50 ml). The product was slurried in water (25 ml) and sulfuric acid bubbled through the suspension for 10 minutes. The slurry was filtered and the filtrate was freeze-dried to give the title compound (95mg). IR (KBr) 1770cm " ¹ .

NMR (DMSO-D ₆ ) δ = 1.1 (t, J = 7.1, 3H), 3.1-4.0 (brm, 14H), 4.9 (s, 1H, C (6) -H), 5.1-5.4 (brm, 2H), 5.7 (d, J = 7.2.1H, O-CH-NH), 6.4 (s, TH, Exchange, 7 , 2-7.6 (m, 5H), 8.15 (s, 1H, exchange), 7.9, 8.35 and 9.15 (m, 3H, pyridine), 9.5-9.6 (brs, NH), 9.88 (d, J = 7.2, NH).

Example 9

3 - [(1-Carboxymethyl-1H-tetrazol-5-yl) thiomethyl] -7jS- [D-2- (4-ethyl-2- _r 3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetaminol-Ta-hydroxyaminocephite] S-em ^ -carboxylic

(a) 3 - [(1-carboxymethyl-1H-tetrazol-5-yl) thiomethyl] -7 _J ß [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido ] -7α-methylthioceph-3-em-4-carboxylic acid

7 / 3- [D-2- (4-Ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthiocephalosporanic acid (Example 6 (a)) (1.3g) was dissolved in water (20 ml) containing sodium bicarbonate (565 mg), then 1-carboxymethyl-iH-tetrazole-5-thiol (403 mg) was added. The solution was stirred for 0.5 h 6 h at 65 ⁰ C is heated under a nitrogen atmosphere, then cooled and diluted with decolorizing charcoal (0.5 g). After filtration, the solution was cooled to 5 ⁰ C and acidified to pH 2 with concentrated hydrochloric acid. The precipitated solid was filtered, washed with water (10 ml) and dried under vacuum to give the title compound (1.05 g).

IR (KBr) 1775cm " ^1. - '·,

NMR (DMSO-D ₆ ) O = 1.09 (t, J = 7.3H), 2.22 (s, 3H), 3.25-3.70 (m, 6H), 3.87-3, 95 (m, 2H), 4,14 and 4,52 (ABq, J = 13,2H), 5,01 (s, 1H), 5,26 and 5,35 (ABq, J = 18, 2H), 5.65 (d, J = 7.1 H), 7.28-7.50 (m, 5H), 9.69 (s, NH), 9.82 (d, J = 7, NH).

J = 7, NH).

(b) 3 - [(1-carboxymethyl-1H-tetrazol-5-yl) thiomethyl] -7 _J ß [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonyIamino) -2-phenylacetamidol ^ a-hydroxyaminoceph S ERRm-carboxylic acid

Das7a-Methylthiocephem (9 (from Example a)) (144mg) in dimethylformamide (3ml) was cooled to 6O ⁰ C and treated sequentially with solutions of mercury (II) acetate (127 mg) in dimethylformamide (1 ml), hydroxylamine hydrochloride (15.3 mg) in dimethylformamide (1 ml) and triethylamine (31 μλ) . The resulting clear solution was warmed to ⁰ C over 1 h and slowly added to diethyl ether (100 mL) with stirring. After filtration, the ether-wet solid was suspended in methanol (15 ml) and saturated with hydrogen sulfide. The mixture was filtered and evaporated under vacuum. The residue was triturated with methylene chloride (10ml) to give the title compound as a white solid (98mg). IR (KBr) 1775cm " ¹ · · -

NMR (DMSO-D ₆ ) O = 1.09 (t, J = 7, 3H), 3.05-3.82 (m, 6H), 3.85-4.00 (m, 2H), 4, 12 and 4.46 (ABq, J = 13, 2H), 4.98 (s, 1H), 5.22-5.28 (m, 2H) 5.69 (d, J = 7.1H) , 6.51 (brs, 1H), 7.22-7.54 (m, 5H), 8.17 (s, 1H), 9.55 (s, NH), 9.87 (d, J = 7, NH).

Examples 10 to 13

The following compounds of formula (I) were prepared from the appropriate starting materials by the methods described in Example 9, parts (a) and (b).

Example and stereochemistry of the side chain R - R ¹ -CH ₂ -S- R ² C = O I 10 CH ₃ CH (OH) - -CH ₂ -S- Cr * \ 2R, 3S-! N 0 1 Et -CH ₃ S - 11 2R, 3S- CH ₃ CH (OH) - 1 9 = O CX CO ₂ H I et 12 2R, 3S- CH ₃ CH (OH) - 1 CT -CH ₂ -S- ^, Me N ^ T. // \\ \ _s / CH ₂ CO ₂ ^ et 13 Ph I Il \ .D- (L _C0H et

Example and stereo IR (KBr) chemistry of the side, cm " ¹ chain

NMR (DMSO-d ₆ )

1775

1775

1780

1780

5 = 1.1-122 (m, 6H), 3.2-3.6 (m, 6H), 3.9 (m, 2H), 4.15 and 4.5 (ABq, 2H, J = 15);

4.36 (m, 2H); 5.02 (d, 1H, J = 4); 5.08 (s, 1H); 6.38 (s, 1H); 7.75 (d, 1H, J = 10); 7.93 (s, 1H);

8.1 (s, 1H); '

8.56 (d, 1H, J = 10); 8.89 (s, 1H); 9.28 (d, 1H, J = 7).

δ = 1.05-1.1 (m, 6H); 3.18-3.7 (m, 6H); 3.9 (m, 2H); 4.1 and 4.52 (ABq, 2H, J = 14); 4.34 '

(m, 2H); 5.02 (broad, 1H); 5.09 (s, 1H); 6.4 (broad, 1H); 7.93 (s, 1H); 8.1 (s, 1H);

(s, 1H); 9.27 (d, 1H, J = 7).

δ = 1.05-1.12 (m, 6H); 2.22 (s, 3H); 3.2-3.78 (m, 8H); 3.9 (m, 2H); 4.02 and 4.41 (ABq,

2H, J = 14), 5.02 (broad, 1H), 5.06 (s, 1H), 7.93 (s, 1H), 8.1 (s, 1H); 8.89 (s, 1H); 9.28 (d,

1H, J = 7).

δ = 1.07 (t, J = 7.3 H); 2.19 (s, 3H); 3.06-3.52 (m, 6H); 3.72 (s, 2H); (m, 2H);

3.95 and 4.41 (ABq, J = 13.2 H); 4.97 (s, 1H); 5.65 (d, J = 7, CHNH);

6.46 (brs., 1 H); 7.28-7.44 (m, 5H); 8.13 (s, 1H); 9.52 (s, 1H); 9.85 (d, J = 7, NH).

Example 14

3- [2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl) thiomethyl] -7 / 3- [D-2- (4-ethyl- 2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyaminoceph-3-em-4-carboxylic acid

(a) 3 - [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl) thiomethyl] -7 / 3- [D-2- { 4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthioceph-3-em-4-carboxylic acid 7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazine 1-ylcarbydylamino) -2-phenylacetamidol-7a-methylthiocephalosporanic acid (Example 6 (a)) (619 mg) in water (20 ml) containing sodium bicarbonate (185 mg), then became 2.5-dihydro-e-hydroxy-methyl -ö-oxo-1,2,4-triazine-3-thiol (191 mg). The solution was heated 5 h under a nitrogen atmosphere at 65 ⁰ C, basified with the addition of 5% aqueous sodium bicarbonate solution as needed to maintain the pH at 6.0-6.5. After cooling to 5 ° C, concentrated hydrochloric acid was added to pH 2 and the mixture was filtered. Wash with water (2 mL), followed by drying

under vacuum gave the title compound (531 mg). ^;

IR (KBr) 1775cm " ¹ .

NMR (DMSO-D ₆ ) O = 1.09 (t, J = 7.3H), 2.24 (s, 3H), 3.20-3.75 (m, 6H), 3.59 (s , 3H), 3.85-3.97 (m, 2H), 4.06 and 4.35 (ABq, J = 13, Ih, 5.05 (s, 1H), 5.65 (d, J = 7.1H), 7.22-7.56 (m, 5H), 9.67 {s, NH), 9.82 (d, J = 7, NH).

(b) 3- [2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl) -thiomethyl] -7i3- [D-2- (4-ethyl -2,3-dioxo-piperazine-1-ylcarbonylaminol ^ ^ -phenylacetamido a-hydroxyamino-ceph-S-em ^ -carboxylic

was prepared from 7a-methylthiocephem of part (a) using the method of Example 9 (b).

IR (KBr) 1775cm- ¹ . '·

NMR (DMSO-D ₆ ) O = 1.09 (t, J = 7.3H), 3.05-3.75 (m, 6H), 3.59 (s, 3H), 3.83-3, 97 (m, 2H), 4.03 and 4.33 (ABq, J = 13.2H), 5.03 (s, 1H), 5.69 (d, J = 7.1H), 6.52 ( br, 1H), 7.20-7.56 (m, 8.18 (s, 1H), 9.55 (s, NH), 9.87 (d, J = 7, NH).

Example 15

'3 - [(5,6-dioxo-4-methyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) thiomethyl] -7j6- [D-2- (4- ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyaminoceph-3-em-4-carboxylic acid

(a) 3 - [{5,6-dioxo-4-methyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thiomethyl] -7β- [D-2- ( 4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthioceph-3-em-4-carboxylic acid 7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazine 1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthiocephalosporanic acid (Example 6 (a)) (619 mg) was 5,6-dioxo-4-methyl-1,4,5,6-tetrahydro-1,2,4- triazine-3-thiol (191 mg) similar to that described in Example 14 (a) to give the title compound (470 mg).

IR (KBr) 1.775cm " ¹ .

NMR (DMSO d ₆ ) δ = 1.09 (t, J = 7, 3H), 2.23 (s, 3H), 3.27 (s, 3H), 3.29 (m, 6H), 3, 91 (m, 2H), 3.97 and 4.16 (ABq, J = 13, 2H), 5.06 (s, 1H), 5.65 (d, J = 7.1 H), 7, 35-7.48 (m, 5H), 9.69 (s, 1H), 9.83 (d, J = 7.1H), 12.45 (s, 1H).

(b) 3 - [(5,6-dioxo-4-methyl-1,4,5,6-tetraphydro-1,2,4-triazin-3-yl) -thiomethyl] -7j3- [D-2- ( 4-ethyl-2,3-dioxo-piperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyaminoceph-3-ene-4-carboxylic acid The title compound (330 mg) was prepared from the 7a-methylthiocephem of the above part (a ) (420 mg) according to the method of Example 9 (b).

IR (KBr) 1780cm " ¹ .

NMR (DMSOd ₆ ) O = 1.09 (t, J = 7.3H), 3.26 (s, 3H), 3.24-3.57 (m, 6H), 3.89 (m , 2H), 3.94 and 4.13 (ABq, J = 13.2H), 5.03 (s, 1H), 5.70 (d, J = 7.1H), 7.28 -7.47 (m, 5H), 9.56 (s, 1H), 9.87 (d, J = 7.1H), 12.43 (s, 1H).

Example 16

7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3 - [(1- (2-hydroxyethyl) -1H-tetrazol- 5-yl) thiomethyl] ceph-3-em-4-carboxylic acid

(a) 7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -3- (1- (2-hydroxyethyl) -1H-tetrazole-5 yl) -thiomethyll ^ a-methylthioceph-S-em ^ -carboxylic

7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthiocephalosporanic acid (Example 6 (a)) (1.18 g) was added 1- (2-hydroxyethyl) -1H-tetrazole-5-thiol (835 mg) similarly treated again in Example 6 (b) to give the title compound (810 mg).

IR (KBr) 1780cm- ¹

NMR (DMSO-D ₆ ) δ = 1.09 (t, J = 7.5, 3H), 2.22 (s, 3H), 3.31-3.65 (m, 6H), 3.75 ( t, J = 5, 2H), 3.91 (m, 2H), 4.16 and 4.42 (ABq, J = 13.2H), 4.32 (t, J = 5, 2H), 5, 01 (s, 1, H), 5.65 (d, J = 7, 1H), 7.28-7.47 (m, 5H), 9.68 (s, 1H), 9.83 ( d, J = 7, 1H).

(b) 7β- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3 - [{1- (2-hydroxyethyl) -1H-tetrazole -5-yl) thiomethyl] ceph-3-em-4-carboxylic acid

The title compound (160mg) was prepared from the 7a-methylthiocephem (from Example 16 (a) above) (200mg) by treatment with mercury (II) acetate and hydroxylamine hydrochloride as described in Example 9 (b).

IR (KBr) 1775 cm " ¹ .

NMR (DMSO-D ₆ ) δ = 1.09 (t, J = 7, 3H), 3.24-3.62 (m, 6H), 3.74 (t, J = 5, 2H), 3, 89 (m, 2H), 4,13 and 4,42 (ABq, J = 13,2H), 4,33 (t, J = 5,2H), 5,00 (s, 1H), 5,70 ( d, J = 7.1 H), 7.25-7.49 (m, 5H), 8.19 (wides, IH), 9.57 (s, 1 H), 9.89 (d, J = 7,1H), 10,27 (broad

Examples 17 to 35

The following compounds of formula (I) were prepared from the appropriate starting materials using the methods of Example 16, parts (a) and (b). In part (a) was generally reflux for 14 to 16h (CBZ = benzyloxycarbonyl).

Example and stereochemistry of the side chain

17 2R, - 3S-

CH ₃ CH (OH) -

-C-N N-Et

N ^N i

me

18 2R, 3S-

CH ₃ CH (OH) -

-C-N N-Et 0 0

-CK ₀ -S '2

¹ O

me

DL

CBZ-O- /

-C-N N-Et

N '

me

D-

Ph-Ν-Ν

-C-N N-Et

, If

21 DL

Μ-Ν

-C-N N-Et

O O

D-

Ph

-C-O

23, 2R, 3S-

CH ₃ CH (OH) -

-C-N N-E!

ö cK

N "

24 D

Ph

-C-N N-n-octyl

 r \

Example and stereochemistry of the side chain

25 D

26 D

Ph

-C-

-et

Ph

-C-N Ν-Ώ-octyl

it \ /

⁰ O -CH ₂ -S 4,

me

27 2R, 3S-

CH ₃ CH (OH) -

-C-

ι *

-Et CH-S

CH ₉ H ₉ CO

28 2R ₁ 3S-

CH ₃ CH (OH) -

-C-N N-n-octyl

SX ~

O-CH ₂ -S

μ N

J I!

me

29 2R, 3S-

CH ₃ CH (OH) -

-C-N N-n-butyl

30 D

Ph

-C-N N-Et .. \ /

O 'S ^ O OEt)

31 2R, 3S-

CH ₁₃ CH (OH) - _ _C _ _N ^ -n-butyl

-CH-S

me

Example and stereochemistry of the side chain

32

2R, 3S-

CH CH (OH) -

-C-N N-n-butyl

Ν-Ν

-CH ₂ -S

LOH

33 2R, 3S-

CH ₃ CH (OH) -

C-N N-n-butyl) 4

CH ₂ -S

34 2R, 3S-

CH ₃ CH (OH) -

-C-N N-EtO 0

 CH, -SJ

35 2R, 3S-

CH ₃ CH (OH) -

-C-N N-I-Bu ty I

^: 0

me

Example and stereochemistry of the side chain IR (KBr) cm ' ¹ 172R, 3S 1777 182R, 3S 1 775 19 DL 1775 20 D 1778 21 DL 1780

NMR (DMSO-d ₆ )

δ = 1.1 (m, 6H); 3.32-3.76 (m, 6H); 3.91 (s, 3H); 3.97 (m, 2H); 4.15 and 4.35 (ABq, 2 H,

J = 12); 4.31 (m, 2H); 5-05 (s, 1H); 8.88 (s, 1H); 9.27 (d, 1 H, J = 6).

δ = 1.08 (m, 6HJ ;, 3.27 (s, 3H); 3.29-4.14 (m, 1HH); 4.36 (m, 2H); 5.09 (s, 1H); 8.91 (s,

1H); 9.28 (d, 1H, J = 9).

δ = 1.07 (t, J = 7.3 H); 3.24 and 3.26 (2 x s, 3 H); 3.20-3.67 (m, 6H); 3.82-4.13 (m, 4H);

5.00 and 5.06 (2 xs, C ₆ -H); 5.23 and 5.24 (2 χ s, 2 H); 5.70 (d, J = 7, CHNH);

7.18-7.50 (m, 9H); 8.12 (brs., 1 H); 9.50 and 9.56 (2Xs, 1H); 9.83 and 9.86 (2xd, J =), NH).

δ = 1.15 (t, 3H, J = 6); 2.95 (t, 2H, J = 6); 3.00-3.95 (m, 10H); 4.10 and 4.48 (ABq, 2 H,

J = 15); 5.01 (s, 1H); 5.68 (d, 1H, J = 6); 7.10-7.50 (m, 5H); 9.52 (s, 1H); 9.83 (d, 1H, J = 6).

δ = 1.08 (t, 3H, J = 6); 3.25-4.05 (m, 10H); 4:10 to 4:44 (m, 4H); 5.01 and 5.03 (2 x s, 1 H, D

and L-forms); 5.97 (m, 1H); 6.90-7.55 (m, 3H); 9.67 and 9.69 (2 x s, 1 H, D and L NH);

9.79 (m, 1H). , -

δ = 1.05 (t, J = 3 Hz, 3 H); 3.1-3.65 (m, 6H); 3.85 (m, 2H); 4.12 and 4.73 (ABq., J = 12 Hz,

2H); 4.98 (s, 1H); 5.65 (d, J = 6 Hz, 1H); 6.48 (s, 1H);

7.24-7.45 (m,.

8 H); 7.85 (d, J = 12 Hz, 1H); 7.99 (d, J = 12 Hz, 1H); 8.13 (s, 1H); 9.53 (s, 1H); 9.84 (d,

J = 6Hz, 1H).

δ = 1.05-1.15 (m, 6H); 3.35-4 (m, 10H); 4.1-4.4 (m, 6H); 5.05 (s, 1H); 8.9 (s, 1H); 9.25 (d,

1H, J = 7).

δ = 0.85 (t, J = 7.3 H); 1.24 (s, 1 OH); 1.48 (br. 2 H); 3.25 and 3.57 (ABq, J = 18.2 H); 3:33

-3.38 (m, 2H); 3.53 (m, 2H); 3.72 (m, 2H); 3.86 (m, 2H); 4.18 and 4.41 (ABq, J = 12.2 H);

4.32 (m, 2H); 4.97 (s, 1H); 5.08 (brs., 1h); 5.68 (d, J = 8, CHNH); 6.50 (brs., 1 H); 7:29 to 7:45

(m, 5H); 8.18 (s, 1H); 9.42 (brs, 1H, 9.54 (s, 1H); 9.86 (d, J = 8, NH).

δ = 1.06 (t, J = 6Hz, 3H); 3.53 (m, 2H); 3.25-3.45 (m, 4H); 3.88 (m, 2H); 4.13 and 5.62

(ABq, J = 12 Hz, 2H); 5.00 (s, 1H); 5.66 (d, J = 6 Hz, 1H); 6.50 (Aust); 7.24-7.63 (m, 10H);

8.15 (Aust.); 9.54 (Aust); 9.86 (d, J = 6 Hz, 1 H).

δ = 0.83 (t, J = 6.3H); 1.22 (s, 10H); 1.46 (s, 2H); 3.23 (s, 3H); 3.25-3.58 (m, 6H); 3.86 (m,

2H); 3.90 and 4.08 (ABq, J = 12.2 H); 4.99 (s, 1H); 5.66 (d, J = 8, CHNH); 5.64 (brs., 1h);

6.48 (s, 1H); 7.25-7.44 (m, 5H); 8.16 (s, 1H); 9.54 (s, 1H); 9.78 (brs., 1 H); 9.85 (d, J = 8,

N).

δ = 1.06 (m, 6H); 3.20-3.61 (m, 6H); 3.91 (m, 2H); 4.15 and 4.38 (ABq, 2H, J = 15); 4:36

(m, 2H); 4.93 (s, 1H); 5.26 (s, 2H); 8.09 (s, 1H); 8.89 (s, 1H); 9.26 (d, 1 H, J = 6).

δ = 0.83 (t, J = 6.3H), 1.06 (d, J = 6.3H), 1.23 (m, 10H), 1.47 (m, 2H), 3.0-4.0 (m, 8H and

s, 3H (δ = 3.9); 4.10-4.40 (m, 3H); 5.02 (m, 2H); '6.40 (s, NH); 8.10 (s, NH-OH); 8.88 (s, NH);

9.30 (d, J = 6, NH).

δ = 0.86 (t, 3H, J = 7.5); 1.07 (d, 3H, J = 6); 1.25 (m, 2H); 1.47 (m, 2H); 3.23-3.77 (m, 8H);

3.89 (m, 2H), 4.03 (m, 2H), 4.14 and 4.36 (ABq, 2H, J = 12); 4.22 (t, 2H, J = 6); 5.04 (s, 1H);

6.41 (broad, s, 1 H); 8.10 (s, 1H); 8.89 (s, 1H); 9.27 (d, 1 H, J = 6).

δ = 1.04 (t, J = 6Hz, 3H); 1.32 (t, J = 6 Hz, 3 H); 3.35 (ABq, J = 4 Hz, 2 H); 3.52 (br, 2H);

[wide. HOD Peak hood. Protons between 3.9-4.8]; 4.98 (s, 1H); 5.64 (d, J = 6 Hz, 1 H);

7.03-7.73 (m, 9H); 9.53 (s, 1H); 9.84 (d, J = 6 Hz, 1 H).

δ = 0.86 (t, 3H, J = 7.5); 1.07 (d, 3H, J = 6); 1.25 (m, 2H); 1.47 (m, 2H); 3.32-4.10 (m, 8H);

3.91 (s, 3H); 4.14 and 4.34 (ABq, 2H, J = 12); 4.33 (m, 2H); 5.05 (s, 1H); 8.89 (s, 1 H); 9.27

(d, 2H, J = 6).

δ = 0.86 (t, 3H, J = 7.5); 1.07 (d, 3H, J = 6); 1.24 (m, 2H); 1-47 (rTi, 2H); 3.13 (t, 2 H, J = 4.5);

3.34-3.74 (m, 6H); 3.89 (m, 2H); 4:03 (m, 2H); 4.16 and 4.48 (ABq, 2H, J = 15); 4:34

(m, 2H); 5.01 (d, 1 H, J = 3); 5.07 (s, 1H); 6.41 (broad, s, 1 H); 8.10 (s, 1H); 8.89 (s, 1H);

9.27 (d, 1H, J = 6).

δ = 1.11 (m, 6H); 2.80-4.10 (m, 12H); 4.15 and 4.45 (ABq, 2H, J = 15); 4.31 (m, 2H);

5.05 (s, 1H); 8.88 (s, 1H); 9.31 (d, 1 H, J = 6).

δ = 0.87 (t, 3H, J = 6), 1.08 (d, 3H, J = 6), 1.25 (m, 2H), 1.46, (m, 2H), 3.26 (s, 3H);

3.33-3.72 (m, 6H); 3.90-4.13 (m, 4H); 4.35 (m, 2H); 5.03 (m, 1H); 5.07 (s, 1H); 8.12 (s, 1H);

8.90 (s, 1H); 9.27 (d, 1H, J = 9).

2 R, 3 S-322R, 3S-

1780

1775 1780

1780 1780

27 2 R, 3S 777 28 2 R, 3S 1775 29 2 R, 3 ε- 1778

1780 1778 1777

1780 1778

Example 36

yjs-tD ^ -f ^ ethyl ^ .S-dtoxopiperazin-i ^ ylcarbonylaminoJ -phenylacetamidol-Ta-hydroxyamino-S-KI-kaliumsulfomethyl-IH-tetrazol-S-S-yOthiomethyllceph-em ^ carboxylic acid

[Potassium sulfomethyl = -CH ₂ SÖ ₂ O ^e K®]

(a) 7β- [D-2- (4-ethyl-2,3-dioxopipeΓazin-1-ylcarbonylamino) -2-phenylacetamido] -7α-methylthio-3 - [(1-potassium sulfomethyl-1H-tetrazole-S-y-thiomethynecph -S-em ^ -carborisäure

Tetrabutylammonium hydrogensulfate (1.65g) was added to a suspension of i-sulfomethyltetrazole-5-thiol-sodium salt (1.05g) in 1,2-dichloroethane (30ml) at room temperature and the mixture stirred for 15min. Filtration gave a clear, colorless solution of i-sulfomethyltetrazole-5-thiol-tetrabutyl-ammonium salt, which was added to a suspension of 7/3 [D-2- (4-ethyl-2, S-dioxopiperazin-i-ylcarbonylamino] -. phenylacetamido-α-methylthiocephalosporanic acid (Example 6 (a)) (1.0g) in 1,2-dichloroethane (200ml) and the mixture was heated to reflux temperature The resulting clear solution was stirred at reflux for 17h, cooled, filtered The residual oil was taken up in acetone (100 ml) and a solution of potassium nonafluorobutanesulphonate (1.64 g) in acetone (20 ml) was added and the resulting slurry was stirred for 15 minutes The acetone was decanted, the solid was washed with Acetone (3 × 50 ml) and dried under vacuum to give the title compound (1.04 g)

IR (KBr) 1776cm " ¹ .

NMR (DMSO-D ₆ ) δ = 1.09 (t, J = 7, 3H), 2.22 (s, 3H), 3.36 ^ -3.64 (m, 6H), 3.92 (m , 2H), 4,05 and 4,47 (ABq, J = 13, 2H), 4,94-5,10 (m, 3H), 5,65 (d, J = 7, 2H), 7, 31-7.47 (m, 5H), 9.68 (s, 1H), 9.82 (d, J = 7.1H).

(b) 7/3 - [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3 - [(1-potassium-sulfomethyl-1H-tetrazole] S-ylthiomethyl lceph-S-em ^ carboxylate, triethylammonium salt The title compound (124 mg) was prepared from the 7a-methylthiocephem (from Example 36 (a)) (200 mg) by the method described in Example 9 (b) except that two equivalents each Hydroxylamine hydrochloride and triethylamine were used.

IR (KBr) 1775cm " ¹ ... ·· '

NMR (DMSO-D ₆ ) S = 1.09 (t, J = 7.3H), 1.20 (t, J = 7.9H), 3.09 (q, J = 7.6H), 3, 19-3.63 (m, 6H), 3.91 (m, 2H), 4.03 and 4.43 (ABq, J = 13.2 H), 4.97-5.06 (m, 3 H), 5.68 (d, J = 7.1H), 7.29-7.48 (m, 5H), 8.16 (broad, 1H), 9.56 (s, 1H), 9, 88 (d, J = 7.1 H).

Example 37

7 _{L of} O- [2- (R) - (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -3- (S) -methoxybutanamido] -7a-hydroxyamino-3- [1-potassium sulfomethyltetrazol-5-yl ) thiomethyl] ceph-3-em-4-carboxylic acid

(a) 7β- [2- (R) - (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -3- (S) -methoxybutanamido] -3- (1-potassium-sulfomethyl-tetrazol-5-yl) -thiomethyl ) -7a-methylthioceph-3-em-4-carboxylic acid

7j8- [2- (R) - (4-Ethyl-2,3-di-quinopiperazine-1-ylcarbonylamino) -3- (S) -methoxybutanamido] -7a-methylthiocephalosporanic acid was added to the title compound using the method of Example 36 (a ) converted using appropriate Ausgangsmateriaiien.

IR 1780cm " ¹ ... -

NMR300MHz (DMSO) 5 = 1.05-1.17 (m, 6H), 2.24 (s, 3H), 3.1-3.92 (m, 9H), 3.25 (s, 3H), 4.08 and 4.43 (ABq, 2H, J = 7 Hz), 4.4-4.5.

(m, 3H), 9.23 (d, 1H, J = 6Hz), 9.27 (s, 1H).

(b) 7 / 3- [2- (R) - (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -3- (S) -methoxybutanamido] -7a-hydroxyamino-3 - [(1-potassium sulfomethyltetrazole -B-yll-thiomethyllceph-S-em ^ -carboxylic

The 7a-methylthiocephalosporin of part (a) was converted to the title compound using the method of Example 9 (b)

transformed. '

IR 1780cm " ¹ .

NMR 300 MHz (DMSO), δ = 1-1.1 (m, 6H), 3-3.95 (m, 9H), 3.24 (s, 3H), 4.06 and 4.38 (ABq, 2H, J = 8Hz), 4.42-4.5 (m, 1H), 4.9-5.04 (m, 3H), 9.02 (s, H), 9.24 (d, 1H, J = 6Hz).

Example 38

 7 / 3- [D-2-ureido-2-phenylacetamido] -7a-hydroxyaminocephalosporansäure

(a) Benzhydryl-7 / 3- [D-2-ureido-2-phenylacetamido] -7a-methylthiocephalosporanate

D-2-amino-4-phenyl-5 (4H) -oxazolone hydrochloride was prepared from D-phenyl glycine using the general procedure described by Breuter et al. in J. Antibiotics, 31 (6), 546, (1978)

IR (Nujol) 1870, 1720 br. cm " ¹ .

The oxazolone hydrochloride (2,12g) was added (to a (-60 ⁰ C) cold solution of benzhydryl-7/3-amino-7amethylthiocephalosporanat (1.94 g) and propylene oxide (3.5 ml) in dichloromethane (20ml) and dimethylformamide 20ml). After stirring at this temperature for 3 h, the suspension was heated to -20 ° C. over 0.5 h, giving a clear solution. Ethyl acetate (100 ml) and water (100 ml) were added, the aqueous layer separated and back-extracted with ethyl acetate (50 ml). The combined organic extracts were washed with 5% aqueous sodium bicarbonate (50 ml), 0.01M hydrochloric acid (50 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo gave a yellow oil, which was purified by silica gel chromatography (dichloromethane / ethyl acetate gradient) to give the title compound as a white solid after trituration with dichloromethane (25ml) (1.08g).

IR (KBr) 1780cm " ¹ .

(b) Benzhydryl-7 / 3- [D-2-ureido-2-phenylacetamido] -7a-hydroxyaminocephalosporanate

The 7α-methylthiocephem (from Example 38 (a)) (330mg) in dimethylformamide (5ml) was cooled to -55 ° C and treated with a solution of mercuric acetate (159mg) in dimethylformamide (1ml) followed by hydroxylamine. Hydrochloride (38 mg) in dimethylforamide (1 ml). The solution was warmed to 0 ^° C. with stirring after 1 h, then added to ethyl acetate (50 ml) and water (25 ml). The organic phase was washed with water (2 × 25 ml), dried and evaporated under vacuum. The resulting crude product was purified by silica gel chromatography (dichloromethane / ethyl acetate gradient) to give the title compound (225 mg).

IR (KBr) 1775cm " ¹ .

(c) 7/3 - [D-2-ureido-2-phenylacetamido] -7a-hydroxyamino-cephalosporanic acid The benzhydryl ester (from Example 38 (b)) (220mg) in dichloromethane (5ml) containing anisole (220mg) Pre-cooled to -65 ° C and treated with a solution of aluminum chloride (135 mg) in nitromethane (1 ml). The resulting dark brown suspension was stirred for 10 minutes at this temperature, then added to saturated aqueous sodium bicarbonate (15 ml) and ethyl acetate (25 ml). After filtration, the aqueous layer was separated and acidified to pH 2 with concentrated hydrochloric acid. Extraction with ethyl acetate (3 × 25 ml), followed by drying solvent evaporation and trituration with dichloromethane; gave the title compound as a white solid (52 mg)

IR (KBr) 1770cm " ^1. "

NMR (DIvISO-D ₆ ) O = 2.13 (s, 3H), 3.32 and 3.62 (ABq, J = 17.2H), 4.70 and 4.98 (ABq ₁ J = 13.2H), 5, 17 (s, 1H), 5.64 (d, J = 7.1H), 5.82 (s, NH ₂ J m, 6.61 (s, 1H), 6.91 (d, J = 7 , NH), 7.30-7.63 (m, 5H), 8.27 (s, 1H), 9.48 (s, 1H), 13.78 (br., 1H).

Example 39

7 _/ S- [D-2- {4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3 - [(2-methyl-1,3,4-thiadiazole] 5-yl) thiomethyl] ceph-3-em-4-carboxylic acid

(a) 7j3-fD-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -3 - [(2-methyl-1,3,4-thiadiazol-5-yl) -thiomethyl] -7a-methylthioceph-3-em-4-carboxylic acid '·

A solution of 7/3 - [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonyiamino) -2-phenylacetamido] -7a-methylthiocephalosporanic acid (Example 6 (a)) (0.50 g) and 5 Me, rcapto-2-methyl-1,3,4-thiadiazole (0.20g) in 1,2-dichloroethane (50ml) was refluxed 4H under nitrogen. The mixture was cooled and a little insoluble material was filtered off. The filtrate was evaporated to dryness and the residue was partitioned between ethyl acetate (50ml) and saturated sodium bicarbonate solution (50ml). The saturated sodium bicarbonate layer was washed with ethyl acetate (2 x 25 ml) and acidified to pH 2 with concentrated hydrochloric acid. The aqueous phase was extracted with ethyl acetate (2 × 50 ml), washed with brine, and dried over sodium sulfate to give, after evaporation, a yellow solid (0.42 g)

IR (KBr) 1780cm " ¹ .

NMR (acetone-D ₆ ) δ = 1.17 (t, J = 7.3H), 2.26 (s, 3H), 2.7 (s, 3H), 3.2-3.85 (m, 6H), 3.85-4.16 (m, 2H), 4.18 and 4.62 (2H, ABq, J = 13), 4.92 (s, 1H), 5.7 (d, J = 7.1 H), 7.15-7.8 (m, 5H), 8.45 (s, 1H), 9.84 (d, J = J, NH).

(b) Beπzyhydryl-7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamidol] 3 - [(2-methyl-1,3,4-thiadiazole) 5-yl) thiomethyl] -7a-methyithioceph-3-em-4-carboxylate

To a solution of 7-di- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -3 - [(2-methyl-1,3,4-thiadiazole-S) yOthiomethylJ ^ a-methylthioceph-S-em ^ -carboxylic acid (0.42 g) in dichloromethane (20ml) b & room temperature was added excess diphenyldiazomethane with stirring. After 0.5 h, the resulting pale pink colored solution was

evaporated to give a yellow foam (0.16g). "

IR (KBr) 1780cm " ¹ .

NMR (DMSOD ₆ ) O = 1.14 (t, J = 6.3H), 2.18 (s, 3H), 2.6 (s, 3H), 3.2-3.55 (m, 6H) , 3.80-4.20 (m, 2H), 4.22 and 4.6 (2H, ABq, J = 13), 4.85 (s, 1H), 5.64 (d, J = 7.1 H), 6.8 (s, 1H), 7.1-7.55 (m, 15H), 9.85 (d, J = 7, NH).

(c) Benzhydryl-7jS- [D-2- {4-ethyl-2,3-dioxopiperazin-1-yl-carbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3 - [(2-methyl-1 , 3,4-thiadiazol-5-yl) thiomethyl] ceph-3-em-4-carboxylate

To a solution of benzhydryl-7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -3 - [(2-methyl-, S ^ "-thiadiazole-6-ythiomethyl-1-methylthioceph-S-em-carboxylate (0.276g) in DMF (20ml) at -60 ° C under nitrogen was added a solution of mercury (II) acetate (0.103g) in dimethylformamide (5ml). After 5min, a solution of hydroxylamine hydrochloride (0.023g) in dimethylformamide (2ml) was added and the mixture stirred for one hour at ⁰ ° C. Water (50ml) and ethyl acetate (50ml) were added and stirring continued for 15min The mixture was filtered and the ethyl acetate layer separated, washed with brine and dried over sodium sulfate and evaporated to give a yellow JDI Re-evaporation from dichloroethane gave the product as a white foam (0.26 g) _a IR (KBr) 1780 cm ^-1 ,

NMR (CDCI ₃₎ O = 1.23 (t, J = 7,3H), 2.62 (s, 3H7,2,9-3,64 (m, 6H), 3.75-3.95 (m , 2H), 4.28 and 4.52 (2H, ABq, J = 13), 5.22 (s, 1H), 5.5 (d, J = 7.1 H), 6.45 (brs, H ), 6.8 (s, 1H), 7.0-7.55 (m, 15H), 8.4 (brs, 1H), 9.82 (d, J = 7, NH).

(d) 7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazine-1-ylcarbonyl-amino) -phenylacetamido] -? a-hydroxyamino-3- [2-methyl-1,3,4-thiadiazole -5-yl) thiomethyl] ceph-3-em-4-carboxylic acid

To a solution of benzhydryl-7j8- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7ahydroxyamino-3 - [(2-methyl-1,3, 4-thiadiazol-5-yl) thiomethyl] ceph-3-em-4-carboxylate (0,260g) in dichloromethane (5ml) at -70 ⁰ C under nitrogen anisole (0.20 g) was added, followed by a solution of Aluminum chloride (0.124g) in nitromethane (2ml) with stirring. After 5min ethyl acetate (40ml) and saturated sodium bicarbonate solution (40ml) were added and stirring was continued at 0 ⁰ C for 15 minutes. After filtering through "Hyflo", the sodium bicarbonate layer was separated and washed with ethyl acetate (20 ml) and washed with

acidified hydrochloric acid to pH 2. The aqueous layer was extracted with ethyl acetate (3 × 20 ml) and the combined extracts were washed with brine and dried over sodium sulfate. Evaporation provided the product as

white solid (66mg). '

IR (KBr) 1780cm " ¹ .

NMR (DMSOD ₆ ) O = 1.1 (t, J = 7.3H), 2.7 (s, 3H), 3.2-3.65 (m, 6H), 3.85-3 , 95 (m, 2H), 4.15 and 4.5 (2H, ABq, J = 13), 5.05 (s, 1H), 5.70 (d, J = 7.1H) , 6.51 (brs, 1H), 7.28-7.52 (m, 5H), 8.18 (s, 1H), 9.56 (s, NH), 9.90 (d, J = 7, NH).

Example 40

[DL-2- (2-methyl-4-hydroxypyrid-5-yl-carbonylamino) -2-phenylacetamido] cephalosporanic acid 7-hydroxyamino-7ß-

(a) Benzhydryl-7β- [DL-2- (2-methyl-4-hydroxypyrid-5-ylcarbonylamino) -2-phenylacetamido] -7a-methylthiocephalosporanate Benzyl-hydryl-7β-amino-7α-methylthiocephalosporanate (507 mg) in dichloromethane (30 ml ) was cooled to -10 ⁰ C and a 'minute treated with a solution of D-2- [2-methyl-4-hydroxypyrid-5-ylcarbonylamino] -2-phenylacetyl chloride (333 mg) in dichloromethane (10ml) was added dropwise. Pyridine (85μ, Ι) was added during 1 min, and the solution was stirred at -10 ° C for 1 h, then washed with 1% hydrochloric acid (50 ml), saturated sodium bicarbonate (50 ml), and (over MgSO ₄ ).

dried. The solvent was removed in vacuo and the residue chromatographed on silica gel eluting with methanol / ethyl acetate, 1: 9, to give the title compound (130mg).

NMR (DMSO-D ₆ ) O = 2.02 (s, 3H), 2.08 (s, 3H), 2.18 (s, 3H), 3.2-3.4 {m, 2H), 4 , 62-5.14 (m, 3H), 5.72 (d, J = 6.1H), 6.13 (s, 1H), 6.85 (s, 1H), 7.15-7 , 75 (m, 15H), 8.38 (d, J = 6.1H), 10.86 (s, 1H), 11.43 (d, J = 6.1H).

(b) 7β- [DL-2- (2-Methyl-4-hydroxypyrid-5-ylcarbonylamino) -2-phenylacetamido] -7a-methyl thiocephaosporanic acid was obtained from the product of Example 40a according to the deY method of Example 39 (d) manufactured.

IR (KBr) 1776cm " ¹ : '.

NMR (DMSO-D ₆ ) δ = 2.05 and 2.06 (2 xs, 3H), 2.22 and 2.26 (2 xs, 3H), 3.2-3.8 (m, 2H), 4.6-5.05 (m, 2H), 5.05 and 5.06 (2 χ s, 1 H), 5.82 + 5.9 (2 χ d, J = 7 Hz, 1 H), 6.27 (s, 1H), 7.22-7.53 (m, 5H), 8.22-8.32 (m, 1H), 9.6-9.65 (m, 1H) , 11.18 and 11.21 (2 xd, J = 7Hz, 1H), 12.18 (s, 1H), 13.75 (brs, 1H).

(c) 7a-Hydroxyamino-7β- [DL-2- (2-methyl-4-hydroxypyrid-5-ylcarbonyl-amino-p-2-phenylacetamido] cephalosporanic acid

The title compound (88mg) was prepared from the 7a-methylthiocephem (Example 40 [b]) (100mg) after that previously in Example 9 (b). produced method described.

NMR (DMSO-D ₆ ) δ = 2.02 (s, 3H), 2.28 (s, 3H), 3.16-3.58 (m, 2H), 4.58-4.95 (m, 2H), 5.0 and 5.06 (2 xs, 1H, 6-H), 5.9 and 5.98 (2 xd, J = 7Hz, 1H), 6.27 and 6.4 (2 x s , 1H), 7.22-7.56 (m, 5H), 8.06 and 8.13 (2 xs, 1H), 8.27 and 8.29 (2 xs, 1H), 9.29 and 9.45 ( 2 xs, 1H), 11.18-11.35 (m, 1H), 12.43 (brs, 1H).

Examples 41 and 42

These compounds of formula (I) were prepared from the appropriate starting materials using the method described in Example 40, parts (a) to (c).

Example and stereochemistry of the side chain

DL

42 DL

-C-N

-CH ₉ OAc

-CH ₉ OAc

Example and stereo IR (KBr) chemistry of the side cm " ¹ chain

NMR (DMSO-de)

1778

1784

δ = 1.09 (m, 2H); 2.04 and 2.06 (2χs, 3H, D and L OCOCH); 3.18-3.54 (m, 6H); 3.86-3.98 (m, 2H); 4.58-5.02 (m, 2H); 5.08-5.14 (2 xs, 1H, D and L (6H); 5.95-6.00 (m, 1H); 6.69-7.54 (m, 3H); 8.15 and 8.22 (2 χ s, 1H, D) and L-forms); 9.55 and 9.58 (2 xs, 1H); D and L forms); 9.75-9.84 (m, '1H). ,

δ = 1.11 (m, 3H); 2.05 and 2.06 (2 χ s, 3 H, D and L forms); 3.25-3.70 (m, 6H); 3.92 (m, 2H); 4.61 ^ 1.98 (m, 2H); 5.06 and 5.09 (2 xs, 1 H, DL forms); 5.68 (m, 1H); 7.11 (m, 1H); 7.48 (m, 2H); 7.96 (s, 1H); 9.46 and 9.54 (2 x s, 1 H, DL forms); 9.76 (m, 1H).

Example 43

7ß- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3 - [(1- (2-kaliumsulfoxyethyl) -

IHL-tetrazol-S-y-thiomethyllcpeh S ERRm-carboxylic acid

[2-potassium sulfoxyethyl = - (CH ₂ ) 2OSO ₂ O®K®]

(a) 7β- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthio-3 - [(1- (2-potassium-sulfoxyethyl) -

1 H-tetrazole-S-y-thiomethyl-lceph-S-em ^ -carboxylic acid

A solution of 7β- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -3 - [(1- (2-hydroxyethyl) -1H-tetrazole-ö] YD-thiomethyl-α-methylthioceph-S-em -carboxylic acid (Example 16 [a]) (300 mg), stirred under nitrogen at 0 ° C, was treated with a solution of dimethylformamide-sulfur trioxide complex (prepared from trimethylsilyl chlorosulfonate and dimethylformamide). The mixture was stirred for 20 minutes, in a 0.5 η solution of

Potassium hydrogen orthophosphate (50 ml) and the solution extracted with methylene chloride (2 x 50 ml). The aqueous phase was treated with tetrabutylammonium hydrogen sulfate (289 mg) and extracted with methylene chloride (2 × 50 ml). The extract was washed with 0.5 ή potassium dihydrogen orthophosphate solution (50 ml), dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The oily residue was taken up in acetone (20 ml) and a solution of potassium nonafluorobutanesulphonate (288 mg) in acetone (10 ml) added dropwise to give a white precipitate. Diethyl ether (100 ml) was added to give further precipitate, which was separated by filtration and dried under vacuum to give the title compound (270 mg). ,

NMR (DMSO-D ₆ ) δ = 1.08 (t, J = 7.3H), 2.22 (s, 3H), 3.20-3.75 (m, 6H), 3.93 (m, 2H), 4.13 (m, 3H), 4.47 (m, 3H), 5.03 (s, 1H), 5.66 (d, J = 7.1H), 7.30-7 , 55 (m, 5H), 9.77 (s, 1H), 9.85 (d, J = 7.1 H).

(b) 7j8- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonyl) -2-phenylacetamido] -7a-hydroxyamino-3 - [(1- (2-potassium sulfoxyethyl) -1H-tetrazole -B-yOthiomethyflceph-S-em - ^ - carboxylic acid

The title compound (19 mg) was prepared from the 7x-methylthiocephem (Example 43 [a]) (260 mg) according to the method previously described in Example 9 (b).

IR (KBr) 1780cm " ¹ .

NMR (DMSO-D ₆ ) O = 1.09 (t, J = 7.3H), 3.23-3.66 (m, 6H), 3.92 (m, 2H), 4.12 (m, 3H), 4.51 (m, 3H), 5.01 (s, 1H), 5.72 (d, J = 7.1H), 7.27-7.55 (m, 5H), 9 , 60 (s, 1H), 9.89 (d, J = 7.1 H).

Example 44

7 / 3- [2- {R) - {4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -3- (S) - (potassium sulfoxy) -butanamido] -7Q: - ~ - ~

hydroxyaminocephalosporansäure

(a) 7/3 [2- (R) - (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -3- (S) -potassium sulfoxy) -butanamido] -7-thio-thiocephalosporanic acid

The title compound (195 mg) was prepared from 7 (S- [2- (R) - (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -3- (S) -hydroxybutanamido] -7a-methylthiocephalosporanic acid (330 mg ) and dimethylformamide sulfur trioxide complex were prepared by the method of Example 43 (a).

IR (KBr) 1780cm " ¹ .

NMR (DMSOd ₆ ) O = 1.06 (t, 3H, J = 4.5), 1.18 (d, 3H, J = 6), 2.00 (s, 3H), 2.29 (s , 3H), 3.2-3.4 (m, 4H), 3.54 (m, 2H), 3.90 (m, 2H), 4.38 (m, 1H) 4.64 and 4 , 98 (ABq, 2H, J = 15), 4.80 (m, 1H), 5.01 (s, 1H), 9.11 (s, 1H) 9.24 (d, 1H, J = 6).

(b) 7 / 3- [2- (R) - {4-ethyl-2,3-dioxopiperazin-1-ylcarbonyiamino) -3- (S) - (potassium sulfoxy) -butanamido] -7ahydroxyaminocephalosporanic acid

The title compound (115 mg) was prepared from the 7a-methylthiocephem of Example 44 (a) (182 mg) by the method of Example 9 (b).

IR (KBr) 1780cm- ¹ . '

NMR (DMSOd ₆ ) O = 1.06 (t, 3H, J = 4.5), 1.18 (d, 3H, J = 6), 2.0i (s, 3H), 3.21-3, 63 (6H), 3.91 (m, 2H), 4.39 (m, 1H), 4.65 and 4.97 (ABq, 2H, J = 15), 4.68 (m, 1H), 5 , 06 (s, 1H), 8.83 (s, 1H), 9.23 (d, 1H, J = 6).

Example 45 '

3-Acetoxymethyl-7 _j 8- [DL-2- (4-ethyl-2,3-dioxopiperazin-1-yl-carbonylamino) -2- (4-hydroxyphenyl) acetamido] -7ahydroxyaminoceph-3-em-4-carboxylic acid sodium salt

(a) Benzhydryl-3-acetoxymethyl-7 / 3- [DL-2- (4-benzyloxycarbonyloxyphenyl) -2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -acetamido] -7o <-methylthioceph- 3-em-4-carboxylate

D-2- (4-Benzyloxycarbonyloxyphenyl) -2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) acetic acid (1.25g) in dichloromethane (20ml) was treated with oxalyl chloride (1.36g) after 5min followed by dimethylformamide (1 drop). After stirring at room temperature for 1 h, the solution was evaporated to dryness, the residue was dissolved in a mixture of dichloromethane and carbon tetrachloride and re-evaporated. The resulting acid chloride in dichloromethane (5 ml) was added dropwise to a precooled (-60 ° C.) solution of benzhydryl-7/3-amino-7a-methyl thiocephalosporanate (1.3 g) and propylene oxide (3 ml) in dichloromethane (20 ml) , After one hour at - ^ 60 ⁰ C the solution was 2 h at 20 ⁰ C brought, then allowed to stand for 18 hours at room temperature. Ethyl acetate (100 ml) was added and the solution washed with 5% aqueous sodium bicarbonate (20 ml) followed by 0.01M hydrochloric acid (50 ml) and finally dried over sodium sulfate. Evaporation of the solvent gave the crude product, which after chromatography on silica gel (eluting with dichloromethane / ethyl acetate gradient) afforded the title compound (1.1 g).

IR (KBr) 1780cm- ¹ .

IMMR (CDCl ₃ ) O = 1.21 (t, J = 7.3H); 2.02,2.04,2.07 and 2,26 (4 xs, 6H, SCH ₃ and OCOCH ₃ ); 3.18-3.63 (m, 6H); 3.93 ^ 1.16 (m, 2H); 4.86 and 5, 12, 4, 89 and 5, 12 (2 x ABq, J = 14.2H); 4.89 and 4.92 (2 xs, 1H); 5.26 and 5.27 (2 xs, 2H); 5.50-5.58 (m, 1H), 6.57 and 6.66 (2 χ s, NH); 6.88 (s, 1H); 7.15-7.56 (m, 19H); 9.98 (d, J = 7, NH). ,

(b) Benzhydryl-3-acetoxymethyl-7 / 3- [DL-2- (4-benzyloxycarbonyloxyphenyl) -2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) acetamido] -7a-hydroxyaminoceph-3 -em-4-carboxylate

This compound was prepared from the 7a-methylthiocephem (example 45 [a]) (1.1 g) according to the method described for Example 38 (b). Silica gel chromatography (eluting with dichloromethane / ethyl acetate) gave the title compound as a white solid (0.95g).

IR (KBr) 1775cm " ¹ .

NMR (CDCl ₃ ) O = 1.07-1.22 (m, 3H), 1.97 (s, 3H), 2.68 and 3.07 (2H, ABq, J = 14), 3.27-3, 63 (m, 4H), 3.78-4.14 (m, 2H), 4.80-5.35 (m, CH ₂ OAc, OCH ₂ Ph, C ₆ -H and 1 H Aust), 5, 53-5.65 (m, CHNH), 6.85-7.65 (m, 19H), 8.02 (s, NH), 8.15 and 8.80 (2 brs, 1H Aust.),

10.08 (d, J = 7, NH). ,

(c) 3-Acetoxymethyl-7/3 [DL-2- (4-benzyloxycarbonyloxyphenyl) -2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) acetamido] -7a-hydroxyaminoceph-3-em-4 carboxylic acid

The benzhydryl ester (0.95 g) obtained in the previous step was treated with aluminum chloride anisole as described for Example 38 (c). The crude product was triturated with diethyl ester (15ml) to afford the title compound (545mg). IR (KBr) 1765cm ~ ¹ . , '

NMR (DMSO-D ₆ ) δ = 1.09 (t, J = 7, 3H), 2.02 and 2.04 (2 χ s, OCOCH ₃ ), 3.08-3.66 (m, 6H) , 3.84-4.00 (m, 2H)., 4.63 and 4.92,4.67 and 4.95 (2H, 2ABq, J = 14), 5.05 and 5.11 (2 x s , C ₆ -H), 5.29 (s, CH ₂ Ph), 5.73 (d, J = 7, CHNH), 6.55 (brs, 1H), 7.23-7.62 (m , 9H), 8.11 and 8.21 (2 χ s, 1H), 9.52 and 9.58 (2 xs, 1H) 9.88 and 9.93 (2d, J = 7, NHCH).

(d) 3-Acetoxymethyl-7 / 3- [DL-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2- {4-hydroxyphenyl) acetamido] -7a: - hydroxyaminoceph-S-em ^ -carboxylic acid, sodium salt

, The cephalosporanic acid (300 mg) from the previous example was stirred in a solution of sodium bicarbonate (33.6 mg) in water (15 ml) until dissolved. 10% palladium on carbon (100 mg) was added and the mixture was shaken under 0.689 bar (10 psi) of hydrogen at room temperature for 0.5 h. Filtration followed by lyophilization gave the title compound as an amorphous solid (215 mg).

IR (KBr) 1765cm " ¹ .,.

NMR (D ₂ O) O = 1.21 (t, J = 7.3H), 2/08 and 2.11 (2 xs, OCOCH ₃ ), 3.10-3.82 (m, C2-2H, CH ₂ CH ₃ and piperazine CH ₂ ), 3.92-4.15 (m, piperazine-CHz), 4.62-5.15 (m, CH ₂ OAc and C ₆ -H), 5.43 and 5.47 (2 xs, CHNH), 6.85-7.50 (m, 4H.

Example 46 7 / 3- [2- (R) - (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -3- (S) -hydroxybutanamido] -7a-hydroxyaminocephalosporanic acid

(a) Benzhydryl-7) 3- [2- (R) - {4-ethyl-2,3-d ^ oxopiperazine-1-ylcarbonylamino) -3- (S) -hydroxybutanamidol · 7α; -methylthiocephalosporanate

2- (R) - (4-ethyl-2,3-dioxopiperazin-1-yicarbonylamino) -3- (S) -hydroxybutyric acid (11.4 g) was suspended in CH ₂ Cl ₂ (120 cm ³ ) and N-methylpiperidine ( 3.93g) was added! to convert the suspension into a solution. The solution was cooled under nitrogen to -20 ⁰ C and ethyl chloroformate (4.2 g) was added. The mixture was stirred for 30 min and a solution of benzhydryl-7 (3-amino-7a-methylthiocephalosporanate (19.2g) in methylene chloride (30cm ³ ) was added.) The mixture was allowed to reach room temperature, stirred for 0.2h, 0.2 hydrochloric acid (2 × 50 cm ³ ) and saturated sodium bicarbonate solution (2 × 50 cm ³ ), dried over magnesium sulfate and evaporated to dryness The residue was purified by column chromatography (silica gel, eluted with 5% methanol in ethyl acetate) to give the title compound ( 15.8 g). '

¹ IR (KBr Preßling) 1737 cm " ¹ , 1715 cm ¹ , 1688 cm- ¹ - ·

NMR (DMSO) O = 1.13 (t, 3H, J = 7), t, 30 (d, 3H, J = 6), 2.05 (s, 3H), 2.35 (s, 3H), 3.46 (m, 6H), 4.10 (m, 2H), 4.47 (m, 2H), 4.93 and 5.15 (ABq, 2H, J = 12), 4.96 (s, 1 H), 6.89 (s, 1H), 7.27-7.48 (m, 10H), 7.99 (s, 1H), 9.58 (d, 1H, J = 9).

(b) 7 / 3- [2- (R) - (4-Ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -3- (S) -hydroxybutanamido] -7-methylthiocephalosporanic acid The title compound (2.5g) was prepared from the product of Example 46 (a) (5.0 g) using the method of Example 39 (d).

IR (KBr Preßling) 1 778crrr \ 1711 cm " ¹ , 1 675cm" ¹ .

NMR (DMSO d ₆ ) δ = 1.07 (m, 6H), 2.00 (s, 3H), 2.25 (s, 3H), 3.33-3.61 (m, 6H), 3, 90 (m, 3H), 4.33 (m, 1H), 4.64 and 4.94 (ABq, 2H, J = 13), 5.05 (s, 1H), 5.07 (d, 1H, J = 6), 9.15 (s, 1H), 9.26 (d, 1H, J = 6).

c) 7 / 3- [2- (R) - (4-Ethyl-2- _r 3-dioxo-1-piperazine-1-yicarbonylamino) -3- (S) -hydroxybutanamido] -7ahydroxyaminocephalosporanic acid

The 7α-methylthiocephem (from Example 46 [b]) (250 mg) was converted to the title compound (142 mg) by the method of Example 9 (b).

IR (KBr) 1776cm ' ^1. ' -

NMR (DMSOd ₆ ) O = 1.10 (m, 6H) -, 2.07 (s, 3H), 3.2-4.2 (m, 9H), 4.35 (m, 1H), 4.61 and 4.90 (ABq, 2H, J = 10), 5.10 (s, 1H), 8.91 (s, 1H) 9.30 (d, 1H, J = 7). ,

Example 47

7a-hydroxyamino-7 ^ - (D-2- [2-oxoimidazoiidin-1-ylcarbonylamino] -2-phenylacetamido) cephalosporanic acid

(a) Diphenylmethyl-7α-methylthio-7 / 3- [D-2- (2-oxoimidazolidin-1-ylcarbonylamino) -2-phenylacetamido / cephalosporanate o diphenylmethyl-β-aminoethyl thiocephalosporanate (0.48 g) in dry dichloromethane ( 5ml) was cooled to -20 ⁰ C and treated for 1 min with a solution of D-2- (2-oxoimidazolidin-1-ylcarbonylamino) -2-phenylacetyl chloride (0.26 g) in dry dichloromethane (2ml). Pyridine (80 μ l) was added over 1 min and the reaction was allowed to warm to + 10 ⁰ C over 30 min. The solution was then washed with 1% hydrochloric acid (20 ml), saturated sodium bicarbonate (20 ml) and dried (over MgSO ₄ ). The solvent was removed in vacuo and the residue was chromatographed (silica gel, dichloromethane / ethyl acetate 7: 3) to give the title compound (0.37g).

IR (CH ₂ Cl ₂ -LSg.) 1780cm- ¹ .

NMR (CHCl ₃ ) δ = 1.98 (s, 3H), 2.28 (s, 3H), 3.4-3.6 (m, 4H), 3.9-41 (m, 2H), 4 , 95-5.15 (ABq, J = 13Hz, 2H), 5.2 (s, 1H), 6.9 (s, 1H), 7.2-7.6 (m, 15H), 9 , 1 (tr, 1H).

tb) diphenylmethyl-7 ^ = - hydroxyamino-7 / 3- [D-2- (2-oxoimidazolidin-1-ylcarbonylamino) -2-phenylacetamido] cephalosporanate diphenylmethyl-7a-methylthio-β- [D-2- (2- oxoimidazolidin-1-yl) carbonylamino) -2-phenylacetamido] cephalosporanate (0.37 g) was added 5 ml) dissolved in dry DMF (cooled under nitrogen to ⁰ -5o C and treated sequentially with a solution of mercury (II) acetate ( 170μg) in DMF (1ml) followed by hydroxylamine hydrochloride in DMF (1ml). The mixture was allowed to warm to 0 ⁰ C over 1.5 h and was then added to ethyl acetate (50ml). The solution was washed with water (5 x 50 ml), dried and evaporated in vacuo. The residue was chromatographed (silica gel / dichloromethane ethyl acetate, 6: 4) to give the title compound (0.31g).

IR (CH ₂ Cl ₂ solution) 1790 cm " ¹ .

NMR (CDCl ₃ ) δ = 2.03 (s, 3H), 2.75 and 2.98 (ABq, J = 16.2H), 3.5 (m, 2H), 3.8-4, 1 (m, 2H), 4.85-5.1 (m, 2H), 5.4 (s, 1H), 5.6 (s, 1H exchange), 5.7 (d, J = 61H), 6.2 (s, 1H exchange), 6.9 (s, 1H), 7.1-7.6 (m, 15H), 8.7 (s, 1H exchange), 9 , 3 (d, J = 6.1 H).

(c) 7a-Hydroxyamino-7α- [D-2- (2-oxoimidazolidin-1-ylcarbonylamino) -2-phenylacetamido] cephalosporanic acid was prepared from the product of Example 47 (b) (85 mg) by the method of Example 38 ( c) produced.

IR (KBr) 1780cm- ¹ .

NMR (DMSOd ₆ ) O = 2.07 (s, 3H), 3.18 and 3.45 (ABq, J = '16Hz, 2H), 3.3 (m, 2H), 3.7 (m, 2H), 4.57 and 4.86 (ABq, 2H, J = 12), 5.0 (s, 1H), 5.62 (d, J = 6.1H), 6.5 (s, 1H), 7 , 2-7.6 (m, 5H), 8.15 (s, 1H), 9.10 (d, J = 6.1 H), 9.45 (s, 1H).

Example 48

y ^ -TDL ^ -t ^ BenzyloxYcarbonyloxyphenyO ^ -f ^ ethyl ^ S-dioxopiperazin-i-ylcarbonylaminolacetamidol-Ta-hydroxyamino-S - [(i-methyl-IH-tetrazol-S-S-yllthiomethynceph-em-'l- carboxylic acid

(a) S-acetoxymethyl ^ / S-tDL ^ rt ^ benzyloxycarbonyloxyphenyll-a ^ -ethyl ^^ dioxopiperazine-i-ylcarbonylamino] -? - - methylthioceph-S-em- carboxylic acid

The benzhydryl ester (from Example 45 [a]) (4.67 g) was treated with aluminum chloride and anisole as described previously for Example 39 (d) to give the title compound (3.1 g) as a white solid.

IR (KBr) 1780CiTT ¹ .

NMR (DMSO-de) δ = 1.07 (t, J = 7, 3H), 1.89, 2.01, 2.03 and 2.21 (4 xs, 6H ₁ SCH ₃ and OCOCH ₃ ), 3 , 22-3.64 (m, 6H), 3.87-3.91 (m, 2H), 4.64 and 4.95, 4.67 and 5.00 (2 x ABq, J = 13.2H), 5, 09 (s, 1H), 5.27 (s, 2H), 5.66 (d, J = 7.1H), 7.23-7.51 (m, 9H), 9.74 ( s, 1 H),

9.85 and 9.92 (2 x d, J = 7.1H). ,

(b) 7/3 (DL-2- (4-Benzyloxycarbonyloxyphenyl) -2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) acetamido] -3 - [{1-methyl-TH-tetrazole; B-yllthiomethyll ^ a-methylthioceph-S-em ^ -carboxylic

The 3-acetoxymethylcephem (from Example 48 [a]) (335 mg) and 5-mercapto-1-methyl-1H-tetrazole (116 mg) in 1,2-dichloroethane were refluxed under nitrogen for 6 hours. The mixture was evaporated to dryness in vacuo and the residue triturated with isopropanol (10ml) to give the title compound (325mg).

IR (KBr) 1775cm " ¹ .

NMR (DMSO-d ₆ ) δ = 1.07 (t, J = 7, 3H), 1.87 and 2.21 (2 χ s, SCH ₃ ), 3.32-3.82 (m, 6H) , 3.88 (m, 2H), 3.91 and 3.94 (2 xs, 3H), 4.12-4.42 (m, CH ₂ OAc), 5.05 and 5.06 (2 s s , C ₆ -H), 5.27 (s, 2H), 5.67 (d, J = 7, CHNH), 7.25-7.52 (m, 9H), 9.74 (s, 1H ), 9.85 and 9.91 (2 xd, J = 7, NH).

(c) 7/8 [DL-2- (4-Benzyloxycarbonyloxyphenyl) -2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) acetamido] -7ahydroxyamino-3 - [(1-methyl-1H- tetrazol-5-yl) thiomethyl] -ceph-3-em-4-carboxylic acid This compound was prepared from the 7 <* -methylthiocephem (Example 48 [b]) (320 mg) according to the method described for Example 9 (b) , Trituration of the crude product with isopropanol (10ml) gave the title compound (270mg).

IR (KBr) 1775cm- ¹ .

NMR (DMSOd ₆ ) O = 1.07 (t, J = 7, 3H), 3.23-3.72 (m, 6H), 3.89 (m, 2H), 3.91 and 3.94 ( 2 χ s, 3H), 4,11 and 4,34,4,17 and 4,35 (2 x ABq, J = 14,2H), 4,99 and 5,05 (2 χ s, 1 H), 5.26 and 5.27 (2 χ s, 2H), 5.70 and 5.71 (2 xd, J = 7, CHNH), 6.55 (brs, 1H), 7.22 to 7.52 (m, 9H), 8.06 and 8.17 (2 xs, 1H), 9.48 and 9.55 (2 xs, 1H), 9.85 and 9.88 (2 xd, J = 7 , NH).

Example 49

7 / 3- [D-2- (4-ethyl-2,3-dioxbpiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3 - [(1,3,4-thiadiazol-2-yl) thiomethyl] ceph-3-em-4-carboxylic acid, sodium salt

(a) 7i3- [D-2- {4-ethyl-2,3-dioxbpiperazin-1-ylcarbonylamino) -2-phenylacetamido] -3 - [{1,3,4-thiadiazol-2-yl) thiomethyl] -7o: - methylthioceph-S-em ^ -carboxylic acid

7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthiocephalosporanic acid (Example 6 [a]) (1.0g) was treated with 2-mercapto -1,3,4-thiadiazole (0.38g) in a manner similar to that described in Example 39 (a) to give the title compound (0.45g)

¹

NMR (DMSO d ₆ ) δ = 1.08 (t, J = 7.3H), 2.22 (s, 3H), 3.10-3.71 (m, 6H), 3.81 ^ 1.00 (m, 2H), 4.20 and 4.59 (ABq, J = 13.2H), 5.06 (s, 1H), 5.66 (d, J = 7.1H), 7.25 -7.56 (m, 5H), 9.56 (s, 1H), 9.69 (s, 1H), 9.84 (d, J = 7, NH).

(b) 7/3 - [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3 - [(1,3,4-thiadiazole-2 -yl) thiomethyl] ceph-3-em-4-carboxylic acid, sodium salt

The title salt (285 mg) was prepared from the 7a-methylthiocephem (from Example 49 [a] above) (400 mg) by treatment with mercury (II) acetate and hydroxylamine as described in Example 9 (b). The sodium salt was then obtained by treating the acid with sodium bicarbonate (36 mg) in water, followed by lyophilization.

IR (KBr) 1780CITT ¹ . ·

NMR (D ₂ O) δ = 1.19 (t, J = 6.3H), 3.11 ^, 63 (m, 10H), 5.08 (s, 1H), 5.52 (s, 1 H) 7.39-7.62 (m, 5H), 9.38 (s, 1H).

Example 50

S-acetoxymethyl ^ a ^ ß-hydroxyamino-LD ^ -lS-methanesulfonyl-i ^ -oxoirnidazolidin ylcarbonylaminoJ ^ -phenylacetarnido] ceph-S-em ^ -carboxylic acid

(a) Benzhydryl-3-acetoxymethyl-7 / 3- [D-2- (3-methanesulfonyl-2-oxo-imidazolidin-1-ylcarbonylamino) -2-phenylacetamido] -7-methylthioceph-3-em-4-carboxylate

A suspension of D-2- (3-methanesulfonyl-2-oxoimidazolidin-1-ylcarbonylamino) -2-phenylacetic acid (1.18g) in dichloromethane (25ml) was treated with pyridine (280μ.Ι). After 5 min stirring at room temperature the almost clear solution was cooled to -60 ⁰ C and trichloroacetyl chloride (387μΙ) was added. The solution was then gradually over 1 h to -40 ⁰ C heated, cooled erneutauf-60 ⁰ C and a solution of benzhydryl-7/3-amino-7a-methylthiocephalosporanat (1.67 g) in dichloromethane (5ml) was added. The reaction mixture was warmed to room temperature over 1 h, stirred for a further 18 h and then washed with water (2 × 30 ml). Drying followed by evaporation of the solvent in vacuo gave the crude product, which after chromatography on silica gel (eluting with dichloromethane / ethyl acetate gradient) afforded the title compound as a light yellow solid (815 mg). ... '.

IR (KBr) 1785 crrT ¹ .

NMR. (CDCl ₃ ) δ = 2.02 (s, 3H); 2.25 (s, 3H); 3.31 (s, 3H); 3.24-3.34 (m, 2H); 3.88-3.93 (m, 4H); 4.85 and 5.09 (ABq, J = 14, 2H); 4.92 (s, 1H); 5.50 (d, J = 7, CHNH); 6.53 (s, NH); 6.89 (s, 1H; 7.29-7.48 (m, 15H); 8.85 (d, J = 7, CHNH).

(b) 3-Acetoxymethyl-7 / 3- [D-2- (3-methanesulfonyl-2-oxo-imidazolidin-1-ylcarbonylamino) -2-phenylacetamido] -7-methylthioceph-3-em-4-carboxylic acid

The benzhydryl ester of the previous step (50 [a]) (403 mg) was treated with aluminum chloride and anisole as previously described for Example 39 (d). Renewed evaporation of the crude product from 2: 1 dichloromethane / carbon tetrachloride afforded the title compound as a white solid (255 mg).

NMR (CDCl ₃ ) δ = 2.10 (s, 3H), 2.37 (s, 3H), 3.26 and 3.47 (ABq, J = 18, 2H), 3.55 (s, 3H) , 3.91-3.92 (m, 4H), 4.89 and 5.15 (ABq, J = 13, 2H), 5.01 (s, 1H), 5.57 (d, J = 7, CHNH), 7.22-7.65 (m, 6H, CONH and C ₆ H ₅ ), 9.15 (d, J = 7, NH).

(c) S-acetoxymethyl-ya-hydroxyamino-Tss-tD ^ -tsS-methanesulfonyl-oxo-imidazolidin-1-ylcarbonylamino'i-phenylacetamido] -ceph-3-em-4-carboxylic acid

The 7a-methylthiocephem from the previous example (50 [b]) (250 mg) was treated with mercury (II) acetate and hydroxylamine hydrochloride as previously described for Example 9 [b]. Trituration of the crude product with isopropanol (3ml) gave the title compound (166mg). '

IR (KBr) 1780cm " ¹ .

NMR (DMSO-d ₆ ) 5 = 1.98 (s _r 3H), 3, 16, and 3.48 (ABq ₁ J = 18.2 H) 3.33 (s, 3 H), 3.67-3.81 (m, 4H), 4.56 and 4.86 (ABq, J = 12.2H), 5.01 (s, 1H), 5.64 (d, J = 7, CHNH), 6.49 (s, 1H), 7.26-7.43 (m, 5H), 8.17 (s, 1H), 8.77 (d, J = 7, NH), 9.51 (s, 1H).

Example 51

7 ^ - [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7o; -hydroxyarnino-3-azidornethylceph-3-s-4-carboxylic acid

(a) 7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthio-3-azidomethylceph-3-em-4-carboxylic acid

7 / HD-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthiocephalosporanic acid (0.880g) was dissolved in a saturated aqueous solution of sodium bicarbonate (20ml) and washed with 2 η hydrochloric acid adjusted to pH 6.5. Lithium azide (0.105g) was added and the reaction stirred at 60 ° C for 4h. The mixture was allowed to cool, was overlaid with ethyl acetate (100 ml) and adjusted to pH 2. The layers were separated, the aqueous layer was extracted with ethyl acetate (2 × 100 ml) and the organic layers were combined, dried over magnesium sulfate and the solvent removed in vacuo. The crude product was chromatographed on silica (gradient elution isopropyl alcohol / acetic acid / dichloromethane). Capturing and evaporating the appropriate fractions gave the title compound (0.340g).

IR (KBr) 178OCiTT ¹ . '

NMR (DMSO-d ₆ ) δ = 1.06 (t, J = 6Hz, 3H), 2.21 (s, 3H), 3.2-3.6 (m, 6H), 3.89 (m, 2H), 3.98 and 4.29 (ABq, J = 14Hz, 2H), 5.07 (s, 1H), 5.63 (d, J = 6Hz, 1H), 7.28-7, 48 (m, 6H), 9.69 (s, 1H), 9.80 (d, J = 6Hz, 1H).

(b) 7/3 - [D-2- (4-Ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3-azidomethylceph-3-em-4-carboxylic acid

Das7 <x-Methylthiocephem (from Example 51 [a]) (0,230g) in dimethylformamide (4ml) was cooled to-60 ⁰ C. A solution of mercury (II) acetate (0.266 g) in dimethylformamide (2 mL) was added followed immediately by hydroxylamine hydrochloride (0.030 g) in dimethylformamide (2 mL) and triethylamine. The reaction mixture was stirred for 1.5 hours, allowing the temperature to rise to +10 ⁰ C. The mixture was then added dropwise to ether (400 ml) and the solid was filtered off and suspended in methanol (40 ml). Hydrogen sulfide was bubbled through the suspension for 10 minutes with stirring, the mixture was filtered through "Hyflo" (Trade Mark) and the solvent removed in vacuo to give the title compound (0.205g).

NMR (DMSO-d ₆ ) δ = 1.06 (t, J = 6Hz, 3H), 3,1Ö-3,55 (m, 6H), 3,88 (m, 2H), 3,94 and 4,23 ( ABq, J = 12Hz, 2H), 5.02 (s, 1H), 5.67 (d, J = 6Hz, 1H), 6.50 (s, 1H) 7.30-7, 50 (m, 5H), 7.84 (s, 1H), 8.20 (s, 1H), 9.58 (s, 1H), 9.87 (d, J = 6Hz, 1H) ,

Example 52

7ß- [D-2- (4-benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyaminocephalosporansäure

(a) Benzhydryl-7/3-tD-2- (4-benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthiocephalosporanate

Benzhydryl ^ ß-amino ^ a-methylthiocephalosporanat (1.38 g) in dichloromethane (25ml) was cooled to -30 ⁰ C and over 1 min dropwise (with a solution of D-2- 4-Benzyl-2,3-dioxopiperazin 1-ylcarbonylamino) -2-phenylacetyl chloride (1.22g) in dichloromethane (25ml). Pyridine (237 / xl) was added over 1 min and the solution was stirred for 30 min while allowing the temperature to rise to ⁰ ° C, then with 2N hydrochloric acid (50 ml), saturated sodium bicarbonate (50 ml) and saturated sodium chloride solution (50 ml). The reaction mixture was then dried (over Na ₂ SO ₄ ), the solvent removed in vacuo and the residue chromatographed (silica gel), dichloromethane / ethyl acetate) to give the title compound (1.3g). "· '.' -

IR (KBr) 1785cm " ¹ .

NMR (CDCl ₃ ) δ = 2.04 (s, 3H), 2.25 (s, 3H), 3.28 and 3.38 (ABq, J = 13, 2H), 3.35-3.52 fm , 2H), 3.84-4.10 (m, 2H), 4.63 and 4.72 (ABq, J = 12, 2H), 4.63 and 4.71 (ABq, J = 10, 2H) , 4.95 (s, 1H), 5.58 (d, J = 7.1H), 6.82 (s, NH), 6.90 (s, 1H), 7.18-7, 68 (m, 20H), 9.98 (d, J = 7, NH).

(b) Benzyldryl-7 / 3- [D-2- (4-benzyl-2,3-dioxopiperazin-1-yl-carbonylamino) -2-phenylacetamido] -7ahydroxyaminocephalosporanate

The title compound (0.36g) was prepared from the 7a-methylthiocephem (from Example 52 [a] above) (0.85g) similar to the procedure of Example 38 (b)

IR (KBr) 1780cm- ¹ .

NMR (CDCl ₃ ) O = 2.09 (s, 3H), 2.78 and 3.02 (ABq, J = 12.2H), 3.24-3.48 (m, 2H), 3, 72 ^ 1.04 (m, 2H), 4.58 and 4.72 (ABq, 2H), 4.88. and 4.98 (ABq, J = 12, 2H), 5.37 (s, 1H), 5.54 (d, J = 6.1H), 6.67 (brs, NH), 6.92 (s, 1H), 7.04 (brs, 1H, Aust.) 6.99-7.64 (m, 20H), 8.72 (brs, 1H Aust), 10.04 (d, J = 6, NH).

(c) 77 / 3- [D-2- (4-Benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyaminocephalosporanic acid The title compound (95mg) was prepared from the benzhydryl ester (from Example 52 above) [b]) (360 mg, similar to the procedure of Example 38 (c).

IR (KBr) 1780cm " ¹ .

NMR (DMSO d ₆ ) δ = 2.02 (s, 3H), 3.21-3.65 (m, 4H), 3.81-4.01 (m, 2H), 4.61 and 4.91 (ABq, J = 12, 2H), 4.62 (s, 2H), 5.07 (s, 1H), 5.71 (d, J = 6.1H), 6.54 (brs, 1 H, Aust), 7.24-7.58 (m / 1OH), 8.21 (s, 1H), 9.56 (s, 1H), 9.90 (d, J = 6, NH ).

Examples 53 and 54

The following compounds of formula (I) were prepared from the appropriate starting materials using the method of Example 52, parts (a) and (b).

Example and stereochemistry of the side chain R 1 R ~ R ^{2 1} 53 D ?H- CN 'Np.-octyl ö y ~ ^ OO. -CH ₇ -OAc. 54 D Ph -C-M N-n-butyl -CH ₇ ¹ OAc

Example and stereochemistry of the side chain

IR (KBr) cm " ¹

NMR (DMSO-d ₆ )

1780

1780

S = 0.88 (t, J = 6.3H); 1.16-1.40 (m, 1 OH); 1.42-1.64 (m, 2H); 2.02 (s, 3H); 3.08-3.68 (m, 6H); 3.79-4.06 (m, 2H); 4.60 and 4.89 (ABq, J = 12.2 H); 5.04 (s, 1H); 5.70 (d, J = 6, 1H); 6.52 (br.s., 1H); 7.23-7.59 (m, 5H); 8.20 (s, 1H); 9.56 (s, 1H); 9.88 (d, J = 6, NH). δ = 0.87 (t, J = 6.3H); 1.18-1.26 (m, 2H); 1.39-1.59 (m, 2H); 1.99 (s, 3H); 3.05-3.69 (m, 6H); 3.78-4.02 (m, 2H); 4.56 and 4.87 (ABq, J = 12.2H); 5.02 (s, 1H); 5.66 (d, J = 6.1 H); 6.49 (s, 1H); 7.14-7.61 (m, 5H); 8.18 (s, 1H); 9.54 (s, 1H); 9.85 (d, J = 6, NH).

Example 55

7 / 3- [D-2- (3-ethyl-2-oxo-imidazolidin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyaminocephalosporansäure

(a) Ββη2ΚγαΓγΙ-7 / 3- [0-2- (3-βίΗγΙ-2-οχο-ΪΓηϊα3ΖθΙϊαιη-1-γΙο3ΓΟοηγΐ3Γηϊηο) -2-ρΗβπγΐ3οβί3ΐτιίαο] -7α-ΓΠθίΚγΚΗίοοβρΗ3ΐθ3ρθΓ3η3ΐ A solution of D ^-tS-ethyl ^ -oxo imidazolidin-i-ylcarbonylaminolphenylessigsäure (0,800g) (DE-OS 2152968) and pyridine (0,208ml) in dichloromethane (24ml) was cooled to -40 ⁰ C and trichloroacetyl chloride (0,288ml) were added. The reaction mixture was stirred for 15 min, cooled to -60 ° C and benzhydryl-7j8-amino-7o; -methylthiocephalosporanate (1.28g) in dichloromethane (24ml) added over 3min. The mixture was stirred for 1 h, allowing to warm to + 20 ^° C., washed with saturated sodium bicarbonate solution (20 ml), the organic phase dried over magnesium sulfate and the solvent removed in vacuo. The crude product was purified by chromatography on silica. Elution was carried out with dichloromethane / ethyl acetate (4: 1) and collection and evaporation of appropriate fractions gave the title compound (1.24g). ,

NIvIR (CDCl ₃ ) S = 1.19 (t, J = 6Hz, 3H), 2.06 (s, 3H), 2.32 (s, 3H), 3.29-3.50 (m, 6H) , 3.90 (m, 2H), 4.89 and 5.15 (ABq, J = 12Hz, 2H), 4.96 (s, 1H), 5.60 (d, J = 6Hz, 1H) , 6.92 (s, 1H), 6.94 (s, 1H), 7.30-7.53 (m, 15H), 9.22 (d, J = 6Hz, NH).

(b) TjS-tD-α-O-ethyl-a-oxo-imidazolidin-1-ylcarbonylaminoJ ^ -phenylacetamidol-Ta-methylthiocephalosporanic acid

The benzhydryl cephalosporanate (0.83 g) (from Example 55 [a]) in dry dichloromethane (560ml) was cooled to-60 ⁰ C. Anisole (0.715 ml) was added, followed by aluminum trichloride (0.440 g) in nitromethane (2 ml). The mixture was stirred for 20 minutes and then partitioned between saturated sodium bicarbonate solution (30 ml) and ethyl acetate (300 ml). The mixture was filtered through "Hyflo" (trade mark), the aqueous layer was separated, washed with ethyl acetate (50 ml), overlaid with n-butanol / ethyl acetate (1: 3) (200 ml) and adjusted to pH 2 with 2N hydrochloric acid The layers were separated, the aqueous layer re-extracted with n-butanol / ethyl acetate (150 ml), the organic layers were combined, dried over magnesium sulfate and the solvents removed in vacuo to give the title compound (0.34 g) (KBr) 1785cm " ¹ ,. -

NMR (CDCl ₃ ) S = 1.17 (t, J = 6Hz, 3H), 2.10 (s, 3H), 2.39 (s, 3H), 3.20-3.50 (m, 7H) , 3.83 (m, 2H) "4.89 and 5.15 (ABq, J = 13Hz, 2H), 5.04 (s, 1H), 5.60 (d, J = 6Hz, 1H), 7.36-7.53 (m, 5H), 7.97 (s, NH), 9.60 (d, J = 6Hz, NH).

(c) 7 ^ - [D-2- (3-Ethyl-2-oxo-imidazolidin-1-ylcarbonylamino) -2-phenylacetamido] -7a; -hydroxyaminocephalosporanic acid

The compound from the previous step (55 [b]) was reacted with hydroxylamine in a manner similar to the method of 51 (b) to give the title compound.

IR (KBr) 1775cm " ¹ .

NMR (DMSO-d ₆ ) 8 = 1.08 (6, J = 6Hz, 3H), 2.00 (s, 3H), 3.20-3.50 (m, 6H), 3.62 (m, 2H), 4.57 and 4.86 (ABq, J = 13Hz, 2H), 4.99 (s, 1H), 5.63 (d, J = 6.Hz, 1H), 6.43 ( s, NH), 7.26-7.42 (m, 6H), 8.13 (s, OH), 9.08 (d, J = 6Hz, NH), 9.46 (s, OH).

Example 56

hydroxyaminocephalosporansäure

(a) diphenylmethyl-yβ-ipL ^ -i ^ ethyl ^ thiocephalosporanate -

DL ^ -I ^ Ethyi ^^ - dioxopiperaziri-1-ylcarbonylamino] ^ -O-diacetoxyphenyl diacetic acid [EP 0071395, Example 18 (b)], (2.3g) was rhitrichloroacetyl chloride (0.96g), triethylamine (740μΙ) and diphenylmethyl β-amino-α-methylthiocephalosporanate (2.56g), similar to the procedure of Example 50 (a), to give the crude title compound. Chromatography on silica (20 g) eluting with a n-hexane / ethyl acetate gradient afforded the pure title compound (1.6 g).

IR (film) 1775cm "" ¹ .

NMR (CDCl ₃ ) δ = 1.1 (t, J = 7.3H), 2.0 (s, 3H), 2.25 (m, 9H), 3.0-4.2 (m, 8H) , 4.6-5.1 (m, 3H), 5.8 + 6.2 (d + brs, J = 6.1 H), 6.8 (s, 1H), 7.0-7, 6 (m, 13H), 7.9 and 8.1 (2χ s, NH), 9.7-10.1 (m, NH) - (60MHz).

(b) Diphenylmethyl-7/3 [D-2- (4-ethyl-2,3-dioxopiperazine-1-yicarbonylamino) -2- (3,4-diacetoxyphenyl) acetamido] -7a-t-butyldiphenylsilyloxyaminocephalosporanate.

Isomer 1 '. -.

The 7a-Methyithiocephem (from Example 56 [a]) (0.6 g) in dimethylformamide (10 ml) was cooled under nitrogen to ⁰ -5o C and treated sequentially with a solution of mercury (II) acetate (0.24 g) in dimethylformamide (1 ml) followed by a solution of O- (t-butyldiphenylsilyl) hydroxylamine (see Example 60a) (0.2 g) in dimethylformamide (1 ml). The mixture was warmed to 20 ° C over 0.5 h and added to ethyl acetate (100 ml). This solution was washed with water (3 x 50 ml), dried (over Na ₂ SO ₄ ) and evaporated in vacuo. The crude product was purified by chromatography (silica gel, hexane / ethyl acetate gradient) to give two separate isomers.

Isomer 1 (0.2 g) (D-isomer, eluted first)

IR (KBr) 1780cm ' ^1. '.

NMR (CDCl ₃ ) δ = 1.05 (s, 9H), 1.2 (t, J = 6, 3H), 1.65 (s, 2H, H ₂ O), 2.07 (s, 3H) , 2,3 (2 xs, 6H), 2.95 and 3.18 (2H, ABq, J = 14), 3.35-3.6 (m, 4H), 4.05 (m, 2H), 4.7 (s, 1H), 4.9 and 5.1 (2H, ABq, J = 13), 5.75 (d, J = 7.1 H), 6.65 (s, NH), 6.95 (s, 1H), 7.1-7.8 (m,

24H), 10.15 (d, J = 7, NH). ,

Only "isomer 1", the D-form, was processed further in the subsequent steps, in parts (c) and (d). "Isomer 2", eluted last, was discarded.

(c) Diphenylmethyl-7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2- (3,4-diacetoxyphenyl) acetamido] -7ahydroxyaminocephalosporanic acid

The D-isomer ("isomer I"), product of Example 56 (b), (0.55g) in acetonitrile (10ml) was cooled to 0 ° C with stirring. Aqueous hydrofluoric acid (40%) (4rnl) was added After one hour, the mixture was diluted with ethyl acetate (100 ml) and water (50 ml) Saturated aqueous sodium bicarbonate was added until pH 7 and the organic phase was separated, washed with hydrochloric acid and dried (over Na ₂ SO ₄ ). The solvent was evaporated in vacuo to give the crude product (0.43g), which was purified by chromatography (silica gel, dichloromethane / ethyl acetate gradient) to afford the title compound (0.27g).

IR (film) 1770crrT ¹ .

NMR (CDCl ₃ ) O = 1.25 (t, J = 7.3H), 1.6 (s, 2H, H ₂ O), 2.05 (s, 3H), 2.15 (s, 3H) , 2.25 (s, 3H) 2.55 and 3.15 (2H, ABq, J = 16), 3.4-3.7 (m, 4H), 3.95-1.2 (m, 2H), 4.95 and 5.2 (2H, ABq, J = 13), 5.45 (s, 1H), 5.65 (d, J = 6.1H), 6.7 (s, NH), 6 , 9-6.95 (m, 2H), 7.0-7.5 (m, 13H), 8.9 (brs, NH), 10.2 (d, J = 6, NH).

(d) 7 _/ 8- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino-2- (3,4-dihydroxyphehyl) acetamido] -7ahydroxyaminocephalosporansäure

The Diphenylmethylesteraus part (c) (0.25 g) in dichloromethane (5ml) and anisole (181 μ.Ι) was cooled under nitrogen to-60 ⁰ C. A solution of aluminum triethyl chloride (0.224g) in nitromethane (2ml) was added dropwise over 2min with rapid stirring, and after 1.0h the mixture was diluted with ethyl acetate (50ml) and 2m hydrochloric acid (25ml). The ethyl acetate layer was back-extracted with saturated aqueous sodium bicarbonate (2 × 5 ml) saturated with NaCl, overlaid with ethyl acetate / tetrahydrofuran (1: 1, 50 ml), and acidified to pH 1.5 with 2M hydrochloric acid. The organic extract was dried (over Na ₂ SO ₄ ) and evaporated in vacuo. The residue (0.12g) in dilute sodium bicarbonate solution (5ml) was adjusted to pH 8.5, stirred for 0.5h, saturated with NaCl, overlaid with ethyl acetate / tetrahydrofuran (1: 1.50ml) and the mixture mixed with 2mL Hydrochloric acid acidified to pH 1.5. The organic extract was dried (over Na ₂ SO ₄ ) and evaporated in vacuo to afford the title compound (60 mg)

IR (KBr) 1775cm " ¹

NMR (DMSO-d ₆ ) 8 = 1.10 (t, J = 6.3H); 2.18 (s, 3H); 3.2-3.4 (m, 4H) and HOD; 3.55 (m, 2H); 3.9 (m, 2H); 4.65 and 4.9 (2H, ABq, J = 12); 5.1 (s, 1H); 5.4 (d, J = 6.1 H); 6.65 and 6.9 (m, 3H, Ar); 8.85 (s, NH); 9.9 (d, J = 6, NH).

Example 57

yl) thiomethyl] ceph-3-em-4-carboxylic acid

(a) 3-Acetoxymethyl-7 / 3- [D-2- (2,3-dioxo-4-n-octyl-piperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthioceph-3-em-4-carboxylic acid

The benzhydryl ester of Example 53 (a) (1.45g) in dichloromethane (50ml). Anisole (1.44 g) was cooled to -5 ° C and added dropwise trifluoroacetic acid (5 ml) over 2 min. After stirring for 2 h at ⁰ ° C, toluene (50 ml) was added and the solution was evaporated to dryness in vacuo at 25 ° C. Additional toluene (50 ml) was added and the solution was re-evaporated in the same manner. Trituration of the residue with diethyl ether (100 ml) gave the title compound as a pale yellow solid (970 mg). -

IR (KBr) 1785cm " ¹ .

NMR (DMSO-d ₆ ) 8 = 0.85 (t, J = 7.3H); 1.24 (s, 1 OH); 1:48 (brs., 2H); 2:00 (s, 3H); 3:24 to 3:53 (m, 6H); 3.86-3.89 (m, 2H); 4.61 and 4.93 (ABq, J = 18; 2H); 5.07 (s, 1H); 5.62 (d, J = 8.1 H); 7.18-7.45 (m, 5H); 9.67 (s, 1H); 9.81 (d, J = 8,1H).

(b) 7/3 - [D-2- {2,3-dioxo-4-n-octylpiperazi-1-ylcarbamoylamino] -2-phenylacetamido] -3 - [(1-methyl-1H-tetrazol-5-yl ) thiomethyl] -7a-methylthioceph-3-em-4-carboxylic acid

Reaction of the S-acetoxymethylcephem (422 mg) obtained in the previous step with 1-methyl-1H-tetrazole-5-thiol (83 mg) according to the procedure described for Example 6 (b) gave the title compound as a white solid (123 mg). IR (KBr) 1785cm " ¹ ...

NMR (DMSO-d ₆ ) S = 0.83 (t, J = 7.3H); 1.22 (s, 1 OH); 1.46 (brs., 2H); 2.18 (s, 3H); 3.30 (brs., 2H); 3.35 and 3.60 (ABq, J = 18.2H); 3.52 (brs., 2H); 3.82-3.86 (m, 2H); 3.88 (s, 3H); 4.12 and 4.36 (ABq, J = 13, 2H); 5.01 (s, 1H); 5.60 (d, J = 8, CHNH); 7.27-7.44 (m, 5H); 9.6B (s, 1H); (d, J = 7, NH). "".

(c) 7j3- [D-2- (2,3-dioxo-4-n-octylpiperazine-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3 - [(1-methyl-1H-tetrazole-5- yl) thiomethyl] ceph-3-em-4-carboxylic acid

The title compound (107 mg) was prepared from the 7a-methylthiocephem of part (b) (120 mg) by reacting with mercury (II) acetate and hydroxylamine hydrochloride and triethylamine as previously described for Example 9 (b). IR (KBr) 1780cm " ¹ .

NMRDMSOd ₆ ) S = (0.85 (t, J = 7.3H); 1.24 (m, 1HH); 1.48 (m, 2H); 3.26 and 3.57 (ABq, J = 18.2H); 3.31 3.38 (m, 2H); 3.46-3.52 (m, 2H); 3.86-3.90 (m, 2H); 3.90 (s, 3H); 4.10 and 4.37 (ABq, J = 13, 2H); 4.99 (s , 1. H); 5.66 (d, J = 8, CHNH); 6.55 (br, 1H); 7.27-7.45 (m, 5H); 8.18 (s, 1H); 9.54 (s, 1H); 9.60 (br., 1H); 9.86 (d, J = 7, NH).

Example 58 *.

7 / 3- [2- (R) - (4-n-butyl-2,3 - dioxopiperazin-1-ylcarbonylamino) -3- (S) -hydroxybutanamido] -7a-hydroxyaminocephalosporansäure

(a) Benzhydryl-7α- [2- (R) - (4-n-butyl-2,3-dioxopiperazin-1-ylcarbonylamino) -3- (S) -hydroxybutanamido] -7a; methylthiocephalosporanate

2- (R) - (4-n-Butyl-2,3-dioxopiperazin-1-ylcarbonylamino) -3- (S) -hydroxybutyric acid (3.25g) and benzhydryl ^ / S-amino - - - - methylthiocephalosporanate (5 , 0g) were coupled by the method of Example 46 (a) to give the title compound (3.23g).

IR (CH ₂ Clf ₂ ) 1783 cm ^-1 .

NMR (CDCl ₃ ) δ = 0.94 (m, 3H); 1.2-1.60 (m, 7H); 2.05 (s, 3H); 2.35 (s, 3H); 3.41 (m, 6H); 4.11 (rri, 2H); 4.50 fm, 2H) 4.93 and 5.16 (ABq, 2H, J = 15); 4.96 (s, 1H); 6.89 (s, 1H); 7.27-7.49 (m, 1 OH); 7.88 (s, 1H); 9.59 (d, 1H, J = 6).

(b) 7 / 3- [2- <R) - (4-n-butyl-2,3-dioxopiperazin-1-ylcarbonylamino) -3- (S) -hydroxybutanamido] -7a-methylthiocephalosporanic acid The title compound (2.9g ) was prepared from the benzhydryl ester (3.8 g) of part (a) using the procedure of Example 5.7 (a).

IR (KBr) 1785cm " ^1. -."'

NMR (DMSO-d ₆ ) S = 0.88 (t, 3H, J = 7); 1.08 (m, 3HJ; 1.27 (q, 2H, J = 7); 1.49 (m, 2H); 2.02 (s, 3H); 2.26 (s, 3H); 3.34-3.63 (m, 6H); 3.90 -4.12 (m, 2H), 4.33 (m, 2H), 4.64 and 4.95 (ABq, 2H, J = 13), 5.07 (s, 1 H), 9.1.6 (s, 1 H), 9.27 (d, 1H, J = 6).

(c) 7/8 - [2- (R) - {4-n-Butyl-2,3-dioxopiperazin-1-ylcarbonylamino) -3- (S) -hydroxybutanamido] -7o; -hydroxyaminocephalosporanic acid

The title compound (220 mg) was prepared from the product of part (b) (300 mg) by the method of Example 9 (b). IR (KBr) 1778cm " ¹ .

NMR (DMSO-d ₆ ) δ = 0.87 (t, 3H, J = 7.5); 1.07 (m, 3H); i ".26 (m, 2H); 1.47 (m, 2H); 2.01 (s, 3H); 3.28-3.54 (m, 6H); 3.89 (m, 2H); 4.33 (m, 2H); 4.61 and 4.89 (ABq, 2H, J = 15), 5.09 (s, 1H), 8.88 (s, 1H), 9.27 (d, 1H, J = 6).

Example 59

7 ^ - [D-2- (4-benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -3 - [(5,6-dioxo-4-methyl-1,4,5,6 tetrahydro-1,2,4-triazin-3-yl) thiomethyl] -7a-hydroxyaminoceph-3-em-4-carboxylic acid

(a) 7 / 3- [D-2- (4-Benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthiocephalosporanic acid

Benzhydryl-7ß- [D-2- (4-benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthiocephalosporanate (Example 52 [a]) (1.5 g) was treated with aluminum chloride ( 0.72 g) and anisole (1.17 g) were treated in a manner similar to that described in Example 38 (c) to give the title compound (0.96 g). "

IR (KBr) 1785CiTT ¹ . ·

IMMR (DMSO-d ₆ ) S = 1.98 (s, 3H); 2.19 (s, 3H); 3.07-3.69 (m, 4H); 3.78-3.98 (m, 2H), 4:58 (s, 2H); 4.60 and 4.92 (ABq, J = 12.2H); 5.06 (s, 1H); 5.62 (d, J = 6.1 H); 7.14-7.66 (m, 1 OH); 9.67 (s, 1H); 9.81 (d, J = 9, NH).

(b) 7 / 3- [D-2- {4-8-Cyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -3- (5,6-dioxo-4-methyl-1, 4,5,6-tetrahydroi ^^ - triazine-S-yOthiomethyll ^ a-methylthioceph-S-em ^ -carboxylic

The title compound (0.29g) was prepared from the product of part (a) (0.31g) from the appropriate starting materials by the method described in Example 14 (a).

IR (KBr) 1780cm " ¹

NMR (DMSO-de) 5 = 2.21 (s, 3H); 3.11-3.67 (m, 4H); 3.25 (s, 3H); 3.78-3.99 (m, 2H); 3.95 and 4.1.12 (ABq, J = 12 , 2H), 4.95 (s, 2H); 5.04 (s, 1H); (d, J = 6.1H); 7.17-7.58 fm, 1 OH); 9.69 (s JH); 9.82 (d _; J = 6, NH).

(c) 7/3 - [D-2- (4-Benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-tert-butyldiphenylsilyloxyamino-3 - [(5,6-dioxo) 4-methyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl) -thioniethyl] -ceph-3-em-4-carboxylic acid, The 7a-methylthiocephem from part (b) (330 mg) in dimethylformamide (5 ml) was cooled to -50 ⁰ C and treated successively with a solution of mercury (II) acetate (162mg) in dimethylformamide (1 ml) and O- (t.Butyldiphenylsilyl) hydroxylamine in dimethylformamide (2 ml) treated. The resulting clear solution was for 1 hour at 0 ⁰ C. and slowly added to diethyl ether (200 ml) with stirring. After filtering, the ether-wet solid was suspended in methanol (20 ml) and saturated with hydrogen sulfide. The mixture was filtered and evaporated under vacuum. Trituration of the residue with isopropanol gave the title compound as a white solid (50mg).

NMR (DMSO-d ₆ ) S = 0.97 (s, 9H); 2.95-3.66 (m, 4H); 3.24 (s, 3H); 3.81-3.92 (m, 2H); 3.96 and 4.09 (ABq, J = 12,2.H); 4.58 (s, 2H); 5.01 (s, 1H); 5.74 (d, J = 6.1 H); 7.02 (s, 1H); 7.02-7.79 (m, 2OH); 9.85 (d, J = 6, NH); 9.91 (s, 1H).

(d) y / S-tD i ^^ - triazine-S-y-thiomethyne-α-hydroxyaminoceph-S-em ^ -carboxylic acid

DasVa-tert-Butyldiphenylsilyloxyaminocephem ausTeil (c) (50mg) was treated with 40% aqueous hydrogen fluoride for one hour at 0 ⁰ C. Evaporation in vacuo and trituration of the residue with isopropanol gave the title compound (38mg). , ,.

IR (KBr) 1785cm " ¹ .

NMR (DMSO-d ₆ ) 8 = 3.24 (s, 3H); 2.98-3.64 (m, 4H); 3.82-3.94 (m, 2H); 3.92 and 4.09 (ABq, J = 12.2H); 4.59 (s, 2H); 5.02 (s, 1H); 5.68 (d, J = 6.1 H); 7.17-7.58 (m, 1 OH); 8.19 (s, 1 H); 9.58 (s, 1H); 9.87 (d, J = 6, NH).

Example 60

yOthiomethyllceph-S-em ^ carboxylic acid

(a) O-tert-butyldiphenylsilylhydroxylamine

Hydroxylamine hydrochloride (3.48g) and triethylamine (7ml) were stirred in DMF (50ml) at ⁰ ° C for 0.25h, tert-butyldiphenylsilyl chloride (13ml) added and the mixture stirred for 1h. The mixture was partitioned between pentane (500 ml) and water (100 ml), the layers separated, and the aqueous phase extracted with ethyl acetate (2 × 100 ml). The organic layers were combined, washed with brine (50 ml), dried over magnesium sulfate and the solvent removed in vacuo. The crude product was triturated with pentane (20 ml) to give the pure title compound as a white solid (4.04 grams), mp. 85-87 ⁰ C, resulted.

Analysis for Ci ₆ H ₂₁ NOSi,%:.

Found: C 70.67 H 7.78 N 4.87

Calculated: 'C70.84 H7.75 N 5.17.

(b) 7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthio-3 - [(5-chlorobenzothiazol-2-y-thiomethyllceph-S -errM-carboxylic acid

This compound was prepared in a manner similar to that described in Example 6 (b) using S-chloro-1-mercaptobenzothiazole and the same cephem.

IR (KBr) 1785cm- ¹ .

NMR (DMSO-d ₆ ) δ = 1.05 (t, J = 6Hz, 3H); 2.18 (s, 3H); 3.35 (m, 3H); 3.52 (m, 2H); 3.63 (V2ABq, J = 18Hz, 1H); 3.86 (m, 2H); 4.09 and 4.84 (ABq, J = 12Hz, 2H); 5.03 (s, 1H); 5.60 (d, J = 6Hz, 1H); 7.26-7.43 (m, 7H); 7.91 (s, 1H); 8.02 (d, J = 6Hz, 1H); 9.65 (s, 1H); 9.80 (d, J = 6Hz, 1H).

(c) 7β [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-tert-butyldiphenylsilyloxyamino-3 - [(5-chlorobenzothiazol-2-yl) thiomethyl) ceph -3-em-4-carboxylic acid

Das7a-Methylthiocephem from part (b) in dimethylformamide (3ml) was cooled to 6O ⁰ C. A solution of mercuric (II) acetate (0.200g) in dimethylformamide was added, followed immediately by a solution of O-tert-butyldiphenylsilylhydroxylamine (0.185g) in dimethylformamide (3ml). The reaction mixture was stirred for 0.75h, taking. could warm up to +20 ⁰ C. The mixture was then added dropwise to a 2: 1 mixture of ether / petroleum ether (300 ml), the solid filtered off and suspended in methanol (30 ml). , ,.

Hydrogen sulfide was bubbled through the suspension for 0.20 hours with stirring, the mixture was filtered through "Hyflo" (Trade Mark) and the solvent removed in vacuo The crude product was chromatographed on silica Elution was with dichloromethane and increasing ratio of 1: 1 isopropyl alcohol / Acetic acid (up to 3% isopropyl alcohol, 3% acetic acid) .capture and evaporation of appropriate fractions gave the title compound (0.225g). IR (KBr) 1785cm " ^1. "

NMR (DMSO-d ₆ ) δ = 0.94-1.06 (m, 12H); 3.15-3.45 (m, 4H); 3.50 (m, 2H); 3.82 (m, 2H); 4.07 and 4.90 (ABq, J = 12Hz, 2H); 4.91 (s, 1H); 5.72 (d, J = 6Hz, 1H); 7.00 (s, 1H); 7.27-7.65 (m, 17H); 7.93 (s, 1H); 8.00 (d, J = 6Hz, 1H); 9.81 (d, J = 6Hz, 1H); 9.85 (s, 1H).

(d) 7β- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3 - [(5-chlorobenzothiazol-2-yl) thiomethyl] ceph -3-em-4-carboxylic acid

'The 7a-tert-Butyldiphenylsilyloxyaminocephem from part (c) (0.200 g) in acetonitrile (3 ml) was cooled to 0 ⁰ C and treated with 40% hydrofluoric acid (1 ml) for 0.5 h. The reaction mixture was diluted with ethyl acetate (50 ml) and washed thoroughly with saturated brine (4 × 50 ml). The organic layer was dried over magnesium sulfate and the solvent removed in vacuo. The residue was triturated with ether (2 × 30 ml) and the title compound filtered off as a white solid (95 mg). ,

IR (KBr) 1775cm- ¹ . ,

NMR (DMSO-d ₆ ) δ = 1.07 (t, J = 6Hz, 3H); 3.20 and 3.58 (ABq, J = 15Hz, 2H); 3.3-3.45 (m, 2H); 3.53 (m, 2H); 3.85 (m, 2H); 4.08 and 4.79 (ABq, J = 12Hz, 2H); 4.98 (s, 1H); 5.65 (d, J = 6Hz, 1H); 6.46 (s, 1H); 7.23-7.43 (m, 7H); 7.91 (s, 1H); 8.02 (d, J = 6Hz, 1H); 8.12 (s, 1H); 9.52 (s, 1H); 9.85 (d, J = 6Hz, 1H).

Example 61 -

7ß- [D-2- (4-benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] ceph-3-em-4-carboxylic acid

(a) 7β- [D-2- (4-Benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] - 7a-methylthioceph-3-em-4-carboxylic acid

A solution of 7β- [D-2- (4-benzyl-2,3-dioxopiperazin-1-yl-carbonylamino) -2-phenylacetamido] -7amethylthiocephalosporanic acid (Example 59 [a]) (0.31 g) and 5- Mercapto-i-methyl-IH-tetrazole (0.16g) in 1,2-dichloroethane (10ml) was refluxed under nitrogen for 8h. The mixture was cooled to room temperature and the title compound was filtered off and dried in vacuo (0.15 g).

IR (KBr) 1785cm " ¹ .

NMR (DMSO-de) δ = 2.18 (s, 3H); 3.37 and 3.61 (ABq, J = 12.2H); 3.42-3.52 (m, 2H); 3.78-3.99 (m, 2H); 3.89 (s, 3H), 4.13 and 4.36 (ABq, J = 12.2H); 4.58 (s, 2H); 5.02 (s, 1H); 5.61 (d, J = 6.1 H); 7.18-7.54 (m, 10H); 9.67 (s, 1H); 9.81 (d, J = 9, NH).

(b) 7β- [D-2- (4-Benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-t-butyldiphenylsilyloxyamino-3 - [(1-methyl-1H-tetrazole) S-yOthiomethyflceph-S-em ^ -carboxylic

The 7α-methylthiocephem (from Example 61 [a]) (131 mg) in dimethylformamide (5 ml) was cooled to -20 "C and treated successively with mercuric acetate (68 mg) and O-t-butyldiphenylsilylhydroxylamine (58 mg) The resulting clear solution was warmed to room temperature for 1 h and ethyl acetate (75 ml) was added The solution was washed with 2N hydrochloric acid (4 × 25 ml) and saturated sodium chloride (2 × 25 ml), dried over Na ₂ SO ₄ and concentrated by evaporation Evaporated to give the title compound (169 mg) as a yellow solid

IR (KBr) 1785cm- ¹ .

NMR (DMSO-d _e ) .5 = 0.94 (m 9H); 3.04-3.61 (m, 4H); 3.76-3.97 (m, 2H); 3.87 (s, 3H); 4.14 and 4.32 (ABq, J = 12.2H); 4.57 (s, 2H); 4.98 (s, 1H); 5.71 (d, J = 6.1 H); 7.02 (s, 1H); 7.17-7.82 (m, 20H); 9.84 (d, J = 9, NH); 9.89 (s, 1H).

(c) 7β- [D-2- (4-Benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3 - [(1-methyl-1H-tetrazole-S- yl) thiomethyl] ceph-3-em-4-carboxylic acid '

The title compound (85 mg) was prepared from the product of Example 61 (b) (169 mg) by the method described in Example 59 (d).

IR (KBr) 1785cm " ^1. 'Ν

NMR (DMSO-d _e ) δ = 2.95-3.68 (m, 4H); 3.75 to 3.99 (m, 2H); 3.89 (s, 3H); 4.09 and 4.33 (ABq, J = 12.2H); 4.57 (s, 2H); 4.98 (s, 1H); 5.66 (d, J = 6.1 H); 7.08-7.58 (m, 10H); 8.18 (brs., 1 H); 9.52 (s, 1H); 9.86 (d, J = .9, NH).

Examples 62 to 68

The following compounds of formula (I) were prepared from the appropriate starting materials using the method of Example 61 parts (a) to (c). '

Example and Steech Chemistry of the Side Chain R Ph 0 O -CN R ¹ R ² 62 D Ph r -CNO N-benzyl N-CH -S-X (C 63 D N-Et - < 0 ~ ^CH 2 ~ ^S ~ ^ S ^> 1 OH

Example and R Ph R ¹ _ca JbO Ma I Stereochemistry of CH ₂ COOH side chain , Ph -CH -, - O N-a // Vl 64 -C-N N-benzyl -CH - "= - ^ _"> D- 65. . Ph -C-N N-B.enzyl me M \ / N - ^ * D- o * ^ 0 0 -CH «? - ti 66 Ph C-N N-benzyl D- ο σ ^ b 67 / - \ -C N-Et Ph tf / D- ⁰ O ^ O 68 -CU ^ ^ -Et D- °

Example and stereochemistry of the side chain

I.R. (KBr) cm "

IM.'MR (DMSO-d _e )

1785 1780

1780 1785 1785 1785 1785

δ = 2.85-4.01 (m, 8H); 4.09 and 4.38 (ABq, J = 12.2 H); 4.21-4.37 (m, 2H); 4.57 (s, 2H);

4.96 (s, 1H); 5.66 (d, J = 6.1 H); 7.12-7.61 (m, 10H); 9.53 (s, 1H); 9.86 (d, J = 9, NH);

δ = 1.06 (t, J = 6Hz, 3H); 3.19 (1 / 2ABq, J = 18Hz, 1H); 3.23-3.52 (m, 5H); 3.87 (m, 2H);

4.49 (s, 1H); 5.66 (d, J = 6Hz, 1H); 6.87-7.66 (m, 10H); 9, 54

(s, 1H); 9.79 (br.1 H); 9.86 (d, J = 6Hz, NH).

5 = 2.84-4.01 (m, 6H); 4.13 and 4.74 (ABq, J = 12.2H); 4.59 (s, 2H); 5.00 (s, 1H ); 5.66

(d, J = 9.1 H); 7.04-7.62 (m, 12H); 7.87 (d, J = 6.1 H); 8.01 (d, J. = 6.1 H); 8.18 (brs.1 H);

9.54 (s, 1H); 9.87 (d, J = 6, NH).

δ = 2.67 (s, 3H); 3.22 and 3.56 (ABq, J = 12.2 H); 3.42-3.56 (m, 2H); 3.76-3.99 (m, 2H);

4.10 and 4.47 (ABq, J = 15.2 H); 4.59 (s, 2H); 5.01 (s, 1H); 5.67 (d, J = 9.1 H); 6.99 to 7.61

(m, 10H); 9.55 (s, 1H); 9.88 (d, J = 6, NH).

δ = 3.02-3.87 (m, 4H); 3.89-3.97 (m, 2H); 4.10 and 4.44 (ABq, J = 15.2 H); 4.58 (s, 2H);

4.94 (s, 1H); 5.25 and 5.29 (ABq, J = 12.2 H); 5.66 (d, J = 6.1H); 7.03-7.58 (m, 10H); 9.53

(s, 1H); 9.86 (d, J = 6, NH).

5 = 1.02 (t, J = 6.3H), 3.08-3.78 (m, 6H + HOD), 3.87 (m, 2H), 4.06 and 4.42 (ABq, J = 12 .

2H); 4.97 (s, 1H); 5.67 (d, J = 6.1 H); 7.12-7.58 (m, 5H) 7.61-7.78 (m, 2H); 9.56 (s, 1H);

9.86 (d, J = 6, NH). .

δ = 1.05 (t, J = 6.3 H); 2.48 (s, 3H); 2.98-3.63 (m, 6H); 3.87 (m, 2H); 4.13 and 4.56 (ABq,

J = 15.2H); 5.00 (s, 1H); 5.66 (d, J = 9.1 H); 7.16 to 7.57 (m, 5H); 8.17 (brs.1 H); 9.53 (s, 1H);

9.86 (d, J = 9, NH).

Beispiel69

3 - [(1-carboxymethyl-1-H "tetrazol-5-ylthiomethyl] -7ß [(2R, 3S) -3-hydroxy-2- (2-oxo-3-methansulfonylimidazolidin-1-ylcarbonylaminolbutanamidol-Ta-hydroxyaminoceph- S-em-'l-carboxylic acid

(a) (2R, 3S) -3-hydroxy-2- (2-oxo-3-methanesulfonylimidazolidin-1-ylcarbonylamino) butanoic acid

D-Threonine (5.0g) was suspended in water (50ml) and treated with 2M aqueous sodium hydroxide solution until pH = 10 to give a clear solution. The pH was then readjusted to 7.5 with concentrated hydrochloric acid and the still clear solution cooled to 15 ° C. 3-Methanesulfonyl-2-oxoimidazolidine-i-carbonyl chloride (9.5 g) was then added portionwise over 2 min, with the simultaneous addition of 2 M aqueous sodium hydroxide to maintain the pH at 6.0 to 7.5. Thereafter, acetone (30 ml) was added to give a clear solution, which was then stirred at room temperature for 1 h, while maintaining the pH at 6.0 to 7.5. After evaporation of the acetone in vacuo, the aqueous residue was extracted well with ethyl acetate and the organic extracts were discarded. The pH of the aqueous phase was then adjusted to 1.5 with concentrated hydrochloric acid and the mixture extracted with 3 x 50 ml portions of ethyl acetate / tetrahydrofuran (1: 1). The organic extracts were dried and the solvent was evaporated to give the title compound as a white solid (7.3 g).

IR (KBr) 1735cm " ^1. ·· · ·.

NMR (DMSOd ₆ ) 5 = 1.08 (d, J = 6.3H), 3.35 (s, 3H), 3.72-3.85 (m, 4H), 4.11-4.21 ( m, 2H), 8.21 (d, J = 8, NH).

(b) Ben2hydryl-3-acetoxymethyl-7β - [(2R, 3S) -3-hydroxy-2- {2-oxo-3-methanesulfonyl-imidazolidin-1-ylcarbonylamino) -butanamido] -7a-methylthioceph-3-em-4 carboxylate -

The product of the preceding step (69 [a]) was coupled with benzhydryl-7β-amino-7a-methylthiocephalosporanate (9.5 g) according to the procedure used for Example 46 (a) Silica gel chromatography (methylene chloride / ethyl acetate gradient).

gave the title compound as a yellow foam (6.5g). ,

IR (KBr) 1785CITT ¹ . ,

NMR (CDCl ₃ ) δ = 1.29 (d, J = 6, 3H); 2.05 (s, 3H); 2.36 (s, 3H); 2.94 and 3.33 (ABq, J = 21, 2H); 3.01 (d, J = 3.1 H Aust); 3.35 (s, 3H); 3.96 (s, 4H); 4.43-4.49 (m, 2H); 4.90 and 5.14 (ABq, J = 13, 2H); 4.97 (s, 1H); 6.92 (s, 1H); 7.29-7.50 (m, 11H, 2 x C ₆ H ₅ and CONH); 8.62 (d, J = 6, CNNH).

(c) 3-Acetoxymethyl-7β - [(2R, 3S) -3-hydroxy-2- (2-oxo-3-methanesulfonylimidazolidin-1-ylcarbonylamino) butanamido] -7-thioceioceph-3-em-4-carboxylic acid

Treating the benzhydryl ester (from Example 69 [b]) (4.5g) with trifluoroacetic acid and anisole as in Example 57 (a) gave the title compound (2.85g) as a white solid from dichloromethane / diethyl ether.

IR (KBr) 1785Cm " ¹ .

NMR (DMSOd ₆ ) δ - 1.09 (d, J = 6.3H); 2.02 (s, 3H); 2.26 (s, 3H); 3.36 (s, 3H); 3.38 and 3.59 (ABq, J = 18.2H); 3.74-3.84 (m, 4H); 3.96-4.00 (m, 1H); 4.29-4.35 (m, 1H); 4.65 and 4.95 (ABq, J = 14, 2H); 5.06 (s, 1H); 8.25 (d, J = 7, NH); 9.17 (s, 1H).

(d) 3 - [(1-Carboxymethyl-1H-tetrazol-5-yl) thiomethyl] -7β - [(2R, 3S) -3-hydroxy-2- (2-oxo-3-methanesulfonyl-imide-azolidin-1-one ylcarbonylaminoibutanamidol ^ a-methylthioceph-S-em ^ -carboxylic

The product from the previous Example (69 [c]) (426 mg) was reacted with 1-carboxymethyl-1H-tetrazole-5-thiol (134 mg) as in Example 9 (a) to give the title compound as a light tan solid after trituration with ethyl ether (20ml) (310mg) too

_Hefem. =. __:

IR (KBr) 1780cm " ¹ .

NMR (DMSOd ₆ ) δ = 1.08 (d, J = 6, 3H) ;, 2.23 (s, 3H); 3.20-3.49 (m, 5H); 3.73-3.79 (m, 4H); 3.97 (m, 1H); 4.16 and 4.45 (ABq, J = 14, 2H); 4.27-4.28 (m, 1H); 4.98 (s, 1H); 5.04-5.05 (m, 1H Aust.); 5.29-5.30 (m, 2H); 8.23 (d, J = 6, NH); 9.17 (s, 1H, Aust).

(e) 7a- (t-butyldiphenylsilyloxyamino) -3 - [{1-carboxymethyl-1H-tetrazol-5-yl) thiomethyl] -7β - [{2R, 3S) -3-hydroxy-2- (2-oxo) 3-methansulfonylimidazolidin-i-carbonylaminoJ butanamidolceph-S-em ^ -carboxylic acid A solution of the 7a-Methylthiocephem (from example 69 [d]) (310 mg) in dimethylformamide (5ml) was cooled to -30 C and ^c (with mercury ll The clear solution was warmed to 0 ° C for 0.5h, added to 0.5m hydrochloric acid (25ml) and 2 x 20ml portions of ethyl acetate / tetrahydrofuran The combined organic extracts were washed with 3 x 20 mL water, 1 x 20 mL hydrochloric acid, dried, and the solvent was evaporated to give a tan solid, trituration with diethyl ether afforded the title compound (210 mg).

IR (KBr) I 785cm " ¹ .

NMR (DMSOd ₆ ) δ = 0.96 (s, 9H); 1.08 (d, J = 6, 3H); 3.35 (s, 3H); 3.37-3.79 (m, 6H); 4.02 (brs., 1H); 4.19 and 4.38 (ABq, J = 12, 2H); 4.34 (m, 1H); 4.99 (s, 1H); 5.00 (brs., 1 H Aust.); 5.27 (s, 2H); 6.98 (s, 1H); 7.35: 7.66 (m, 10H); 8.24 (d, J = 7, NH); 9.33 (s, 1H).

(f) 3 - [{1-carboxymethyl-1H-tetrazol-5-ylthiomethyl] -7a-hydroxyamino-7β - [{2R, 3S) -3-hydroxy-2- [2-oxomethanesulfonyiimidazolidin-1-ylcarbonylaminolbutanamidolceph-S] em ^ -carboxylic acid the protected hydroxylamine derivative from the previous step (69 [e]) (205 mg) in acetonitrile / tetrahydrofuran (4ml 1: 1) was cooled to 0 to 5 ⁰ C and then treated with 40% aqueous hydrogen fluoride ( 0.25 ml). After 0.5 h, the solution was evaporated to dryness in vacuo, the residue dissolved in 1: 1 isopropanol / methanol (20 ml) and evaporated again. The crude product was dissolved in methanol (10 ml), filtered and the solution evaporated to about 2 ml. It was then added dropwise to stirred diethyl ether (25ml) to give the title compound as a white solid after filtration and drying in vacuo (137mg).

IR (KBr) 1780cm " ¹ .

NMR (DMSOd ₆ ) δ = 1.08 (d, J = 6.3H); 3.35 (s, 3H); 3.42-3.89 (m, 6H); 4.02-4.03 (m, 1H); 4.15 and 4.41 (ABq, J = 15, 2H); 4.32-4.34 (m, 1H); 5.03 (s, 1H); 5.30 (s, 2H); 8.26 (d, J = 6, CHNH); 8.92 (s, 1H).

Example 70

3-acetoxymethyl-7.beta. - [(2R, 3S) -3-hydroxy-2- {2-oxo-3-methansuIfonyiimidazolidin-1-ylcarbonyIamino) butanamido3-7ahydroxyaminoceph-S-em ^ -carboxylic acid

(a) 3-Acetoxymethyl-7a> {t-butyldiphenylsilyloxyamino) -7β - [(2R, 3S) -3-hydroxy-2- (2-oxo-3-methanesulfonyl-imidazolidin-1-ylcarbonylamino] butanamidolceph-S-enicarboxylic acid

The title compound (315 mg) was prepared by reacting the 7-methylthiocephem (from Example 69 [c]) (305 mg) with O-t-butyldiphenylsilylhydroxylamine and mercuric acetate as previously described in Example 69 (e).

NMR (DMSOd ₆ ) O = 0.99 (s, 9H); 1.11 (d, J = 6.3H); 2.02 (s, 3H); 3.33 and 3.52 (ABq, J = 18.2H); 3.34 (s, 3H); 3.67-3.78 (m, 4H); 4.01-4.05 (m, 1H); 4.34-4.37 (m, 1H + 1H Aust.); 4.66 and 4.93 (ABq, J = 12.2H); 5.03 (s, 1H); 7.02 (s, 1H); 7.31-7.69 (m, 10H); 8.27 (d, J = 8, CHNH); 9.33 (s, 1H).

(b) 3-Acetoxymethyl-7β - [(2R, 3S) -3-hydroxy-2- (2-oxo-3-methanesulfonylimidazolidin-1-ylcarbonylamino) butanamido] -7ahydroxyaminoceph-S-emcarboxylic acid

The protected 7a-hydroxyaminocephem from the previous example (70 [a]) (310 mg) was treated with 40% aqueous hydrofluoric acid according to the procedure previously described in Example 69 (f). Trituration of the crude product with dichloromethane (10ml) at ⁰ ° C gave the title compound as an off-white solid (205mg).

IR (KBr) 1785cm " ¹ '',

NMR (DMSOd ₆ ) δ = 1.09 (d, J = 6, 3H); 2.02 (s, 3H); 3.35 (s, 3H); 3.32 and 3.52 (ABq, J = 18, 2H); 3.77-3.83 (m, 4H); 4.02rA05 <n% 1H); 4.31-4.35 (m, 1H); 4.61 and 4.90 (ABq, J = 14, 2H); 5.10 (s, 1H) 8.26 (d, J = 7, CHNH); 8.90 (s, 1 H est).

Example 71. , .-

7β- [D-2- (4-Benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -3 - [(5-carboxymethyl-4-methylthioazol-2-yl-thiomethyl) -1-hydroxyaminoceph-S em ^ -carboxylic

(a) 7β- [D-2- (4-Benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -3 - [(5-carboxymethyl-4-methylthiazol-2-yl) thiomethyl] - 7a-methylthioceph-3-em-4-carboxylic acid

The title compound (155 mg) was prepared by reacting the corresponding 3-acetoxymethylcephem (Example 59 [a]) (204 mg) with o-carboxymethyl-methylthiazole-thiol (85 mg) according to the method previously described in Example 9Ja). 1R (KBr) 1785cm " ^1. " .-. -

NMR (DMSO-d _e ) δ = 2.19 (s, 6H, 2xCH ₃ ); 3.22-3.58 (m, 4H); 3.73 (s, 2H); 3.86-3.87 (m, 2H); 3.98 and 4.46 (ABq, J = 16, 2H); 4.58 (s, 2H); 5.02 (s, 1H); 5.62 (d, J = 7, CHNH); 7.25-7.44 (m, 10H); 9.66 (s, 1H); 9.82 (d, J = 7, NH).

(b) 7β- [D-2- (4-Benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-t-butyldiphenylsilyloxyamino-3 - [(5-carboxymethyl-4-methylthiazole-2 -yl) thiomethyl] ceph-3-em-4-carboxylic acid

The 7a-methylthiocephem from the previous example (71 [a]) (280 mg) was treated with mercury (II) acetate and ot-butyldiphenylsilylhydroxylamine as previously described for Example 69 (e). Trituration of the crude product with

Diethyl ester gave the title compound (255mg). , ,

IR (KBr) 1785crrr ¹ .

NMR (DMSO-d _e ) δ = 0.96 (s, 9H); 2.19 (s, 3H); 3.11-3.45 (m, 4H); 3.72 (s, 2H); 3.86 (m, 2H); 4.00 and 4.46 (ABq, J = 16.2H); 4.58 (s, 2H); 4.98 (s, 1H); 5.71 (d, J5 = 7, CHNH); 7.02 (s, 1H); 7.29-7.68 (m, 20H); 9.84-9.88) (m, 2H).

Jc) 7β- [D-2- (4-Benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -3 - [(5-carboxymethyl-4-methylthiazole-2-yl]

yOthiomethyll ^ a-hydroxyaminoceph-S-em ^ -carboxylic

Deprotection of the 7a-t-butyldiphenylsilyloxyaminocephem (250 mg) obtained in Example (71 [b] above) with 40% aqueous hydrofluoric acid as previously described for Example 69 (f) afforded the title compound as a white solid

(172 mg). .

IR (KBr) 1785cm " ¹ .

NMR (DMSO-de) δ = 2.19 (s, 3H); 3.15 and 3.56 (ABq, J = 18, 2H); 3.47 (m, 2H); 3.73 (s, 2H); 3.86-3.87 (m, 2H); 3.96 and 4.42 (ABq, J = 16, 2H); 4.57 (s, 2H); 4.98 (s, 1H); 5.66 (d, J = 7, CHNH); 7.30-7.45 (m, 10H); 9.53 (s, 1Ή); 9.87 (d, J = 7, CHNH).

Example 72

7ß- [D-2- (4-benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -3 - [(5-carboxymethyl-4H-1,2,4-triazol-3-ylJthiomethyn ^ a-hydroxyaminoceph-S-em ^ -carboxylic

(a) 7β- [D-2- (4-Benzyl-2,3-dioxopiperazine-1-ylcarbonyl-amino) -phenylacetamidol-S-KB-carboxymethyl-H-1,2,4-triaol-3-yl) -thiomethyl] -7a-methylthioceph-3-em-4-carboxylic acid

The 3-acetoxymethyl cephem (204 mg) obtained in Example 59 (a) was suspended in water (7 mL) and acetone (3 mL) and treated with S-carboxymethyl-HI ^ atriazole-S-thiol (57 mg). Sodium bicarbonate (55mg) was added to give a clear solution (pH 6.5) which under a nitrogen atmosphere for 5 hours with addition of 5% aqueous sodium bicarbonate to maintain the pH at 6.0-6.5 6O ⁰ C was heated. The solution was cooled to room temperature, extracted with ethyl acetate, and the organic extracts were discarded. The aqueous phase was then acidified with a concentrated hydrochloric acid (pH 2) and the precipitated oily solid extracted with 2 χ 20ml portions of ethyl acetate / tetrahydrofuran. The extracts were dried, yielding a pale yellow solid which on trituration with ethyl acetate (5mL) gave the title compound as a white solid (115mg).

IR (KBr) 1780cm- ¹ . '·

NMR (DMSOd ₆ ) O = 2.20 (s, 3H), 3.23-4.27 (m, 11H, 2 x piperazine-CH 2 Cl- ^ H ^ H ^ -Het-O ^ CC ^ H and triazole NH), 4.59 (s, 2H), 5.01 (s, 1H), 5.62 (d, J = 7, CHNH), 7.32-7.45 (m, 10H, 9 , 67 (s, 1H), 9.83 (d, J = 7, NH).

jb) 7β- [D-2- (4-Benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-t-butyldiphenylsilyloxyamino-3 - [(5-

carboxymethyl ^ H ^ I Atriazol S yllthiomethynceph-S-em ^ -carboxylic

The product from the previous example (72 [a]) (100 mg) was treated with mercury (II) acetate and O-t-butyldiphenylsilylhydroxylamine as previously described for Example 69 (e). Trituration of the crude product with diethyl ether (5ml) gave the title compound as a white solid (87mg).

NMR (DMSO-ds) δ = 0.95 (s, 9H); 3.09-3.45 (m, 6H, C ₂ -2H, piperazine CH ₂ and Het-CH ₂ CO ₂ H); 3.73 (s, 1H); 3.83-3.86 (m, 2H); 3.95 and 4.21 (ABq, J = 16, 2H); 4.57 (s, 2H); 4.97 (s, 1H); 5.70 (d, J = 7, CHNH); 7.00 (s, 1H); 7.27-7.67 (m, 20H); 9.85 (d, J = 7, NH);

(c) 7β [D-2- (4-Benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -3 - [(5-carboxymethyl-4H-1,2,4-triazole-3-one yOthiomethy ^ a-hydroxyaminoceph-S-em ^ -carboxylic

Deprotection of the 7a-t-butyldiphenylsilyloxyamino cephem (80 mg) obtained in the previous example (72 [b]) with 40% aqueous hydrofluoric acid as described for Example 69 (f) gave the title compound (47 mg).

NMR (DMSOd ₆ ) δ = 3.11-4.35 (m, 11 H, C ₂ -2H, 2 x piperazine-CH ₂ , CH ₂ S-Het-CH ₂ CO ₂ H and triazole-NH); , 57 (s, 2H); 4.96 (s, 1H); 5.65 (d, J = 6, CHNH); 6.45 (s, 1H); 7.25-7.44 (m, 10H); 8.13 (s, 1H); 9.53 (s, 1H); 9.86 (d, J = 6, CHNH).

Example 73

(a) 7β- [D-2- (4-Benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthio-3 - [(1-potassium-sulfomethyl-1H-tetrazole-B-y-thiomethylcylph -S-em ^ -carboxylic

7β- [D-2- (4-Benzyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-methylthiocephalosporanic acid (Example 59 [a]) (306 mg) was treated with 1-sulfomethyl-iH tetrazole-5-thiol-sodium salt (196 mg) in a similar manner as described in Example 36 (a) to give the title compound (278 mg).

IR (KBr) 1780cm- ¹ . :.

NMR (DMSO-d ₆ ) 5 = 2.18 (s, 3H); 3.16 and 3.56 (ABq, J = 9.2H); 3.41 to 3.55 (m, 2H); 3.80-3.97 (m, 2H); 4.05 and 4.43 (ABq, J = 9, 2H); 4.57 (s, 2H); 4.88-5.13 (m, 3H); 5.61 (d, J = 6.1 H); 7.16-7.62, (m, 10H); 9.65 (s, 1H); 9.80 (d, J = 6, NH).

(b) 7β [D-2- (4-Benzyl-2,3-dioxopiperazin-1-yl-carabonylamino) -2-phenylacetamido] -7a- (t-butyldiphenylsilyloxyamino) -3 - [(1-sulfomethyl-1H-tetrazole -5-yl) thiomethyi] ceph-3-em-4-carboxylic acid

The title compound (208 mg) was prepared from the 7a-methylthiocephem (Example 73 [a]) (272 mg) following that described in Example 61 (b).

produced method described.

IR (KBr) 1785cnrr ¹ . , '. ,

NMR (DMSO-d ₆ ) δ = 0.96 (s, 9H); 3.09-3.62 (m, 4H); 3.78-3.97 (m, 2H); 4.07 and 4.38 (ABq, J = 12, 2H); 4.58 (s, 2H); 4.88-5.10 (m, 3H); 5.71 (d, J = 6.1 H); 7.02 (s, 1H); 7.16-7.82 (m, 20H); 9.86 (d, J = 6, NH); 9.92 (s, 1H).

(c) 7β- [D-2- (4-Benzyl-2,3-dioxopiperazine-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3 - [(1-sulfomethyl-1H-tetrazole-S-y-thiomethylcylceph- S-em ^ -carboxylic

The title compound (58 mg) was prepared from the product of Example 73 (b) (200 mg) by the method described in Example 59 (d).

IR (KBr) 1790cm "" ¹ .

NMR (DMSO-d ₆ ) δ = 2.95-3.78 (m, 4H + HOD); 3.79-3.96 (m, 2H); 4.02 and 4.41 (ABg, J = 12, 2H); 4.58 (s, 2H); 4,87-5,13 (m,

3H); 5.67 (d, J = 6.1 H); 7.01-7.62 (m, 10H); 9.56 (s, 1H); 9.86 (d, J = 6, NH). - '

Example 74

7ß- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3 - [(4-carboxy-3-hydroxyisothiazole-S-S- yOthiomethyllceph em ^ -carboxylic

(a) 7β- [D-2- {4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylac8-tamido] -7a-methylthio-3 - [(4-carboxy-3-hydroxyisothiazole-S-y-thiomethyllceph -S-ERRM-carboxylic acid

This compound was prepared from the appropriate starting materials by the method of Example 9 (a).

IR (KBr) 1770cm " ^1. · .., · '

NMR (DMSO-d ₆ ) δ = 1.05 (t, J = 7.3H); 2.25 (s, 3H); 2.9-3.9 (m, 8H + HOD); 3.95 and 4.25 (2H, ABq, J = 12); 5.1 (s, 1H); 5.65 (d, J = 6.1H); 7.2-7.5 (m, 5H); 9.65 (s, NH); 9.8 (d, J = 6, NH).

(b) 7β- [D-2- {4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-t-butyldiphenylsilyloxyamino-3 - [{4-carboxy-S-hydroxyisothiazole-B yo-thiomethyflceph-S-em ^ -carboxylic

The above compound was prepared from the product of the preceding step (74 [a]) by the method of Example 59 (c).

IR (KBr) 1770cm "" ¹ . -

NMR (DMSO-d ₆ ) δ = 0.95 (s, 9H); 1.05 (t, J = 7, 3H); 3.1-4.3 (m, 10 + HOD); 4.81 (s, 1H); 5.75 (d, J = 6.1 H); 6.95 (s, NH-OH); 7.2-7.8 (m, 15H); 9.75 (s, NH); 9.85 (d, J = 6, NH).

(c) 7β- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylo} amino) -2-phenylacetamido] -7a-hydroxyamino-3 - [{4-carboxy-3-hydroxyisothiazole-5 -yl) thiomethyl] ceph-3-em-4-carboxylic acid

The above compound was prepared from the product of the previous step (74 [b]) by the method of Example 59 (d).

IR (KBr) 1780cm "· ^1. '-

NMR (DMSO-d ₆ ) δ = 1.03 (t, J = 7, 3H); 3.1-3.7 (m, 6H); 3.85-3.90 (m, 2H); 3.95 and 4.2 (2H, ABq, J = 12); 5.03 (s, 1H); 5.66 (d, J = 6.1 H); 6.5 (brs, NH-OH); 7.1-7.5 (m, 5H); 8.18 (s, NHOH); 9.54 (s, NH); 9.86 (d, J = 6, NH).

Example 75

7β- [2- (R) - (4-Ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -3- (S) -hydroxybutanamido] -7ahydroxyamino-3 - [(1-potassium-sulfomethyl-1H-tetrazole-S -ylJthiomethyllceph-S-em ^ carboxylic acid

(a) 7β - [(2- (R) - {4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -3- (S) -t-butyldimethylsilyloxybutanamido] -7-thio-thiocephalophosphoric acid

A suspension of 7β - [(2- (R) - (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -3- (S) -hydroxybutanamido] -7-thio-thiocephalosporanic acid (2.0g) in methylene chloride (50ml) was added Stirred at room temperature under a nitrogen atmosphere and treated with 2,6-Lutidih (1.19 ml) to give a clear solution To this solution was added t-butyldimethylsilyl trifluoromethylsulfonate (2.35 ml) and the mixture was stirred for 5 min, 1 m Hydrochloric acid, (dried over MgSO4 and evaporated to dryness.) The residue was triturated with hexane and filtered to give the title compound (1.56g)

IR (KBr) 1786crrT ¹ .

NMR (DMSO-d ₆ ) 5 = 0.05 (s, 6H), 0.85 (s, 9H), 1.08 (t, 3H, J = 6), 1.14 (d, 3H, J = .6), 2.02 (s, 3H), 2.24 (s, 3H); 3.29 to 3.62 (m, 6H); 3.91 (m, 2H); 4.20 (m, 1H); 4.41 (m, 1H); 4.64 and 4.94 (ABq, 2H, J = 12); 5.02 (s, 1H); 9.03 (s, .1H); 9.30 (d, 1H, J = 6).

(b) 7β- [2- {R) - (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -3- (S) -t-butyldimethylsilyloxybutanamido] -7a-methylthio-3 - [(1-potassium sulfomethyl -1 H-tetrazole-B-ythiomethyl-ceph-S-em ^ -carboxylic acid

This compound was prepared from the product of the previous step by the method of Example 36 (a) using suitable starting materials. »

¹ '

NMR (DMSO-d ₆ ) δ = 0.04 (s, 6H); 0.83 (s, 9H); 1.07 (t, 3H); J = 6); 1.14 (d, 3H, J = 6); 2.23 (s, 3H); 3.29-3.72 (m, 6H); 3.88 (m, 2H); 4.05 and 4.47 (ABq, 2H, J = 15); 4.19 (m, 1H); 4.40 (m, 1H); 4.95 (m, 2H); 4.99 (s, 1H); 9.05 (s, 1H); 9.27 (d, 1H, J = 9).

(c) 7β- [2- (R) - (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -3- {S) -t-butyldimethylsilyloxybutanamide d] -7a-hydroxyamino-3 - [(i-kaHum sulfomethyl -IH-tetrazol-B-y-o-thiomethyl-ceph-S-em -carboric acid This compound was prepared from the product of the preceding step by the method of Example 9 (b).

IR (KBr) 1780cm- ¹ /

NMR (DMSO-d ₆ ) δ = 0.03 (s, 6H); 0.84 (S, 9H); 1.08 (t, 3H, J = 6); 1.18 (d, 3H, J = 6); 3.21-3.63 (m, 6H); 3.90 (m, -2H); 4.08-4.48 (m, 4H); 4.99 (m, 3H); 6.38 (brs, 1H); 7.95 (s, 1H); 8.83 (brs, 1H); 9.31 (d, 2H, J = 6).

(d) 7β- [2- (R) - (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -3- (S) -hydroxybutanamido] -7a-hydroxyamino-3 - [(1-potassium-sulfomethyl-1 H-tetrazol-B-y-thiomethyll-ceph-S-em ^ -carboxylic

A suspension of dilated cephem of part (c) (80 mg) in acetonitrile (5 cm ³ ) was treated dropwise with aqueous hydrogen fluoride (2 ml 40% HF) for 2 min to give a clear solution. The mixture was stirred for 5min, evaporated to dryness, the residue taken up in methanol (5cm ³ ), filtered, evaporated to dryness, triturated with methylene chloride and the solid separated by filtration to give the title compound (38mg).

IR (KBr) 1785cm " ¹ .

NMR (DMSO-d ₆ ) δ = 1.06 (m, 6H), 3.36-4.40 (m, 12H), 4.98 (m, 3H), 8.96 (s, 1H) , 9,26 (d, 1 H, J = 6).

Example 76

3-acetoxymethyl-2ß- [DL-2- [3- (2-hydroxyethyl) -2-oxoimidazolidin-1-ylcarbonylamino] -2-phenylacetamido] -7ahydroxyaminoceph-3-em-4-carboxylic acid

(a) 1- (2-t-butyldiphenylsilyloxyethyl) -2-oxoimidazolidine

A solution of 1- (2-hydroxyethyl) -2-oxoimidazolidine (13g) in dimethylformamide (50ml) containing imidazole (7.5g) was treated with n-butyl chloride-phenylsilane (28.6ml) and the clear solution was added 3h Room temperature stirred. The formed white suspension was dissolved in water (200 ml) and ethyl acetate (500 ml). The aqueous phase was back-extracted with ethyl acetate (100 ml) and the combined organic phases were washed with 3 x 100 ml portions of water, 1 x 100 ml brine, dried and evaporated to a solid. Trituration of the solid with diethyl ether (100 mL) afforded the title compound as a white solid (33.7 g). *

NMR (CDCl ₃ ) O = 1.08 (s, 9H), 3.35-3.42 (m, 4H), 3.57-3.62 (m, 2H), 3.81 (t, J = s, 2H), 4.47 (brs, 1H), 7.38-7.69 (m, 10H). (b) 3- (2-t-butyldiphenylsilyloxyethyl) -2-oxoimidazolidine-1-carbonyl chloride

The product from the previous step (736g) in 1,2-dichloroethane (50ml) was treated with N-trimethylsilyldiethylamine (7.6g) and the solution heated at reflux for 0.5h. After cooling, the solvent was removed by evaporation in vacuo and the residue was re-evaporated with 2 × 50 ml portions of carbon tetrachloride to give the 1-trimethylsilyl derivative as a light orange oil (8.8 g). This was dissolved in dry dichloromethane (50 ml) and treated with 2,2,2-trichloroethyl chloroformate (1.33 ml).

The solution was stirred at room temperature for 18h, evaporated to dryness, and the residue re-evaporated with 2 x 50 mL portions of dichloromethane / carbon tetrachloride (1: 1) to afford the title compound as an orange brown foam (8.45 g).

NMR (CDCl ₃ ) O = 1.05 (s, 9H), 3.27-3.96 (m, 8H), 7.15-7.60 (m, 10H). , -

(c) D-2- [3- (2-t-butyldiphenylsilyloxyethyl) -2-oxoimidazolidin-1-ylcarbonylamino] -2-phenylacetic acid D-phenylglycine (3.02g) and N, N-diethyltrimethylsilylamine (15.1ml). were stirred for 5 h at reflux and the resulting clear solution was evaporated to dryness in vacuo. The residue was re-evaporated from 2 x 40 ml portions of carbon tetrachloride to give a viscous oil. This oil (10 ml) was dissolved in dichloromethane and over 2 min to a precooled (-20 ⁰ C) solution of 3- (2-t-Butyldiphenylsilyloxyethyl) -2-oxoimidazolidine-1-carbonyl chloride (from part (b) 8, 45 g) in dichloroethane (30 ml). The solution was warmed to 20 ^° C. over 1 h, stirred for 18 h, then washed with water (3 × 20 ml), dried and evaporated to dryness in vacuo. The crude product was purified by silica gel chromatography (dichloromethane / isopropanol gradient) to give the title compound as a white foam (8.7 g).

IR (KBr) 1740cm- ¹ . .

NMR (CDCl ₃ ) δ = 1.07 (s, 9H), 3.35-3.50 (m, 4H), 5.54 (d, J = 7, CHNH), 7.32-7.68 ( m, 15H), 8.95 (brs, 1H), 9.16 (d, J = 7, NH).

(d) Benzhydryl-3-acetoxymethyl-7β- [DL-2- [3- (2-t-butyldiphenylsilyloxyethyl) -2-oxoimidazlidine-1-carbonylamino-2-phenylacetamido] -7a-methylthioceph-3-em-4- carboxylate

The product from the previous step (1.09 g) was coupled with benzhydryl-β-amino-α-methylthiocephalosporanate (968 mg) according to the procedure described in Example 50 (a). Silica gel chromatography (dichloroethane / ethyl acetate gradient) gave the title compound as a pale yellow foam (840mg).

IR (KBr) I 785cm- ¹ ..

NMR (CDCl ₃ ) δ = 1.05 and 1.06 (2 χ s, 9H); 2.02,2.03,2,14 and 2,27 (4 χ s, 6H, OCOCH ₃ andSCH ₃ ); 3.31 to 3.54 (m, 6H); 3.69-3.83 (m, 4H); 4.86 and 5.11,4.88 and 5.12 (2 χ ABq, J = 14.2H); 4.91 and 4.92 (2 xs, 1H); 5.60 and 5.62 (2 χ d, J = 7, CHNH); 6.88 (s, TH); 6.92 and 6.93 (2 xs, 1H); 7.25-7.68 (m, 25H); 9.19-9.23 (m, NH).

(e) Benzhydryl-3-acetoxymethyl-7β- [DL-2- [3- {2-hydroxyethyl) -2-oxoimidazol-1-ylcarbonylamino] -2-phenylacetamido] -7-methylthioceph-S-em ^ -carboxylate.

Dast-butyldiphenylsilyloxyethyl derivative from the previous part (Example 76 [d]) (650 mg) in acetonitrile (10 ml) was added

0 to 5 ⁰ C with 40% aqueous hydrofluoric acid (2 ml). The solution was stirred for 3 hours at this temperature and then for a further 3 hours at room temperature. After adding to excess saturated aqueous sodium bicarbonate, the mixture was extracted with ethyl acetate (50 ml) and the organic extract was dried and evaporated. Purification of the crude product by silica gel chromatography (ethyl acetate / isopropanol gradient) gave the title compound (340 mg).

JR (KBr) 1785cm- ¹ . '

NMR (CDCl ₃ ) δ = 1.98, 2.00 and 2.22 (3xs, 6H, SCH ₃ and OCOCH ₃ ); 2.97 (brs., 1H); 3.17-3.46 (m, 6H); 3.72-3.84 (m, 4H); 4.81 and 5.04,4.81 and 5.05 (2 χ ABq, J = 14.2 H); 4.86 and 4.90 (2 xs, 1H); 5.80 and 5.82 (2 xd, J = 7, CHNH); 6.86 and 6.87 (2 χ s,

1H); 7.22-7.50 (m, 15H); 7.64 and 7.68 (2 χ s, 1H); 9.28 and 9.29 (2 xd, J = 7, NH). ^ä

(f) 3-Etcoxymethyl-7β- [DL-243- (2-hydroxyethyl) -2-oxo-imide-azolidin-1-ylcarbonylamino] -2-phenylacetamido] -7-methylthioceph-S-em-1-carboxylic acid

Treating the benzhydryl ester from the previous step (340 mg) with trifluoroacetic acid as described in Example 57 (a) gave the title compound (215 mg).

IR (KBr) 1780 cm ^-1 ; NMR (DMSO-d ₆ ) δ = 1.88, 1.98, 2.00 and 2.18 (4 χ s, 6H, SCH ₃ and OCOCH ₃ ); 3.19-3.72 (m, 10H); 4.60 and 4.91, 4.64 and 4.97 (2 χ ABq, J = 13, 2H); 4.76 (brs., OH); 5.03 and 5.04 (2 xs, 1H); 5.59 and 5.61 (2 xd, J = 7, CHNH); 7.24-7.41 (m, 5H); 9.02 and 9.11 (2 xd, J = 7, NH); 9.57 and 9.60 (2 χ s, 1 H).

(g) 3-Acetoxymethyl-7β- [DL-2- [3- (2-hydroxyethyl) -2-oxo-imidazolidin-1-ylcarbonylamino] -2-phenylacetamido / -7ahydroxyaminoceph-S-em-^ -carboxylic acid

The title compound (53 mg) was prepared by treating the 7a-methylthiocephem (210 mg) obtained in the previous step with mercuric acetate and hydroxylamine hydrochloride and triethylamine as described in Example 9 (b) above.

IR (KBr) 1785cm " ¹ .

NMR (DMSO-d ₆ ) = 1.98 and 2.00 (2 χ s, 3H); 3.13-3.66 (m, 10H); 4.56 and 4.86, 4.60 and 4.90 (2 x ABq, J = 13, 2H); 5.00 and 5.06 (2 xs, 1H); 5.62-5.64 (m, CHNH); 7.24-7.41 (m, 5H); 8.07-8.15 (brm., 1H); 9.05-9.10 (m, NH); 9.35 and 9.45 (2 xs, 1H).

Example 77

7ß- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3-carbamoyloxymethyi-ceph-3-em-4-carboxylic acid

(a) Sodium ^ ß-ID ^^ ethyl - ^^ - dioxopiperazine-i-ylcarbonylaminoJ ^ -phenylacetamido-1-methylthio-S-hydroxymethylceph-S-em ^ -carboxylate

The 3-acetoxymethyl compound of Example 6 (a) (1.5 g) in water (60 ml) was treated with sodium bicarbonate (0.2 g) followed by a solution of wheat germ lipase (Sigma L 3001 [Trade Mark]; 0g) in water (15ml) and the mixture was adjusted to pH 7.0 and heated to 37 ° C for 3.5 hours while maintaining the solution at pH 7.0. The reaction mixture was cooled to 0 ⁰ C, with ethyl acetate / tetrahydrofuran (1: 1) (100 mL) overlaid with 2 M hydrochloric acid to pH 2 treated and then filtered through "Hyflo" The filtrate was separated and the aqueous phase with sodium chloride. The organic extracts were combined, layered with water (50 ml) and basified to pH 7.0 with aqueous sodium bicarbonate, the aqueous layer separated and the water removed in vacuo. 50 ml), then triturated with ether (100 ml) and filtered to give the title compound (1.03 g) as a near-white powder

IR (KBr) 1765cm " ¹ ·

NMR (DMSO-d _e ) δ = 1.07 (t, J = 7.3H); 1.6 (s, 2H, H ₂ O); 2.25 (s, 3H); 2.95 and 3 ^ 25 (2H, ABq, J = 17); 3.3-3.7 (m, 4H); 3.75 and 4.1 (2H, ABq, J = 12); 3.8-4.0 (m, 2H); 4.78 (s, 1H); 5.65 (d, J = 6.1 H); 7.2-7.5 (m, 5H); 7.58 (s, NH); 9.8 (d, J = 6, NH).

(b) Sodium-7β- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7amethylthio-3-carbamoyloxymethylceph-3-em-4-carboxylate

The product from part (a) (1.0 g) suspended in dry acetonitrile (50ml) unter.Stickstoff was cooled to 0 ⁰ C and treated with chlorosulfonyl isocyanate (1 ml). The mixture to 2 M hydrochloric acid (100 ml) and ethyl acetate / tetrahydrofuran (150ml) was added after 2 h and stirred rapidly 10 min at 0 ⁰ C. The organic phase was separated, washed with brine (100 ml), underlaid with water (100 ml) and adjusted to pH 7 with aqueous sodium bicarbonate. This aqueous phase was freeze-dried to yield 1.86 g of a white powder, which was the crude title compound. IR (KBr) 1770cm " ¹

NMR (DMSO-d ₆ ) δ = 1.06 (t, J = 7.3H); 1.63 (s, 2H, H ₂ O); 2.25 (s.3H); 2.95 and 3.18 (2H, ABq, J = 17); 3.2-3.7 (m, 4H and HOD); 3.85 (m, 2H); 4.65 (m, 2H); 4.85 (s, 1H); 5.65 (d, J = 6.1 H); 6.3-6.8 (brs, NH ₂ ); 7.2-7.5 (m, 5H); 9.6 (brs, NH); 9.8 (d, J = 6, NH).

(c) 7β- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-t-butyldiphenylsilyloxyamino-3-carbamoyloxymethyl-ceph-3-em-4-carboxylic acid

The crude product from part (b) (1.86 g) was slurried with dimethylformamide (20 ml) and filtered. The filtrate was cooled to -50 ⁰ C under nitrogen and treated sequentially with a solution of mercury (II) acetate (0.61 g) in dimethylformamide (2 ml), then with a solution of 0- (t-Butyldipnenylsilyl) hydroxylamine (0 , 52g) in dimethylformamide (2ml). The mixture was

heated to 2O ⁰ C over 30 mifi and added to ethyl acetate / tetrahydrofuran (1: 1.200 ml). This solution was washed with 2 M hydrochloric acid (4 × 100 ml), brine (100 ml), dried over Na ₂ SO ₄ and evaporated in vacuo. The crude product was purified by chromatography (silica gel, acetone / 2% acetic acid) to afford 160 mg of the title compound.

NMR (DMSO-d ₆ ) 5 = 0.97 (s, 9H); 1.04 (t, J = 7.3H); 3.05 and 3.3 (2H, ABq, J = 17); 3.2-3.45 (m, 2H); 3.5 (m, 2H); 3.85 (m, 2H); 4.56 and 4.75 (2H, ABq, J-13); 4.99 (s, 1H); 5.69-5.74 (m, 1H); 6.4-6.8 (Brs, NH ₂ ); 7.25-7.55 (m, 11H); 7.67 (d, J = 4H); 9.81-9.86 {m, NH). ' , ,

(d) 7β- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyamino-3-carbamoyloxy-methylceph-S-em ^ -carboxylic acid

The product from part (c) (160 mg) in acetonitrile (1.51 ml) and tetrahydrofuran (1.5 ml) was cooled at O ⁰ C and treated with aqueous hydrofluoric acid (40%) (0.5 ml) treated. After 45min, the solvent was removed in vacuo and toluene (3ml) and methanol (2ml) were added. The resulting solution was evaporated in vacuo and the residue was dissolved in methanol (2 ml), filtered and diethyl ether (50 ml) was added dropwise to the filtrate with rapid stirring. The precipitate was filtered off, washed with diethyl ether (25ml) and dried in vacuo to afford the title compound (14mg). IR (KBr) 1780cm- ¹ .

NMR (DMSO-d ₆ ) 5 = 1.05 (t, J = 7.3H), 3.10 and 3.42 (2H, ABq, J = 17.5); 3.36 (q, J = 6.2H), 3.52 (m, 2H), 3.86 (m, 2H), 4.50 and 4.73 (2H, ABq, J = 12.5); 5.01 (s, 1H); 5.65 (d, J = 7.5.1H); 6.4-6.8 (brs, NH ₂ ); 7.2-7.5 (m, 5H); 9.51 (s, NH); 9.85 (d, J = 7.5, NH).

Example 78

(Alternative route to Example 2) '.

7ß- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino-2-phenylacetamido] -7a-hydroxyaminocephalosporansäure

(a) Benzhydryl-7β- [3,5-di-t-butyl-4-hydroxyphenyl) methylene-amino] cephalosporanate

Benzhydryl-7β-aminocephalosporanate (4.38g) and 3,5-di-t-butyl-4-hydroxybenzaldehyde (2.34g) were dissolved in tetrahydrofuran (25ml) and the solution was evaporated to dryness in vacuo after 10min. The residue was dissolved in 1: 1 dichloromethane / carbon tetrachloride (50 ml) and evaporated again. The procedure was repeated to give the title compound as a tan foam (6.54 g).

IR (KBr) 1775cm ~ ¹ .

NMR (CDCl ₃ ) O = 1.46 (s, 18H); 2.02 (s; 3H); 3.36 and 3.56 (ABq, J = 18.2H); 4.75 and 5.00 (ABq, J = 13.2H); 5.16 (d, J = 5.1H); 5.45 (d, J = 5.1 H); 5.56 (s, OH); 6.97 (s, 1H); 7.29-7.73 (m, 12H); 8.54 (s, 1H).

(b) Benzhydryl-TtO.S-di-t-butyl ^ -oxo ^^ - cyclohexadien-1-ylidene-methyliminolcephalosporanic acid

A solution of the imine from the previous step (78a) (6.54 g) in dichloromethane (100 ml) containing anhydrous magnesium sulfate (9.6 g) was treated with nickel peroxide (6.6 g) and the suspension stirred vigorously for 1 h at room temperature ,

Filtration followed by evaporation of the solvent in vacuo gave the title compound as a dark red foam

IR (KBr) 1775cm- ¹ . ,

NMR (CDCl ₃ ) δ = 1.32 (s, 9H); 1:34 (s, 9H); 2.04 (s, 3H), 3.46 and 3.65 (ABq, J = 18.2H), 4.79 and 5.03 (Abq, J = 13.2H); 5.40 (brs., 1H); 7.00 (s, 1H); 7.02 (s, 1H); 7.30-7.50 (m, 10H); 7.90 (s, 1H); 8.03 (brs., 1h).

(c) Benzhydryl-7β-amino-7a (t-butyldiphenylsilyloxyamino) cephalosporanate

The product from the previous step (78 b) (2.53 g) in dichloromethane (15 ml) was treated with Ot-Butyldiphenylsilylhydroxylamin (1.16 g) and the solution stirred for 18 h at 25 ⁰ C. After evaporation of the solvent in vacuo, the residue dissolved in methanol (25ml) was dissolved, with Girard-T reagent (2-hydrazino-N, N, N-trimethyl-2-oxoethanaminiumchlorid) (975g) and kept at 0 ⁰ C 18h , Evaporation of the solvent gave a red foam which was dissolved in ethyl acetate (25 ml) and water (25 ml). The aqueous layer was back extracted with ethyl acetate (25 mL) and the combined organic extracts were dried and evaporated to give the crude product. Kiesel chromatography (dichloromethane / ethyl acetate gradient) gave the title compound as a pale yellow foam (515 mg).

IR (KBr) 1780cm- ¹ .

NMR (CDCl ₃ ) δ = 1.05 (s, 9H); 2/00 (brs, 5H, OCOCH ₃ and NH ₂ ; 3,24 (s, 2H); 4,47 (s, 1H); 4,73 and 4,90 (ABq, J = 13, 2H) 5.53 (s, 1H), 6.95 (s, 1H), 7.26-7.69 (m, 2OH).

(d) Benzhydryl-7α- (t-butyldiphenylsilyloxyamino) -7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -cephalosporanate

The title compound (415 mg) was prepared by reacting the 7/3 aminocephem from the previous step [78 (c>] (500 mg) with _1- D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) ^ 2-phenylacetic acid (250 mg) prepared according to the method described for Example (45a).

IR (KBr) 1790cm- ¹ . , '

• NMR (CDCl ₃ S = 0.95 (s, 9H); 1.12 (t, J = T ¹ , 3H); 1.96 (s, 3H); 3.04 and 3.12 (ABq, J = 17 , 2H); 3.32-3.50 (m, 4H, CH ₂ CH ₃ and piperazine CH ₂ ); 3.85-4.06 (m, 2H); 4.35 (s, 1H); 4.80 and 4.97 (ABq, J = 14, 2H); 5.44 (d, J = 7, CHNH); 6.53 (s, 1H); 6.84 (s, 1H); 6.85 (s, 1H); 7.12-7.62 (m, 25H); 9.86 (d, J = 7, NH)!

(e) 7a- (t-butyldiphenylsilyloxyamino) -7 / 3- [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] cephalosporanic acid

The product from the previous step (Example [78 (d)] (200 mg) was treated with trifluoroacetic acid / anisole according to the method described in Example 57 (a) to give the title compound (95 mg).

IR (KBr) 1785crrr ¹ . '

NMR (DMSO-de) 8 = 0.96 (s, 9H); 1.06 (t, J = 7, 3H); 1.96 (s, 3H); 3.09-3.38 (m, 4H); 3.45-3.51 (m, 2H); 3.82-3.86 (m, 2H); 4.60 and 4.88 (ABq, J = 13.2H); 4 _; 99 (s, 1H); 5.69 (d, J = 7, CHNH); 7.01 (s, 1H); 7.25-7.66 (m, 15H); 9.81 (d, J = 7, NH); 9.86 (s, 1H).

(f) [D-2- (4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino) -2-phenylacetamido] -7a-hydroxyaminocephalosporanic acid

The title compound (54 mg) was prepared by treating the 7a-t-butyldiphenylsilyloxyaminocephem from the previous step [78 (e)] (90 mg) with 49% aqueous hydrofluoric acid as described for Example 69 (f).

IR (KBr) 1780cm " ¹ .

NMR (DMSO-d ₆ ) δ = 1.09 (t, J = 7, 3H); 2.04 (s, 3H); 3.16-3.56 (m, 6H); 3.89-3.93 (m, 2H); 4.60 and 4.91 (ABq, J = 13, 2H); 5.06 (s, 1H); 5.69 (d, J = 7, CHNH); 6.50 (brs., 1H); 7.30-7.49 (m, 5H); 8.21 (brs., 1H); 9.86 (d, J = 7, NH).

Claims (9)

Invention claim: COOH. or a salt or ester thereof, wherein R is phenyl, substituted phenyl, cyclohexenyl, cyclohexadienyl, CH ₃ -CH (OHKCh ₃ -CH (OSO ₃ H) -, CH ₃ -CH (OCH ₃ ) - or an optionally substituted aromatic group. or 6-membered heterocyclic group having 1, 2 or 3 heteroatoms, each independently selected from O, S and N; R ² -CH ₂ OCOCH ₃ , -CH ₂ OCONH ₂ , -Cl, -F, -OCH ₃ , -CH ₂ N ₃ or a group of the formula CH. - ^CH 2 Y ~ \ ^C i, -alkyl) Q ₀₆₁ - -CH ₂ S.Het -C ^ alkyl) wherein each R ^{3 is} independently H or C 1 -C ₄ alkyl, m is 1 or 2, η is 3 or 4 and Het is an optionally substituted 5- or 6-membered heterocyclic group having up to 4 heteroatoms selected from O, S and N, wherein the heterocyclic group is optionally fused to an optionally substituted benzene ring or to another 5- or 6-membered heterocyclic group having up to 4 heteroatoms selected from O, S and N, and R ^{1 is} a group of the formula-CONR ⁴ R ⁵ or-COR ⁶ , wherein either
(a) R ⁴ and R ^{5 are} each independently H or C ₁ -C ₄ alkyl, R ^{4 is} H or C 1 -C 4 -alkyl and R ^{5 is} an optionally substituted 5- or 6-membered aromatic heterocyclic group having 1 or 2 nitrogen atoms or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form an optionally substituted 5- or 6-membered heterocyclic group having 1 or 2 N atoms and R ^{6 is} optionally substituted phenyl or a substituted or unsubstituted, optionally benzo-fused 5 or ⁶ -membered heterocyclic group or the group -CH ₂ NH-Cf = NH) (4-pyridyl), characterized by reacting a compound of formula (II) R-CH-CONH * NH (II) y? or an O-protected or carboxy-protected derivative thereof, wherein R, R ¹ and R ^{2 are} as defined above and X is C 1 -C 4 -alkylthio, phenylthio or benzylthio, with hydroxylamine or an acid addition salt or O-protected derivative thereof and in Presence of mercury, silver, thallium, lead or copper ions, optionally followed by one or more of the following steps: (a) Conversion of a compound of formula (I) ₂ wherein R ^{2 is} -CH ₂ OCOCH ₃ into a compound wherein R ^{2 is} -CH ₂ SHet, wherein "Het" is as defined above, by reacting with a thiol the formula HSHet or with a salt thereof; (b) Conversion of a compound wherein R ^{2 is} -CH ₂ OCOCH ₃ into a compound wherein R ² -CH -CH C ₄ alkyl). wherein R ³ , m and η are as defined above, by reacting with the appropriate tertiary amine; (c) Conversion of a compound wherein R ^{2 is} -CH ₂ -OCOCH ₃ into a compound wherein R ² or -CH ₂ N® (C 1 -C 4 -alkyl) ₃ is by reacting with pyrrolidine, piperidine or a secondary amine of the formula (C1-C4- -CH Alkyl) ₂ NH, followed by quaternization with an alkyl halide CRC4; (d) converting a compound wherein R ^{2 is} -CH ₂ OCOCH ₃ ISt to a compound wherein R ^{2 is} -CH ₂ N ₃ by reacting with an alkali metal azide; (e) removing any O or carboxy protecting groups; (f) converting a compound of formula (I) into a salt and (g) conversion of an acid of formula (I) into an ester by esterification. . 2. Method according to item 1, characterized in that the carboxy-protected derivative of the compound of the formula (II) is a benzhydryl or tert-butyl ester thereof. 3. The method according to item 2, characterized in that either the Benzhydryi group in step (e) by treatment with anisole and aluminum chloride or with trifluoroacetic acid is removed or that the t-butyl group by treatment with   Trifluoroacetic acid is removed. , , 4. A process according to any one of the preceding claims, characterized in that an O-protected derivative of hydroxylamine is used, said O-protected derivative having the formula H ₂ N-OSiIvIe ₃ , H ₂ N-0SiMe ₂ tBu, H ₂ N -0SiPh ₂ tBu, H ₂ N-0Si (C _r C ₄ -alkyl) ₃ , H ₂ NO-benzyl, H ₂ NO-COO-benzyl, H ₂ NO-COOtBu, H ₂ NO-COOCH ₂ CCI ₃ , H ₂ NO-COOCH ₂ CH = CH ₂ , H ₂ N-OCH ₂ CH = CH ₂ , __. .__. ο-, H ₂ NO-COOCH ₂ OCH. or H ₂ NO-COOCH ₂ CH ₂ Si (CH ₃ ) ₃ has. , 5. The method according to item 4, characterized in that the derivative is H ₂ N-OSiMe ₂ t-8u or H ₂ N-0SiPh ₂ t-Bu. 6. The method according to item 5, characterized in that the O-protecting group in step (e) is removed by treatment with aqueous hydrochloric acid. Process according to any one of the preceding points, characterized in that (a) X is methylthio and (b) the compound of formula (II) with mercury (II) ions and then with the hydroxylamine or its acid addition salt or O-protected derivative is implemented. 8. The method according to any one of the preceding points 1 to 7, characterized in that it is used for the preparation of a compound of formula (I), wherein (a) R is phenyl, 4-hydroxyphenyl, 4-benzyloxycarbonyl-oxyphenyl, 3,4-dihydroxyphenyl, 2-thienyl, 3-thienyl, CH ₃ CH (OH) -, CH ₃ CH (OCH ₃ ) - or CH ₃ CH (OSO ₂ OH) -ist, R ¹ . C = O, I where R. ^c i ~ ^c a ~ 10 or · .VO in which R is H, C ₁ -C-Al) CyI, -So (C -C alkyl) or (CH ₂ ) ₂ OH; is and (c) R ^{2 is} -CH ₂ OCOCH ₃ , -CH ₂ OCONH ₂ , -CH ₂ N ₃ , or a group of the formula: ^ 2 or -CH ₂ SHet, wherein "Het" is a triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, triazinyl, thiadiazolyl, benzoxazolyl, benzothiazolyl or tetrazolopyridazinyl group, all optionally substituted by C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, halogen, oxo or a group of the formula - (CH ₂ ) _P R ¹⁶ , in which ρ is 0,1, 2 or 3 and R ^{16 is} -COOH, -OSO _{2 is} OH, -SO ₂ OH, -PO ₃ H ₂ or -OH, with the proviso that ρ is not zero when Het is tetrazolyl, 9. Method according to item 8, characterized in that Het on the adjacent S atom via a carbon atom of the heterocyclic ring and (i) thiadiazolyl optionally substituted by C ₁ -C ₄ alkyl or 2-hydroxyethyl (ii) 'tetrazolyl optionally substituted by C ₁ -C ₄ alkyl, carboxymethyl, sulfomethyl, 2-hydroxyethyl or 2- (hydroxysulfonyloxy) ethyl, (iii) thiazolyl optionally substituted by 1 or 2 substituents each selected from C ₁ -C ₄ alkyl and carbox ymethyl, (iv) isothiazolyl, optionally substituted by 1 or 2 substituents each selected from hydroxy and carboxy, (v) benzothiazolyl or benzoxazolyl, optionally substituted by hydroxy, C ₁ -C ₄ -alkoxy or halogen, (vi) tetrazolopyridazinyl, optionally substituted by carboxy, (vii) triazinyl optionally substituted by C ₁ -C ₄ -alkyl and / or by 1 or 2 oxo or hydroxy groups, or (vii) triazolyl optionally substituted by carboxymethyl. 10. The method according to item 9, characterized in that it is used for the preparation of a compound of formula (I), wherein (a) run-substituted phenyl or CH ₃ CH (OH) -ist, (b) R ^{1 is} a group of the formula C = O IO O where R -C is H or -so CH, and (c) R ^{2 is} a group of the formula: - ^C V -s N - N // , N - N. // CH CH COOH N - N