DE2912829A1 - O-SUBSTITUTED OXIME DERIVATIVES OF 7-AMINOTIAOYL-ACETAMIDO-CEPHALOSPORANIC ACID, THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS - Google Patents

Description

ROUSSEL-UCLAF Paris, France

O-substituted oxime derivatives of 7-aminothiazolyl-acetamido-cephalosporanic acid, their manufacture and pharmaceutical compositions

The invention relates to new O-substituted oxime derivatives of 7-aminothiazolyl-acetamido-cephalosporanic acid, theirs Manufacture and their use as medicaments or in pharmaceutical compositions.

The invention relates to O-substituted oxime derivatives of 7-aminothiazolyl-acetamido-cephalosporanic acid, syn isomers, of the general formula I ¹

501 - (184-3

§09840 / 0888

-Jt? -

2S1282 ¹

in ec.-r mean;

B: &.) A substituent !!

for his part

one G-r-upp © = -0 =

Il

with Σ =

K ¹ «

S oö.®r O

and

Ga- Ms 0 ,,

I ¹ V

fai'fe O ^ a ^ 4
Ro ήώΔ H-,

or gig H ₀ C / j "= - to

y © eggs together with ä @ ia If = At om

1OS84O / 08Ü

Morpholines) or phthalimidο,

E "
a group -C-GO ₂ A '

with A ¹ = H, an equivalent of an AUcalimetell, alkaline earth metal, magnesium, ammonium or an organic amine base

or

an easily cleavable ester group,

R ^ = phenyl, hydroxyethyl or nitrile

and
E "= H or C ₁ - to C ^

a y-lactone group of the formula F \

-ν

or

a group - (CH _P ), -E ₁ -

with 1 ί = £ η'seS: 4- (whole numbers)
and
Ec = O ₁ - to Cy ₁ -

AlIc-S- with C ₁ - to C ^ -alkyl part and O 5 ns - ■ = 2 (integer) _s

-ΪΓ with

E ₆ and Er ₇ = H ₅ G ₁ - bis

O 3 8 4 υ /

2312829 - € 4-

-Alkyl or, together with the N atom, phthalimides or 1-pyridinyl,

Nitrile, if η ^1/1,

—C-KHo with X ¹ - S or
X ¹ == O, if η ^1/1,

4-methyl, 4-amino-1,3-thiazol-2-yl,

Azido

or

C ₂ - to C ^ acyl,

b) a substituent R _d1
which in turn means:

- a group - (CH ₂ ), -R ^ a

with 1 £ E ^ 4 (integer)
and

R, -a = halogen or

a group -SR ₁ ,. ,,

- Phenyl or an aromatic heterocyclic group with 5 to 6 ring members and 1 to 4 heteroatoms selected from S, Ii and 0, the groups R _eT , possibly also

S09840 / 0888

can be substituted by one or more amino, nitro, C ₁ - "to C ^ -alkyl or nitrile groups,

or

c) a substituent
who in turn

- one group - ₂ J ₁

with 1ä = η ¹ ^ 4 (integer)
and

where Rgb and R ^ b with the N atom to which they are bonded, an imidazolyl, morpholinyl or N-alkylpiperazinyl group with a C ^ - to Cn- -alkyl part

represents

Cl, methoxy,

C ^ j- to Cc-alkyl, C ₁ - to Cc-cycloalkyl, C ₁ - to Cc- -alkylthio,

—CHp-S — R ₁ ρ

with R ₁ O = a nitrogen-containing heterocyclic group,

Co- to C ^ -acyl,
2-Oxo (3H) -thiazolin-4-yl-carbonyl or

909840/0886

2912S2 63-

Acetoxymethyl, carbamoyloaymethyl

ΟΟΘΓ

-HH-O-AlIc ₀ with all ,, _{-C 4} - to G ,, -alkyl

O
and

A: H or an iquiTalent © ines alkali metal ,, alkaline earth = - me'ijalls, HagnesiiaiE, immoniuia or an orgsaiischen AB:; i.nbase or an easily cleavable ester group

as well as their salss with aaorgaaisciien. and organic acidic acid

Bie Er-: ± aäraig 'relates in particular to compounds of the formula I ^ syn-

s 2

CD

^0R o <r ^N τΧ

with E, E ₁ "and A like ob @ n _s

also TerTbindimgen. der Foriael I (syn isomers)

909840/08

- J28--

2917879

with K, IL] and A as above

sorie compounds of formula I. (syn-l3omere)

NII

COMH

/ Γ O

CO ₂ A

with R, Ex, and A as above.

The ßubstituenten E include acetyl, propionyl, butyryl, Isobutyryl, valeryl, isovaleryl and t-valeryl are the same corresponding sulfur-containing derivatives such as thioacetyl.

This also includes methoxycarbonyl, Ätho2ς7carbonyl, Propyloxycarbonyl, isopropyloxycarbonyl, butoxycarbonyl, Isobutyloxycarbonyl and t-butoxycarbonyl as well as the

30984D / 0886

COPY

'p. "jf'"! ~ ΐί. .J "Γ -ii ι

-65- 291282

corresponding sulfur-containing derivatives such as Methoxythiocarbonyl.

Other suitable substituents include carbamoyl., N-methylcarbamoyl, I ^ IT-dimethylcarbamoyl, aminoacetyl, Dimethylaminoacetyl, methylaminopropionyl, dimethylaminopropionyl, Aminovaleryl, dimethylaminovaleryl, IT-pipericinocarbonyl, N-piperidinoacetyl, N-piperidinoprqpionyl, IF-phthalimidocarbonyl, U-phthalimidoacetyl, N-phthalimidopropionyl and benzoyl.

Acetylmethyl, acetylethyl, Propionylmethyl, propionylethyl, methoxymethyl, methoxyethyl, Ethoxyethyl, methoxypropyl, methylthiomethyl, Methylthioethyl, ethylthiomethyl, ethylthioethyl sovrie sulfur-containing groups whose sulfur atom is oxidized, such as methylsulfinylmethyl and methylsulfonylmethyl.

These also include aminomethyl, methylaminomethyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, phthalimidomethyl, phthalimidoethyl, phthalimidopropyl, N-pyridinylmethyl, N-pyridinylethyl, N-pyridinylpropyl, thiocarbamoylmeth3 ^r l, '

Garbamoyläthyl, Carbamoylpropyl, Thiocarbamoyläthyl, 4-aminothiazol-2-yl-methyl, ^ -Methylthiazol-Z-yl-methyl, 1.2.3-4-tetrazol-5-yl-methyl and about 1.2.3.4-tetrazol-5-yl-ethyl.

The substituents R ^ a include fluorine, chlorine, bromine or Iodine and, for example, phenyl, 1.2.3-, 1.2.5-, 1.2.4- or 1.3.4-thiadiazolyl, 1H-tetrazolyl, 1.3-thiazolyl,

909840/0886

COPY

231282:

i.2.3-, 1-2 * 4- or 1.3.4-iriazolyl, 1.2.3-, 1.2.4- ,, 1..2.5- or 1.3.4-0xadiazolyl, 2-, 3- or 4-pyrldinyl, 2- or 3-furyl, 2- or 3-ihienyl and 2- or 3-pyrrolyl. The above groups can be either unsubstituted or one or more times with amino, nitro, methyl ^ jithyl, Propyl, isopropyl, butyl, s-butyl, t-butyl or ffitrile be substituted.

The substituents R, -b include, for example, N-alkylpiperazin-1-yl and in particular 4-methyl, 4-ethyl, 4-propyl, 4-isopropyl, 4-butyl, 4-s-butyl and 4-t- -Butyl-piperazin-1-yl.

The substituent R ^ can, for example, Hethyl, ethyl, Propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, s-pentyl, t-pentyl, cyclopropyl, cyclobutyl or about Mean cyclopentyl, also methylthio, itylthio, Propylthio, isopropylthio, butylthio, isobutylthio or t-butylthio. R ^ j can also be acetamido, propionylamido, Butyrylamido, isobutyrylamido or valerylamido, for example mean.

The substituents R ^ also include groups -CH ₂ -SR ₁₂ , in which R ₁₂ 1.2.3-, 1.2.5-, 1.2.4- or 1.3.4 ~ thiadiazolyl, 1H-tetrazolyl, 1.3-thiazolyl, 1.2 .3-, 1.2.4- or 1.3-4-iCriazolyl, 1.2.3-, 1.2.4-, 1.2.5- or 1.3 »4 - means oxadiazolyl, these groups being either unsubstituted or mono- or polymethyl , Ethyl, propyl, isopropyl, methoxy, ethoxy, propyloxy, isopropyloxy, amino, hydroxycarbonylmethyl, dimethylaminoethyl and / or diethylaminoethyl are substituted. The substituents R _{12 also} include the groups 3-methyl-,

§0 98AO / 0 8 86

3-ltliyl- and 3-propyl-1o2 ₀ 4 - = - tliiaäiasol-5-yl as well as

raid 3 "P3rOpo2sy - = -" 1.2 _e 4-thiadiazol-5-yl «

also mean © la © Acylgnippe, the -under Acetyl, Propionyl and Butyryl is selected «

Sodium, potassium, lithium, calcium, magnesium, and ammonium equivalents belong to Siibstityieat A. This would also include the organic bases, for example trimethylamine Biäthylamin, triethylamine, methylamine, propylamine, FFN-dimethylethanolamine, tris (hydroxymethyl) -aminoEetlian, ltlaanolamin _s pyridine, picoline, Dicyclohesqflamin, N, li'-Dibensylätliyl © ndiamin, morpholine, Bensylamin, procaine , Lysine, arginine, histidine and H-methylglucosamine.

The easily cleavable ester groups A include methoxymethyl, Ithoxymethyl, isopropoxymethyl, oC ~ methoxyethyl, CX-Ithos-iyäthyl, Hethylthiomethyl, Ithylthioinethyl, Isopropylthiomethyl 5 PiTaloylo3cymethyl, acetoxymethyl, Propionyloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl; PiOpioiiyloxyäthyl, IsovalerylO3yäthyl, 1 ~ Acetoxyäthyl, 1 ~ aceto3iypropyl, 1- = acetoxybutyl, 1-AGeto ^ ς5rhexyl and 1-acetosyheptyl

The compounds of the formula I 'can also be in the form of salts with inorganic or organic acids are present, since the compounds have at least one amino group capable of salt formation.

The acids which can be used for salt formation with the amino groups of the compounds of the formula I ¹ include, inter alia, acetic acid, trifluoroacetic acid, maleic acid,

§09840 / 08S ^!

291282

Tartaric acid j methanesulfonic acid, benzenesulfonic acid, p-toluenesulf ση-acid, Hydrochloric acid, hydrobromic acid, hydrogen iodide acid, sulfuric acid and phosphoric acid.

The compounds of the formula I 'in which B represents a group Rj ₃ can also be present in the form of internal salts.

The invention relates in particular to compounds of the formula I ¹ in which R _{12 is} 1.2.3-, 1.2.5-, 1.2.4- or 1.3-4- thiadiazolyl, 1H-tetrazolyl, 1.3-thiazolyl, 1.2.3-, 1.2 .4- or 1.3.4-Triazolyl or 1.2.3-, 1.2.4-, 1.2.5- or 1.3.4-Oxadiazolyl means, these groups either unsubstituted or one or more times with methyl, ethyl, propyl, isopropyl , Methoxy, Athoxy, Propyloxy, IsopiOpyloxy, Amino, Hydroxycarbonylmethyl, Dimethylaminoäthyl and / or Diethylaminoäthyl are substituted. The invention also relates in particular to those compounds of the formula I 'in which R ^ ₂ © ine represents acyl group selected from acetyl, propionyl and butyryl, furthermore the compounds of the Fox'mel I' in which R, -, p acetyl, 1 -Methyltetrazolyl, 2-methyl-1.3.4-thiadiazolyl, 3-methyl-1.2.4-thiadiazol-5-yl, 3-methoxy-1.2.4-thiadiazolyl, 1.3.4-ThXaOXaZOl-S-Yl, 2-amino -1 ^. ^ - thiadiazol-3-yl, 3-hydroxycarbonylmethyl-1.2.4-thiadiazol-5-yl, 5-methoD <y-1.2.4-thiadiazol-3-yl, 4-methyl-5-hydi ^< oxycarbonylmetlr7l Means -1.3-thiazol-2-yl or 1-dimethylaminoethyl-i.2.3.4-tetrasol-5-yl.

The invention relates in particular to the Vex ^ bonds of Formula I as above, in which:

90 9 8 4 0/0 8 8 δ

291282- ' -yr-

R: - a group -GR ¹

Jl

with X = 0

and

R '= C ₁ - to Cj ₄ phenyl or

- (CH ₂ ) _n -N with η = 0 or 1 and

R, R ₀ and R_ as above, ο έ 5 '

R "
a group -C-

with A ¹ and R "= H and

R ^ = phenyl or hydroxyethyl,

- a v - lactone group of the formula

or

a group - _n

with n '= 1 or and

/ 6

c = -N mxt Rg and R ₁ -, as above,

-C-HH ₃ ,

tr c-

1.2.3.4-a? Etrazol-5-yl or Acetyl,

90984X3 / 0886

it |: O ₁ - to tic-alkyl,

—CHp-St

with R ₃₂ = 2-methyl-1.5.4-tliiadiazole or
1-methyltetrazolyl,

or
Acetoxymethyl

A: H or an equivalent of an alkali metal, alkaline earth metal, Magnesium, ammonium or an organic amine base.

The invention further particularly relates to those Compounds of the formula I in which:

R acetyl, benzoyl, phthalimidοacetyl, Ν, Ν-dimethylcarbamoyl, Oi. -Carboxyphenylmethyl, 2-oxo-3-tetrahydropyranyl, 1,4-dihydroxy-1-oxo-2-butyl, phthalimidomethyl, Aminoethyl, tetrazol-5-ylmethyl, 2-amino-2-thioxoethyl or 2-oxopropyl,

E ^ methyl, acetoxymethyl or 2-methyl-1.3.4-thiadiazol-5-yl-thiomethyl or 1-methyltetrazolylthiometlr / l

and
A hydrogen or sodium.

Of particular importance among these are the compounds of the formula I in which:

R acetyl, benzoyl, phthalimidoacetyl, tetrazol-5-y! Methyl,

Ή- 231282!

Aminoethyl or oil-carboxyphenylmethyl and

IL, ethoxymethyl, 2-methyl-1 "3.4-thiadiaz.ol-5-yl-thio methyl or i-

The invention also particularly relates to the compounds of the formula I in which "R ₁ -B. Bromine, iodine, phenylthio, 2-fyridinylthio, 2-amino-1,3.4-thiadiazol-5-ylthio, i-methyl -iH-tetrazol-5-yltnio, 2-aminophersylthio, 5-lfitro-2-pyridinylthio or 3-cyano-6-methyl-2-pyridinylthio means.

Of particular importance according to the invention are also the compounds explained in more detail in the examples, ie particularly

- 3-Acetoxymethyl-7 - ^ [2- (2-aminothiazol-if ™ yl) = - 2- (2-aininoethoxyimino ) -acetyl I -aminoj -ceph-3 ~ © m-4-carboxylic acid (syn isomer) and their salts with alkali metals, alkaline earth metals, Magnesium, ammonium and organic amine bases as well as their esters with easily cleavable groups,

- 3-Acetoxymethyl-7-r [2 - [(2-bromoetho ^) - imino] -2- (2-aminothiazol-4-yl ) -acetyl] -amino J -ceph ^ -em- ^ l-carboxylic acid (syn isomer) and their salts with alkali metals, alkaline earth metals, magnesium, ammonium and organic Amine bases as well as their esters with easily cleavable groups, as well

- 3-Acetoxymethyl-7 - [[2- £ (2-iodoetho3cy) -imino] -2- (2-aminothiazol-4-yl) -acetyl] -amino] -ceph ^ -em - ^ - carboxylic acid (syn isomer) and their salts with alkali metals,

909840 / 088S

- 3-S ¹ "Q 1 9 Ω 0 Q

"^ T" "&" / i j ι <ς Ο ζ, ν)

36 '-

JirdaUtealimetallen ₅ Magnesium, ammonium and organic ataine bases as well as their - ^ ster with easily cleavable groups

Bio Yörbin & ungen der Wotmq-1 I · kann.en entvfedex * in the by the

given formula I 'or in the following by cli ©

]? or? EeI I ^ "described 3timkxiv.r present

WÄ

7 ο

■ ν / \ l

without the substituents en the obsa defines © meaning besitixn.

The invention "also relates to a method of manufacture of the compounds of the formula I "; the according to the invention Procedure can be done as follows

(Al) implementation © in connection fl © r-.? Orm © I II

03840 / 088S

231282;

(ii)

with IL], - = an amino protecting group,

A "= H or an easily cleavable ester group

ILj as above

(a) with a functional derivative of the group -C-R '*

X
with X = 0 or S.

and

fi '= C ₁ - to C ^ -alkyl, C, - to C ^ -alkoxy, phenyl _}

JlI

^κ 3

with O ^ en ^ A (integer) and

R " ₂ and R" ^ = H or C ^ - to C ₁₁

909 8 40/0 88 6

281282

to a compound of the formula

NIIR ₁₆

where at least one of the substituents R " ^ and R ¹ '^ is alkyl when η = 0,
or

together with the N atom phthalimide, Piperidino or morpholine

⁰⁰ 2 ^A "

or

(b) with a connection of the lOrmel X = O = HH with X = O or S

909840/0886

12th

\ -. η ί-ΐί »? - 32 · Ve.rbl: ad, img dej? formula

(e) with; ----- = er Ye rl - charge of the formula

YC-GO ₂ A " ^! RiI; S" = H or C ₁ = to C ^ E ^c . ·. T ~ halogen j sulfate or

SuIf onat, R ^! ^ ~ Plienyl or Hitrile

mid

A "'- an easily cleavable protective group

a verbiadimg of the lormel

098A0 / 08S8

291282 ¹

MH B

(HI ₃₃ )

or

(d) with a Yerbinfeng Y ₁ —I O with Ί _Α = as above X

to, a compound of the formula III,

HHH ₁₀

in rl

J-

CO., A "

(III,

which may be increased by coating with an alkali base

a ρ q S | Λ η / Q S i!

^ J w 3 Ό H Ό a y y v ■

Üfir-

a compound of the formula III ¹ ^

NH R

(III

■ is implemented in the

an easily cleavable ester group or an equivalent of an alkali metal and
an equivalent of an alkali metal

mean,

or

(e) with a compound of the formula

- (CH ₂ ) _n ι-RV with

'& 4 (integer),

= as above Y
and

⁼ ° 2 ~ ^{to G} iT ^ ^c 7l C ^ - to C ^ -alkoxy, G ^ - to σ ^ -Alkyltliio where the S atom of

9098A0 / 0886

Alkylthio group possibly sum sulfoxide or The sulfon is oxidized,

to a compound of the formula

hey

A,

iIo) _n , R ¹ 5

CO ₂ A "

or

(f) with a compound of the formula

Y, - (0H ₂ ) _n -CIi with Y, = as above Y and

4 (integer) to a compound of the formula

9098A0 / 0886

231282 '

₁₆

oaer

(g) with a yerbin axis of the formula Hal- {CH ₂ ) _n , -Hal

ziii eliasr connection to Formula V

IHl

. (CH ₂ ) _n , Hal

which either by treatment with a TTerbindiang of the formula III

909840 / 088S

ORIGINAL INSPECTED

2S1282

NH R

16

(Γ

O ₉ A "R ₁

(IHj)

or with an azide

to a compound of the formula

is implemented,

if necessary with a reducing agent into a compound of the formula III ' _K

909840 / 088S

ME

16

CONH N

CO ₂ A "

is converted,

or

(A2) Implementation of a compound of the formula IV

(CH ₂ ) _n , -CN

CO ₂ A "

R.

(IV)

with

i>. _{as above} (whole number)

909840/0886

2912823

(a) with hydrogen sulfide

or, when η is ¹ ^ 1, by hydrolysis in the presence of a base

au a compound of the formula

with X = S or 0 and

1 ^ n "^. 4 (integer), if X = S

respectively.

n "yf 1, if X = O,

if necessary, if X = S ₇

with a compound of the formula

Shark

309840/0886

2912825

with IV η - methyl or amino

and Hal = halogen

to a compound of the "formula NHR

is implemented, or

(b) with an azide

to a compound of the formula HL

909840/0886

QfWAL INSPECTED

291282 '

- yer-

NHR

or

(A3) Implementation of a compound of the formula V

(a) with an amine derivative of the formula HN ''

with

one that can easily be split off by acid hydrolysis or hydrogenolysis Group or C 1-4 alkyl and

H or C 1 -C 4 alkyl

or together with R ^ g Phthalxmxdo

to a compound of the formula

909840/0886

-SS-

231282

HH R

or

(b) with imidazole, morpliolin or an N-allsylpiperazine to a compound of the formula IH'τ

. CONlI

"Rb

with R ^ as above

CO ₂ A "

or

(c) with a compound of the formula E-S-H

ar

with R as above

S09840 / 0886

to a compound of the formula III »

NHR

16

CONH.

N \

(UI ₁₁ )

and

(B) Implementation of the compounds of the formulas

IH

_A ,

, V,

, IH

III.

with one or more agents for hydrolysis, for hydrogenolysis or with thiourea

- compounds of formula I,

909840/0888

2912823

with X, ILj and R ¹ , as above,

- Links. ^ ^he formula

with X xind ILj as above,

- Compounds of the formula Ig

909840/0888

291282!

Mr.

, COIIk,.

J? Si

R ^!

XiO ₂ Il

with R ₁ , E "

as above

Terbindraigeii der- Foicval I _r

CO ₂ H

(I,

with R ₁ like

9098 /. 0 / 088S

291282

which, if necessary, are converted ^{into compounds of the formula I 1} "with a base and then with a satire:

COHH

CO ₂ H

I-

- CH ₂ OH

(In)

- Compounds of the formula I ' _c as above,

- Compounds of the formula

^J 2 n ^lR 5

^CO 2 ^H

with n ', E ₁ and R', - as above,

909840/0886

- Compounds of the formula

2912S29

: cH ₂ ) _n -c *

O ₂ H

with IL) and ^ as above,

- Compounds of the formula IjH ₂

CO ₂ H

CH ₂ ) _n "-C-MH ₂

with X, n "and R ^ as above,

- Compounds of the formula I «

909840/0886

HBU

2912823

t'O ,. H

-R,

with η ⁵ , IL- 7r, - _: fl T? '., id.

with I ₁ - and n ¹ as above,

909840/0886

-S3-

291282!

- Compounds of the formula

CONH

CO ₁ H

(CIL,).-Hal

"Ζ'τι

with ILj, η ¹ and Hal as above,

the compounds of the formula I ₃ correspond, in which E_ = - (CH _P ).-Ri-a

and R = halogen,

Compounds of the formula HH,

909840/0886

with Hj and η ¹ as above,

- Compounds of the formula

XCII ₉ ) ^ ₁ N

OoH

with ILj and n 'as above,

- Compounds of formula 1 ¹

NII ₂

CONI

CO ₂ H

with R ^ as above,

- Compounds of the formula

909840/0886

291282!

Ji

, COM-

O ^

R.

ΪΟ ₂ Η

(It.)

with IL |, Rx] Q and η 'as above and = fl or C ₁ - to C ^ -alkyl,

- Compounds of formula IV. NIi

with R ^ and R, as above, the compounds of the formula where A = H,

respectively

correspond in

- Compounds of the formula X

SU984Ö / 08

2312820

with R ^, R and rt ^! as above,

the compounds that _{correspond to ΡοιίώθΙ I a} , in the Ε, -a. = -SR ₀ ^,

so / ie if necessary

_D , I _E ,

(0) Production of salts or esterification of the compounds of the formulas 1 ^, 1 '^, I ₅₅ 1 ^, l' _c , I

¹ G ' ¹ H' ^Ι! Η ' ¹ J' ¹ K ^{2 11} K ' ¹ L ^{5 IU} b ^{or 1} M in a manner known per se.

According to the invention, for example C 1-6 alkyl groups, such as preferably t-butyl or t-amyl, can be used as amino protective groups R, jg. R ₁₆ can also represent an aliphatic or aromatic or heterocyclic acyl group or a carbamoyl group. The acyl groups suitable for this include, for example, lower alkanoyl groups such as Forrayl, acetyl, propionyl, butynyl, isobutynyl,

9098A0 / 0886

Gf ^ L INSPECTED

Valeryl, isovaleryl, oxalyl, succinyl and pivaloyl, furthermore lower Alko3cy- or Cycloalkoxycarbonylgruppen such as Methoxycarbonyl, ithozycarbonyl, propoxycarbonyl, "l-cyclopropylathoxycarbonyl, isopropoxycarbonyl, Butoxycarbonyl, t-butoxycarbonyl, pentylo2jycarbonyl, t-Pentoxycarbonyl and Hexyloxycarbonyl and Benzoyl » Toluolyl, liapnthoyl, phthaloyl, mesyl, phenylacetyl, Phenylpropionyl and aralkocarbonyl groups such as benzyloxycarbonyl.

The acyl groups can also be substituted, for example, with a chlorine, bromine, iodine or fluorine atom; Examples these include chloroacetyl, dichloroacetyl, l'richloroacetyl, Trifluoroacetyl and bromoacetyl.

The substituent E ^ g can furthermore also represent a lower aralkyl group such as benzyl, 4-metho3q5rbenzyl, phenylethyl, trityl, 3 ^/ * -dimetho3q5rbenzyl and benzhydryl, and also a haloalkyl group such as trichloroethyl. Further examples of the IL ₁ g substituent are chlorobenzoyl, p-nitrobenzoyl, pt-butylbenzoyl, pheno ^ - acetyl, caprylyl, n-decanoyl and acryloyl,

also methylcarbamoyl, phenylcarbamoyl,

Naphthylcarbamoyl and the corresponding thiocarbamoyl groups.

The above list of substituent meanings is not exhaustive; according to the invention, others can also Amino protective groups can be used in the same way, for example known from peptide chemistry Protection groups.

§098 4 0/0888

2312829

The substituents -CO ^ "include, for example, ester groups, which are formed with easily cleavable groups, for example formed with alkyl groups Esters such as butyl ester, isobutyl ester, t-butyl ester, pentyl ester and hexyl ester.

These also include acetoxymethyl esters, propionyloxymethyl esters, butyryl oxymethyl esters, valeryloxymethyl esters, pivaloyloxymethyl esters, 2-acetoxyethyl esters, 2-propionyloxyethyl esters and 2-butyryloxyethyl esters, and also 2-mesylethyl esters, 2-iodoethyl esters, fi / 3rd ethyl ester. Trichloroethyl ester, vinyl ester, allyl ester, ethynyl ester, propynyl ester, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenylethyl ester, trityl ester, diphenylmethyl ester and 3 · — dimethoxybenzyl ester, as well as phenyl ester, 4-chlorophenyl ester and t-butyl phenyl ester.

The functional derivative of the group -C-R '^ can for example

be an acid halide such as an acid chloride or bromide, a symmetrical or mixed acid anhydride, a ketene and an acyl azide. The acylation can also be carried out with a haloformate if R ¹ ^ represents an alkoxy group, for example with a chloroformate. Isocyanates can also be used if R ¹ ■ * represents a group R "2 in which

-N

^ß 3

the two groups R ¹¹ O or R "^ mean a hydrogen atom.

1098 4 0/0888

As in the case of the isocyanates of the formula X = G = KH, the Acylation of the hydroxyl function in an organic solvent such as a halogenated hydrocarbon, for example methylene chloride, a cyclic ether such as Dioxane or [tetrahydrofuran, a nitrile such as acetonitrile, a nitrated hydrocarbon such as nitromethane or for example in an ester such as ethyl acetate.

If an acid halide is used, it is preferably carried out in the presence of a base such as triethylamine, pyridine, Proceed with propylene oxide, magnesium oxide, sodium carbonate or calcium carbonate.

The preparation of the compounds dex * Formula HIg takes place

R "

by reacting compounds of the formula Y-C-

with compounds of formula II.

Y denotes, for example, a chlorine, bromine or iodine atom or a sulfate or sulfonate group such as mesylate or tosylate.

If appropriate, the etherification takes place in the presence of a base such as, for example, potassium t-butoxide or Sodium hydride. Furthermore, for example, in the presence triethylamine or pyridine.

The reaction is preferably carried out in a solvent such as a halogenated hydrocarbon, e.g. methylene chloride, in a cyclic ether such as tetrahydrofuran or dioxane, in an N, N-disubstituted amide such as

9098A0 / 0888

2912823

Dimethylformamide or in dimethyl sulfoxide.

The separation of the optical isomers present due to the asymmetric carbon atom, which may have to be carried out, can thus probably as well as after etherification.

The preparation of the compounds of the formula III takes place under the same procedural conditions as the preparation of the compounds IUp ₁ . The substituent Y ₁ , like Y, can represent a Cl, Br or J atom or a sulfate or sulfonate group such as mesylate or tofylate.

The conversion of the compounds of formula Hl ^ to compounds of formula III is carried out according to the invention ^ ¹ with an alkali metal base such as dilute Kaoh or KOH, sodium carbonate or Hatriumhydrogenearbonat.

The compounds of the formulas IHt, νοτιά III- ™ are prepared under conditions comparable to those described above for the compounds IIIj or HIq.

The conversion of the compounds of the formula IV to compounds in which Σ denotes a sulfur atom and n " denotes an integer from 1 to M- is carried out by converting the compounds of the formula IV with hydrogen sulfide. This is preferably done in the presence of a base such as triethylamine The solvent in which the reaction is carried out xtfirdj consists of dimethylformamide.

The conversion of the compounds of the formula IV into compounds of the formula HIp in which X is an oxygen atom and n "is an integer from 2 to M- takes place

909840/0886

according to the invention by hydrolysis in a basic medium. Dilute sodium hydroxide solution is preferably used for this purpose.

The implementation of the compounds of the formula ^ /, in which Hai is preferably a Cl or Br atom

indicates, with the compounds of the formula III ™, in which X represents a sulfur atom, can be carried out without catalysis. This gives a thiazole hydrohalide which can be converted into the free base by reaction with a base such as sodium hydrogen carbonate. The reaction can also be catalyzed with a base such as sodium hydrogen carbonate. The azide reacted with the compound of the formula IV to give a compound of the formula III _H is preferably sodium azide. For this purpose, however, other alkali azides such as potassium azide can also be used in the same way, as well as azides of organic amine bases such as tetramethylguanidinium azide and triethylammonium azide. It is also possible to use ammonium azide generated in situ by the reaction of ammonium chloride with sodium azide in this reaction.

The reaction is preferably carried out in dimethylformamide, but ethanol can also be used.

The reaction of the compound of formula V with pyridine or a compound of the formula HN is preferably done

909840/0888

in dimethylformamide. Connections are preferred of the formula V used, in which shark a bromine or Is iodine atom; corresponding compounds with a Cl atom however, they can also be used.

The group R ^ g, which can easily be split off by acid hydrolysis or hydrogenolysis, is preferably a trityl group. However, the other suitable protective groups mentioned above can also be used for this purpose.

The reaction of the compounds of the formula V with an azide to give compounds of the formula III-g- takes place under the same Process conditions such as the reaction of the compounds of the formula IV with azides.

The III _'E reducing agent used for the conversion of compounds of formula HIg- in compounds of the formula is preferably hydrogen sulfide in the presence of triethylamine, which corresponds to the use of formed in situ Triäthylammoniumhydrosulfid; the reaction is carried out in a solvent such as dimethylformamide. However, other methods for mild and specific reduction can also be used, for example methods in which alkali sulfides such as sodium sulfide, potassium sulfide or ammonium sulfide or tin (II) chloride are used.

The reaction of the compounds of the formula V with imidazole, morpholine or an If-alkylpiperazine is preferably carried out in the presence of an acceptor for the resulting hydrohalic acid; this can include, for example, organic Bases such as triethylamine are also used

§09840 / 0888

-402- 291282S

inorganic bases such as sodium carbonate and sodium hydro gene carbonate and other alkali carbonates and hydrogen carbonates.

A salt of a compound of the formula V, such as the diethylamine salt, can also be used for this reaction will.

The reaction can also be carried out in the presence of a quaternary ammonium salt such as methyltricaprylaramonium chloride will.

The reaction of the compounds of the formula V with compounds of the formula R _ar -SII is preferably carried out in the presence of an acceptor for the hydrohalic acid; organic bases such as triethylamine can be used for this purpose, as can inorganic bases such as sodium carbonate and sodium hydrogen carbonate. Salts of the compounds of the formula V, such as the diethylamine salt, can also be used for this reaction.

The reaction can also be carried out in the presence of a quaternary ammonium salt such as, for example, methyltricaprylammonium chloride be performed.

Furthermore, alkali metal derivatives of the compounds of the formula R_ — SH, such as the lithium derivative, can also be used Find; The reaction is also preferably carried out in the presence of a catalyst, for example an alkali metal halide such as lithium iodide.

Conversion of the compounds of the formulas ^ jj and V in compounds of the corresponding formulas Ij ^ bis

909840/0888

291282

Ip ₁ is used to remove the protective groups such as ILj g in all cases and, if necessary, from A "if this substituent is different from hydrogen, and the groups A" ¹ (HLg), A ^ (ni ' _c ) and R ₁₈ (III _L ).

The group K ^ g is split off, for example hydrolytic, for which acidic or basic hydrolysis can be used or hydrazine can be used.

For splitting off optionally substituted alkoxycarbonyl and cycloalkoxycarbonyl groups such as t-pentyloxycarbonyl or t-butyloxycarbonyl, of optionally substituted aralkoxycarbonyl groups such as benzyloxycarbonyl, trityl, t-butyl or 4-methoxybenzyl, acid hydrolysis is preferably used .

The acid used here is preferably mixed with chlorinated water st off acid, benzenesulfonic acid, p-toluenesulfonic acid, Formic acid and trifluoroacetic acid are selected, but other inorganic or organic acids can also be used for this purpose Acids are used.

The basic hydrolysis is preferably carried out to split off acyl groups such as trifluoroacetyl. The base here is an inorganic base such as an alkali hydroxide, for example HaOH or KOH, is preferably used, however, they are also used Magnesium oxide or barium oxide as well as alkali carbonates and hydrogen carbonates such as sodium carbonate, urodium hydrogen carbonate, Potassium carbonate and potassium hydrogen carbonate can be used. Furthermore, sodium or potassium acetate and other bases can also be used.

The hydrolysis using hydrazine is done

909840/0888

preferably used to split off vca groups such as phthaloyl .

The group ILj ₆ (for example trichloroethyl) can also be split off with zinc-acetic acid «

Benzhydryl and Benzylo3Eye © rbo: nyl groups are preferred removed with hydrogen in the presence of a catalyst .

The chloroacetyl group is cleaved with thiourea in a neutral or acidic Meditua by a known method (see _Masaki's JAOS j "(1968) 4508) ο It can, however, other known from literature ä®r means CBX · elimination of Atainoschutzgruppen used to be.

The groups according to the invention include formyl, Acetyl, ethoxycarbonyl, hesyl, iSrifluoroacetyl ^ chloroacetyl and trityl.

The acid used is preferably formic acid or trifluoroacetic acid used.

With regard to the on öar Ossyiainogruppe (substituent R) present Substituenton Mussan determined © Schutagruppan in some Pällen avoided xirerden "So H ^ must g example, no acyl group ₉ when E acetyl or- © ine acyl group, since eggs elimination of Ε -ig otherwise there would be the risk of a simultaneous split-off from 1 _o

Me splitting off the group A '\ u & nn this from hydrogen

6 Π «a /
fei U b ο »

is different, as well as the removal of the groups A "', A ^ and 'R "-j 3 are carried out according to the invention under similar process conditions as described above for the cleavage of R ^ g. Acidic or basic hydrolysis, among other things, can be used for this purpose. To split off groups such as substituted alkyl groups or optionally substituted aralkyl groups saiire hydrolysis is preferably used.

The acid used is preferably hydrochloric acid, formic acid, trifluoroacetic acid or p-toluenesulfonic acid. Other substituents for A ", A" ¹ , A ^ and R ₁₈ are split off in a manner known per se.

The reaction is preferably carried out under mild reaction conditions, ie at room temperature or under only mild conditions Heat.

For example, if R ^ g and A "are different groups to be split off Represent type, the compounds of the formula III can of course also with several of the abovementioned Funds are implemented.

Any conversion of the compounds of the formula Ip into compounds of the formula I ¹ " takes place under conventional conditions; for this purpose, as for converting HIq into IH ¹ Q, a base is used which is selected, for example, from dilute sodium hydroxide solution and potassium hydroxide solution, sodium carbonate and calcium carbonate.

In the reactions explained above and the subsequent reactions, some of the reaction products obtained from the corresponding Ceph-2 ~ em connections exist.

909840/08

In this case, the proportion of the Δ o compounds is converted into ⁿ Δ, .- compounds tim ;; this is done according to a reaction scheme which is known from the literature for compounds with a cephem skeleton; The procedure is as follows: The product containing some Λ 2 ~ compounds is oxidized in such a way that the corresponding sulfoxide is obtained. For this purpose, a peracid such as m ~ chloroperbenzoic acid is preferably used. The conversion of the Λ o-sulfoxide into the Λ ^ -sulfoxide takes place in the presence of a hydroxyl-containing solvent or in the presence of water.

The reduction of the Δ , sulfoxides takes place in the presence of an acid halide or phosphorus trichloride. This procedure for converting the Δ 2 ~ Vex * bonds in / s. , Compounds is known from, for example

Kaiser et al., J. Org. Chem. J £ (1970) 24J0,

Spry et al., J. Org. Chem. 40 (1975) 2411, U.S. Patent 3,705,897 and
DE-PS 1 937 016.

An example of such a reaction is given in the experimental section.

The conversion of the compounds of formula I into the corresponding Salts can be carried out by customary methods, for example by reaction with the appropriate Acids or a solvate (for example the ethanol solvate) or a hydrate of these acids or one inorganic base such as sodium hydroxide, potassium hydroxide, Sodium hydrogen carbonate, potassium hydrogen carbonate,

9 09840/0 8

'D%

Sodium carbonate or KaliiiSDosrbonatc are also. Salts of organic acids such as disodium phosphate can also be used, also, organic salsa! ¹ satires are used «,

Suitable salts of organic acids are, for example, the IT triunis salts of linear cross-linked saturated or unsaturated aliphatic carboxylic acids with 1 M 18 and preferably 2 to 10 carbon atoms, or bi @ aliphatic groups, interrupted or interrupted by one or more heteroatoms such as oxygen or the like sulfur with aryl groups such as phenyl, iDhienyl or furyl, one or more Hjär-ga- ^ flgrt-ppen, one or more halogen atoms and fluorine, Giilv.r or BrOm _9, preferably chlorine, with one or more - 3ren i ^ f 'ponsäursgruppen or ^niedez% en Alkoxyearbony iii upp ©:!? _c: Torzwgsxfsise with Fiethossycarbonyl, Äthosyöarbonyl or pi-jpylos qycar-teoayl or about one or more Ar-ylorr-x-uppen, vorsugswcise I'henosqjr, substituted seiiir

::: ^s * 3iier ^ or-gsidLsehe acid-. «a> i β sufficient soluble cho 3ε" ■ - ■; ■ ... ". λ like 'for example substituted"r'iii,".-.-"" ir-ugswe-ise with n.ieä «ren alky! groups substituted benzonic acids, used stoves«

Examples of such organic acids are, EssigsäuT _.s-5 acrylic acid, butyric ö 5-Ataeisensäure ₉ adipic acid, Isobuttersäuxe, Ji-caproic acid, isocaproic acid, chloropropionic acid, crotonic acid, phenylacetic acid, 2 '~ thienyl acetic acid,? Hienylessigsäure, ^ -JLthylphenylessigsaure, glutaric , Afiipinsäuremonoäthyl © st @ r, hessanoic acid, heptanoic acid, doe-L ^r n acid ^ oleic acid, stearic acid, palmic acid _s 3-Hycb.O3: propionic acid, 3-methoxypropionic acid,

909840/081

3-methylthiobutyric acid, 4-chlorobutyric acid, 4-phenylbutyric acid, 3 ~ phenoxybutyric acid, 4-a'thyrbenzoic acid and 1-propylbenzoic acid.

According to the invention, however, sodium salts are preferably used Sodium acetate, ITatrium - ^ - ethylhexanoate or sodium diethyl acetate used.

The salt formation can also take place through the action of an organic base, for example triethylamine, Diethylamine, trimethylamine, propylamine, ΓΓ, ΪΓ-dimethylethanolamine or tris (hydro3q7inethyl) aminomethane, also by the action of arginine, lysine, methylamine, ethanolamine, pyridine, picoline, Mcyclohesq ^ lamin, procaine, Histidine, K-methylglucosarnine chloropholine or bensylamine.

The salt formation is preferably carried out in a solvent or a mixture of solvents such as water, ethyl ether, methanol, ethanol and acetone.

The salts are obtained in amorphous or crystalline form, depending on the reaction conditions used.

The crystalline salts are preferably obtained by reacting the free acids with one of the abovementioned. Salts more aliphatic Carboxylic acids, preferably with ETatritzmacetat, manufactured.

The possibly carried out esterification of the compounds Formula I occurs under conventional procedural conditions; for this purpose, the acid of the formula I is generally used with a derivative of the SOrmel

9038A0 / 088

.- ■ - ■■ ί ">

Z - R ₂₀

lung set at, in which Z is an OH group or a halogen atom such as fluorine, chlorine, bromine or iodine and Hon ^ ^e to be introduced ester group; suitable ester groups are indicated above, but the groups which can be used are not limited to the exemplary groups listed above.

The invention also relates to a process for the preparation of the compounds of the formula I ¹ as above, which is characterized by:

(A1) Implementation of a compound of the formula VI

f ^HR i6

CO ₂ H

in the R ^, - one by acid hydrolysis or hydrogenolysis easily split off group means

(a) with a functional derivative

of the group -C-R '^
X

with X = 0 or S.
and

909840/0886

R ¹ ^ = C ₁ - to C ^ -alkyl, C ₁ - to
Alkoxy, phenyl or

- (GH ₂ ) _n -N

tl

T? "

with O- ^ n ^ -4 (gg)

and

R " ₂ and R", - H or C ₁ - Ms C ^ -alkyl, where at least one of the substituents R "^ • and R" _{3 is} alkyl, if η =,

or together with the K atom piperidino, morpholino or Phthalimido,

to a compound of the formula VI.
UH R ₁₆

CO ₂ H (VI _A )

I -C - R-5

909840/088 «

291282 ¹

or

(b) with a compound of the formula X = C
with X = O or S.

to a compound of the formula VI '«

NE ₁₆

ßO _p H

S N

Y ^

or

(c) with a compound of the formula

E "
TC-GO ₀ A "'with E" = H or C, - to C ^ -alkyl, ^R 4 X = halogen, sulfate or

SuIf onat,

R ¹ 4 = phenyl or uritrile and

A "'β one through acidic

or hydrogenolysis easily removable protective group

909840 / D88B

a compound of the formula

, / L

0-C-CQ ₀ A " ^{1 R}

or

(d) with a compound of the formula

with Y ₁ as above T to form a compound of the formula VI ₀

MH R ₁₆

909840/0888

2912B29.

or

(e) with a compound Y ₂

with 1 - £ H ¹ ^ 4 (whole number),

Y ₂ = as above Y
and

E'c = C ₂ - "to C ^ acyl, G ^ - to C ^

or C ^ - to O ^ -alkylthio, where the S atom of the alkylthio group, if necessary for corresponding sulfoxide or sulfone is oxidized,

to a compound of the formula

or

(f) with a compound of the formula

with 2iöi ₂ ^ 4 (whole number) and

909840/0888

= like Olsen T

to a compound of the formula

ψ ^{1 R.}

16

) _n2 -CN

or

(A2) Implementation of a compound of the formula VII

16

N = / CO ₂ H

(VII)

(a) either with hydrogen sulfide

or if η ^1/1, with a base to hydrolyze

909840/0886

ZS1282

to a connection of Ikma & l Ti ™

with Λ & χ ^η ^ Α (integer), if X = S,

■ and η "/ 1, if X = O is *,

X = S or O,

if X = S ,, the possibly ^ * with a connection of the lOrmel

Shark

with Ε'ή = methyl or amino

and
Shark = halogen *

^ Q70

or

(b) with an azide to give a compound of the formula VItt

§09840 / 0888

converted to a compound of the formula VIq will,

N ₁

CO ₅ H

2312829

Implementation of a compound of the formula VIII

(VIII)

- (CH ₂ J _n , -Hai

either with pyridine to form a compound of the formula VI _T

NH H

or with an azide to form a compound of Formula VI ^

0/0886

2312829

) _n , -N ₃

with an amine derivative of the formula

with ILjg = one by acid hydrolysis or Hydrogenolysis easily removable group or C ^ - to CL-alkyl

and

= H or C ^ to (V-alkyl

or together with IL ₁₈ Phthalxmido

to a compound of the formula

NHR ₁₆

\ θ- (ΟΗ ₂ ) _η , -1

40/08 8 6

2S1282S

with imidazo !, morpholine or an If-llkylpiperazine. to a compound of the formula ^ V

with E ^ as above
or with a combination of the formula

with R as above

ÖJU

to a compound of the formula

NHR ₁₆

CO "H

9 09 8-407 OS 86

(B) Implementation of the compounds of the formula VI. , VT '., VI _B , VI ₀ , VIj, VI _e , VI ₁ ,, VI _g , VI _h , VIII, VIj, VI _K , VI-r, VI't and VI ™ · or their derivatives

with a compound of the formula IX

(ix)

with A ″ = H or a group which can be easily split off by acid hydrolysis or hydrogenolysis

and
ILj = as above

to compounds of the formulas HL, III '., HIn, IH ₁ ), III _E , HIp, III _G , IIIjj, V, IHj, III _k , ^ III'τ and IIIjvj as above,

where the compounds of the formula III «, if necessary, are converted ^{into compounds of the formula III 1 ^ with an alkali base,}

whereupon the compounds of the formulas III «, III ¹ λ, III _B , III _G , III ' _c , IIIjj, I1I _E , III _F , IIIj, III _K , III _L , III' _Lf III _M or V

9D9840 / 08SS

- AU-

converted into the corresponding compounds of the formula I 'by the procedure given above will.

The compounds of the formula VIa are prepared from compounds of the formula VI under the same process conditions like the preparation of the compounds of the formula III α from compounds of the formula II.

The preparation of the compounds of the formula VI ¹ ^ from compounds of the formula VI is also carried out in the same way as the preparation of the compounds of the formula III ¹ ^ from compounds of the formula II.

For the synthesis of the compounds of the formulas VI-g, VIq, VI-q, VIg, VI-jp, VIq., VIjj, VIj, VIg- and VIj ₁ from compounds of the formula VI, it is also possible in the same way as the synthesis of the compounds IH ₃ , HI ₀ , ΙΙΙ _ρ , III _E , III ^ ,, III _& , IH _R , IHj, IHg; and IHj _{1 are} made from compounds of the formula II.

The reaction of the compounds of the formula VIII with imidazole, morpholine or an N-alkylpiperazine takes place under the same process conditions as the reaction of these Vex compounds with compounds of the formula V.

The reaction of the compounds of the formula H -SH with the

SlJ?

Compounds of formula VIII is made under the same process conditions how the reaction of the same compounds of the formula R-SH with the compounds of the formula V performed.

909840/0888

In a preferred way of carrying out the process, the compound of the formula IX is _{reacted with a functional derivative of one of the abovementioned compounds of the formulas VI A} to VI _L , VI ' _L , VI _M and VIII.

The derivative can be a functional derivative such as a halide, symmetrical or mixed anhydride Be amide or an activated ester.

An example of a mixed anhydride is the anhydride accessible with isobutyl chloroformate. An example of an activated ester is the ester which is formed with 2,4-dinitrophenol or 1-hydroxybenzo-i-triazole. Examples of halides are chloride and bromide.
This also includes the acid azide and the acid amide.

The acid anhydride can in situ by reaction Ν, ΕΓ'-disubstituted Carbodiimides such as Ν, Ν-dicyclohexylcarbodiimide getting produced.

The acylation reaction is preferably carried out in an organic solvent such as methylene chloride. However, there are also other solvents such as tetrahydrofuran, Chloroform or dimethylformamide can be used.

When using an acid halide or a mixed anhydride produced by the reaction of isobutyl chloroformate the reaction is preferably carried out in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, Sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, Sodium acetate, triethylamine, pyridine,

0/0886

Made horpholine or N-methylmorpholine.

The reaction temperature is generally below or at room temperature.

The conversion of the compounds of the formulas III «to III _T , IH ¹ T, IHm and V into the corresponding compounds of the formula Γ is carried out under the abovementioned conditions.

The invention also relates in particular to the above Process, which is characterized in that compounds are used, in your formula the substituent R ^ g Trityl, chloroethyl, t-pentyloxycarbonyl, t-butyloxycarbonyl or benzyloxycarbonyl.

The compounds of Formula VIII as above are as follows manufactured:

A compound of the formula VI ¹

ro R (VI ¹

^CO 2 ^R e

in the Ή. ^^ an amino protective group and R _{e are} hydrogen or G ₁ - to C ^ -alkyl,

is with a compound of the formula Hal- (GE ^) _n , -Bb1

098 40/0 886

ORa SMSPECTED

291282S

implemented, in which η 'is an integer from 1 to 4 and Hal represent a halogen atom; this results in a compound of the formula YI "

NHR ₁₆

(VI ")

(CH ₂ ) _n , - Hal

with E / jc) R _e > n 'and Hal as above,

which, when H _{0 is} C ^ - to C ^ -alkyl, is treated with a base and then with an acid.

The amino protecting group R,] g can be among those listed above Groups must be selected.

The reaction of the compound of the formula Hal- (CH ₂ ) _n , -Hal, in which Hal preferably represents a bromine or iodine atom, with the compound of the formula VI 'is preferably carried out in the presence of a base to bind the hydrohalic acid formed. This can be done, for example, in the presence of an inorganic base such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate or potassium hydrogen carbonate. However, the same procedure can also be used in the presence of a known organic amine base.

The saponification of the compounds of the formula VI ″, in which EL denotes Ci- bis (V-alkyl, takes place according to the invention

909840 / 088S

under customary, known process conditions. Before doing this, you can first use a base such as sodium hydroxide or potassium hydroxide or barium oxide, followed by reaction with an acid such as dilute hydrochloric acid; For this However, acetic acid or formic acid can also be used in the same way.

The compounds of the general formula I ¹ have a very high antibiotic activity both against gram-positive bacteria such as staphylococci, streptococci and in particular penicillin-resistant staphylococci and against gram-negative bacteria, in particular the coli-like bacteria, the Klebsieila and Froteus species and salmonella.

Because of these properties, the compounds according to the invention are suitable for the treatment of sensitive germs caused diseases, especially Stephylococcal infections such as staphylococcal septicemia, malignant Staphylococcal face or skin infections, pyoderma, septic or purulent wounds or anthrax, phlegmon, erysipelas, acute primitive or post-flu staphylococcal infections, bronchopneumonia or pulmonary Suppurations as active ingredients in drugs or as Medicinal applicable.

Pie compounds according to the invention can also be used as medicaments or as an active ingredient in medicaments for treatment Colibacillosis and accompanying infections, infections by Proteus, Klebsieila and Salmonella as well as others affections caused by gram-negative bacteria to be used advantageously »

29128

The invention also relates to the compounds of Formula I 'as defined above and their salts with inorganic or organic, pharmaceutically suitable acids as active pharmaceutical ingredients or medicaments, in particular with antibiotic activity.

The active ingredients or medicaments according to the invention, in particular with antibiotic activity, include in particular the compounds of the formula I ¹ and their salts, in which R ^ _{2 is} 1.2.3-, 1.2.5-, 1.2.4- or 1.3.4-thiadiazolyl, 1H-tetrazolyl, 1.3-riDhiazolyl, 1.2.3-, 1.2.4- or 1.3.4-triazolyl or 1.2.3-, 1.2.4-, 1.2.5- or 1.3.4-oxadiazolyl means, the substituents mentioned both tmsubstituiert and one or more times with methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyloxy, isopropyloxy, aminohydroxycarbonylmethyl, dimethylaminoethyl and / or diethylaminoethyl, also the compounds of formula I 'and their salts, in which R ^ ρ denotes an acyl group such as acetyl, propionyl or butyryl, as well as the compounds of the formula I ¹ , in which ILj ρ acetyl, 1-methyltetrazolyl, 2-methyl-1.3.4-thiadiazolyl, 3-methyl-1 ^^ thiadiazol- ^ -yl, 3-methoxy-1.2.4-thiadiazolyl, 1.3.4-thiadiazol-5-yl, 2-amino-1.3.4-thiadiazol-5-yl, 3-hydroxycarbonylmethyl -i.2.4-thiadiazol-5-yl, 5-methoxy-1.2.4-thiadiazol-3-yl, 4- methyl-5-hydroxycarbonylmethyl-1.3-thiazol-3-yl or 1-dimethylaminoethyl-i.2.3.4 -tetrazol-5-yl means, furthermore the compounds of the formula I ', in which mean:

R -CR ¹ with X = O

It

X and

R '= C ₁ - to C ₄ -alkyl, phenyl or

3D934 0 / 0P8S ORIGINAL INSPECTED

nit η - O or 1
, and

"and E? as above,

- -C-CO ₂ A ¹ with A ¹ and E "VH
E ,, and

= t phenyl or hydroxyethyl,

- a y-lactone of the! formula / ο

or

a group - (CHp) _n r-

with n '= 1 or 2
and

Ε, - = -N with E _c and E _n as above

or

R = -C-IWIo, 1.2.3.4-Tetraz50l-5-yl or acetyl,

P. it <- ■ -

C ₁ - to Cc-alkyl, -CH ₂ -SE ₁₂ with E ₁₂ == 2 ~ methyl-

1.3.4-

thiadiazolyl or

1-methyltetrazolyl

or

9098Ä07O8 86

'cJ ^2im 2 ^ 12829

Ac et oxymethy1
■ and

A H or an equivalent of an alkali metal, alkaline earth metal, magnesium oxide, ammonium or one organic amine base,

The invention also particularly relates to those compounds of formula I as drugs or active ingredients, especially with antibiotic activity, in which:

R acetyl, benzoyl, phthalimidoacetyl, 1T, N-diynethylcarbamoyl, Ci.-Carboxyphenylmethyl, 2-0xo-3-tetrahydropyranyl, 1,4-Dihydroxy-1-oxo-2-TDutyl, Phthalimidomet hy 1., aminoethyl, tetrazol-5-ylmethyl, 2-amino-2-thioxoethyl or 2-oxopropyl,

R ₁ methyl, acetoxymethyl, 2-methyl-1.3. ^z l-thiadiazol-5-ylthiomethyl or 1-methyltetrazolylthiomethyl

and
A hydrogen or sodium,

also those active ingredients of the formula I in which:

R acetyl, benzoyl, phthalimidoacetyl, 5-tetrazolyl, Aminoethyl or oL-carboxyphenylmethyl

and

909840/088 6

Acetoxymethyl, 2-methyl-1.3. ^/ t-thiaaiazol ~ -5-ylt] aiomethyl or i-

The invention also relates to the compounds of formula I _& as active ingredients or as medicaments, in particular with antibiotic activity, in which R ₅ a is bromine or iodine or phenylthio, 2-pyridinylthio, 2-amino-1,3.4-thiadiazol-5-ylthio , i-methyl-iH-tetrazol-5-ylthio, 2-aminophenylthio, 5-nitro-2-pyridinylthio or 3-gyano-6-methyl-2-pyridinylthio means.

The invention relates in particular to the following substances which are used as medicaments or active ingredients in medicaments, in particular with antibiotic activity, the following can be used advantageously:

- 3-acetoxymethyl-7- [[2- (2-aminothiazol-4-yl) -2- (2-aminoethoxyimino) -acetyl] -aminol -ceph-3 ~ em-4 ~ carboxylic acid (syn-isomer) as well as their pharmaceutically suitable salts with alkali metals, alkaline earth metals, Magnesium, ammonium and organic amine bases as well as esters with easily cleavable groups,

- 3-Acetoxymethyl-7- £ jp ~ {(2-bromoethoxy) -imino] -2- (2-aminothiazor-4-yl ) -acetyl] -aminoH -ceph-3-'em-4-carboxylic acid (syn-isomer) and their pharmaceutically acceptable salts with alkali metals, alkaline earth metals, magnesium, Ammonium and organic amine bases as well as esters with easily cleavable groups

and

- 3-Acetoxymethyl-7-LL2 - [(2-iodoethoxy) -iminoJ-2- (2-aminothiazol-4-yl) -acetyl] -aminoj -ceph-3-em- ^ l ~ carbon-

909840/0886

acid (syn isomer) and its pharmaceutically acceptable Salts with alkali metals, alkaline earth metals, magnesium, ammonium and organic amine bases as well as esters with easily split groups.

The invention accordingly also relates to pharmaceutical compositions, which contain at least one of the substances defined above as an active ingredient.

The compositions can be buccal, rectal, parenteral, intramuscular or topically applied administered to the skin and mucous membranes.

The compositions can be solid or liquid and in pharmaceuticals commonly used in human medicine Forms are available, for example as simple or sugar-coated tablets, gelatin capsules, granules, suppositories, injectable compositions, pomades, creams and gels, which in turn can be produced by conventional methods are. The active ingredient (s) can usually be used in pharmaceutical compositions Excipients such as millet, gum arabic, lactose, starch, Magnesium stearate, cocoa butter, aqueous or non-aqueous Carriers, fat bodies of animal or vegetable origin, Paraffin derivatives, Glycols, various network, Dispersants or emulsifiers or preservatives are introduced.

The compositions can also be in the form of a powder, for example immediately before use can be dissolved in a suitable vehicle such as apyrogenic sterile water.

90 98 4 0/0886

424-

The dose to be administered depends; of the disease being treated, the person being treated, the respective type of administration and the compound concerned.

In humans, for example, the dose varies between 0.250 g and 4 g per day for oral administration or of 0.5 g to 1 g with intramuscular administration three times a day of the substances described in Examples 15> 38 and 4-3 described connection.

The compounds of the formula IV and their salts can also as disinfectants for surgical instruments be used.

The invention also relates to the following new compounds:

- Compounds of formula A

NHR

(A)

with R ^ g, Rj and A "as above, in. which mean:

909840/0886

-C-R ',

Il J

Il

R "
-C-CO ₂ A "'

- (CH ₂ ) _n "-c-mi ₂ ,

- - <eH2> _n , -

909840/0886

2912828

291282:

or

/ ^K 18

where R ' ₃ , X, R ", Hp, η.", R ¹ π,

A " ¹ , η ¹ , R ' ₅ ,

, Jg and R ^ q have the above meaning own

with the proviso that R ^ g cannot mean a chloroacetyl group when R- -G-CH ₃

and R: -CH ₀ -OC-CHo; 1 2nd μ J

- Compounds of formula B

909840/0886

NHR

(B)

with Rsic as above, in which means:

^{with R} 'i3 ^{like Ri} 3 except methyl,

- -C-NH ₀ ,

I! C-

R "
- -G-CO ₂ A "·

R ^1,.

903840 / 088S

- Λ2> 5- , 291282

(CH ₂ > n ' in the,
-ψ
H (CH ₂

or

R ₁₈

R ₁₉

with R ' ₅ , X, R ", R' ₄ , A" ¹ , n ', R ¹ ^, n ₂ , n ", RV _? R ^ _ß and R ₁ Q as above;

Compounds of the formula XEI

909840/0886

2912879

^HR 16

CONH ^

1] (XII)

(CII,), -R

2 n '

^C0 2 ^A "

with n ¹ , R ^ ₁ and R _o v / ie above, in which:

R ^ c is an amino protecting group

and
A "hydrogen or an easily split off

Ester group,

in particular the compounds of the formula

CONR

: .CX,

: Ο ₂ Λ «

in dex mean:

R ¹ ^ c one selected from trityl imd Ohloracetyl

909840/0886

- 3 & r

chose amino protection group, η '. 1 or 2,
Hal, j bromine or iodine,

A "hydrogen or an easily cleavable ester group

and

R. hydrogen, acetyloxy, carbamoyloxy,

1-methyltetrazol-5-yl or 2-methyl-1.3.4- ■ thiadiazol-5-yl;

- Compounds of the formula III '

NIIR.

CONH

^s oo ^:

^X Rb

(III

with R ₁ , R,, R ₁ f. and A "as above;

yei'biridungen dei * Formula VI ¹ ^

84 (1/0

-Ί3 & -

with Ri and R ^ g as above

as

- Compounds of the formula XIII

(CHJ _n . -R

(XIII)

n / A

with a ¹ and R _n as above, in which R, _1C -an amino push-

8. Io

grupi> e means, 'in particular compounds of the formula

^ o

u η / ο ρ, 3 = 6

- 439-

2912820

NHR ¹

with e! i £ -, η ¹ · and Hal. * as above.

It) X I

The 'used as starting materials according to the invention Compounds of the formula II can, in particular, by reacting a compound of the formula C

BHB ₁₆ [

GO ₂ H

¹ I.

OCH,

3H,

or a derivative of this acid such as the symmetrical anhydride

with a compound of the formula

9098 40/0 88 $

- 4W-

to a compound of the formula

which is then reacted with an inorganic acid such as dilute hydrochloric acid to form the compound of formula II «

The compounds of the formula C can be selected from compounds of the formula VI

9Q9840 / 088S

NH R

Ti

16

S T

CO ₂ H

(VI),

which are described in BE-PS 850 662, by implementation with 2-Metho: xypropen are produced.

The compounds of the formula used as starting material V are accessible as follows:

Implementation of a compound of the formula VI

NHR

(VI)

with 2-methoxypropene to form a compound of the formula

909840/0886

ο -

NHR

those, for example in the form of an acid derivative such as of the symmetrical anhydride, with a compound of the formula IX

(IX)

to a compound of the formula

NHR

9G98 / .n / 0886

is implemented, in turn, by treatment with a aqueous inorganic satire such as dilute hydrochloric acid to a compound of the formula

HHR

CONH

is implemented after treatment with a compound

the formula

HaI- (CH ₂ ) _p , -Hai
the compound of formula V gives ",

The compounds of the formula HIg- used as starting materials in the production process for the compounds of the formula I " _K " can be produced, for example, by reacting an azide such as sodium aside with a compound of the formula V.

The compound of formula VIII can also also with

an Asid are implemented, whereupon the product obtained is condensed with a compound of formula IX. Examples of these procedures are given in the experimental below Part specified.

909840/0886

291282

In addition to the following embodiments, which the invention To explain only by way of example and without restriction, the following additional substances are also in accordance with the invention accessible;

- 3-Acetoxymethyl-7- [C2- (2-aminothiazol-4-yl) -2- (carb ~ amoyloxyimino) -acetyl] -aminoj -ceph-3- © ni-4 ~ carboxylic acid (syn-isomer), their salts with alkali metals, alkaline earth metals, Magnesium, ammonium and organic amine bases as well as their esters with easily cleavable groups.

Separation of solids is indicated in the following examples by suction filtration; however, it can each centrifuged in the same way.

Example 1: 3-Acetoxymethyl-7 - [[E2- (2-aminothiazol-4- »yl) -2-acetoxyiminoJ -acetyl] -aminoj -ceph ^ -em - ^ - carboxylic acid (syn isomer)

A solution of 0.756 S of the diethylammonium salt of 3 ⁼ acetoxymethyl-7- [_ [2- (2-tritylaminothiazol-4-yl) -2-hydroxyimino] -acetylJ-aminoceph-3-em-4-carboxylic acid (syn -Isoraer) in 1 ml of pyridine and 0.5 ml of acetic anhydride are stirred for 30 min at room temperature, then 3 ml of water / water and then 2N hydrochloric acid are added up to pH 1. Thereafter, it is filtered off with suction, washed with water and dried whereupon _s O received ₅ 750 g crude acylated product.

Dsnach a suspension of 0.520 g of the above

909B40 / 088:

In 1 mL of aqueous formic acid (HCOgH / HgO 2: 1) was stirred for 5 min in a water bath at 45 ⁰ C. Then 0.5 ml of water are added, whereupon the stirring in the water bath of 45 ⁰ G is continued for 10 min.

After adding 5 ml of ethanol, the mixture is made under reduced pressure evaporated. After being taken up in ether, suction is filtered off, washed and dried, whereupon 0.304 g of impure Product (presence of de-acetylated derivative). The product is in 1 ml of acetic anhydride and with 2 drops Pyridine dissolved. After precipitation with 10 ml of ether, 0.300 g of the desired product are obtained.

El em ent ar analysis: C ^ πΗ, ^, -, OgN ₁ -Sp: 523 »0

% G% E% N % S calculated: 44.80 3.75 14.70 12.26 found: 44.6 3.8 14.5 11.7

NMR spectrum:
2.05 ppm: OAc
6.75 ppffl: 5-proton of the thiazole ring.

,, D iäthylammoniumsalzeSy

Production of the »der B-acetoxymethyl -? - I [2- (2-tritylaminothiazol-4-yl) -2-hydroxyimJLnoJ -acetyl] -amino-ceph-3-em-4-carboxylic acid (syn isomer):

ORIGINAL INSPECTED

2912823

Step e_Ai 2- (2-Tritylaminothiazol ~ 4-yl) -2- (1-methyl-1 -

12.9 g of 2 - [(hydroxy) imino] -2 »(2-fcritylatuinothiaz; ol'-4-yl) acetic acid (syn isomer) are 20 min at room temperature stirred in 120 ml of methylene chloride and 12 ml of 2 ~ methoxypropene. It is then evaporated to dryness and again JO min in 60 ml of methylene chloride and 12 ml of methoxypropene touched. It is then evaporated to dryness under reduced pressure.

This results in the desired product, which is used unchanged.

piäthylammoniunisalz _t
§ £ y of 3-acetoxymethyl ~ 7-

j [2- (2-tritylaminothiazol-4-yl) -2- [i-methyl-1-methoxyethoxyj -iminoj-acetyl] -amino-ceph-3-em-

Starting from 47.25 g of 2- (2-tritylamiuoth.iazol-4-yl) ~ 2-hydroxyiminoacetic acid 2- (2-tritylaminothiazol - ^ (- yl) -2- (1-methyl-1-methoxyethoxyimino) acetic acid prepared by the above process in step A (syn isomer) is dissolved in 230 ml of methylene chloride. Then 12.5 g of dicyclohexylcarbidiimide added; and stirred for 1 h at room temperature. The dicyclohexyl hydrogen which is formed is dissolved in liquid form sighed off and washed with a little methylene chloride (Yield 9 »ß2 g). A solution of 13.6 g is added to the filtrate 7-Amiiiocephalosporanäure in 70 ml methylene chloride and 14 ml of triethylamine were added, which took place for 2 hours at room temperature is stirred. It is washed with 30 ml of 1 N hydrochloric acid im

Separating funnel, decanted, washes with water, dries ■ and evaporated to dryness »The residue is in 100 ml Dissolved ethyl acetate, whereupon crystallization is initiated. It is allowed to crystallize for 30 minutes and then suction filtered from whereupon 5t5 S starting product can be obtained. The filtrate is evaporated to dryness and the residue is stirred for 30 minutes with 200 ml of isopropyl ether. To Filtering off with suction and drying, 37 * 35 g of crude condensation product are obtained obtain.

Proceed as follows to incline:

The product is dissolved in 148 ml of ethyl acetate. Hach addition of 5i5 nil diethylamine v / ird with vigorous stirring at 650 ml of ether precipitated, laughing sucking off, washing with ether and drying, 26.35 g of the desired product are obtained » The filtrate is then evaporated to dryness and taken up with 50 oil ether., After which a sweite Quantity of 2.8 g of the product is obtained, the thin-layer chromatography is identical to the first.

That. Diethylamine salt continues to be used in this ITorm.

IMR structure (CDOL ₃ ; 60 MHz):

OH ^ (a) (a) = 1.5 * ppm

0-

-CH ₃ Ca) (b) = 3.27 ppm

6.78 ppm; Proton of the thiazole ring.

2912823

D i at hy 1 ammpniurasalz, -Stufe ^ CT ™ ¹ V "of 3-acetoxymethyl - 7 ~

• 2- (2-tritylaminothiasol-4-yl) -2-hydroxyiminoj-acetyl! ~ Amino-ceph-3-em-4-carboxylic acid i§Y2-li SSiSf El .________.._. , _ "_. _ "__.

7 ₅ 6 g of the diethyiamine salt of the 3 ~ aeto3grmetliyl- »7 ^m rC2 ~ (2 ~ tritylamiaothia2ol-4-yl) -2-C.1-methyl-1-methoxyethoxy] -imino] obtained in the own stage B acetyl] amino-ceph-3-em-4-carl) on _t acid (syii-isomer) are dissolved in 30 ml of acetone and 10 ml of 2 Ii hydrochloric acid! times. 40 min of stirring at Hsuin temperature, 20 μl of water are added, whereupon the acetone is evaporated off at 30 ° C. under reduced pressure. Ethyl acetate is decanted, re-extracted, _{dried with water g®wasela © 2x 3} and suction filtered; after adding τοη 1 sal Mätigrlanun sum filtrate, trituration, cooling τ & Λ Ifeautseiles, eiea gatoild © t © 2i Dietliylasinsalzes Wirt ?: rn.lv Ätner washed 5 the Seiaprodtakt falls in 'a Heage of 6 g.

f5 S % E % Έ% S

₉ 30 5 ₂ 33 Ii ₉ IO ₉ 5 5 ₉ 7 ^ O: 9

^ ääHlSl (GDGI ₅₃ 5 SO MEfejs

S, 6J ppEi Proton ties ThiaEOlrings =

"?: 35 PP2i °? Rofe-oii92i, oiler 3? 2? I-öylgmäj>

3-acetoxymethyl-7- [[2 ~ (2 ~ aminot: hiazol ~ 4-yl) -2-phthalimidoacetoxyin) .inq3 -acetylj -amino- ^ -em - ^ - carboxylic acid (syn isomer)

0.756 g of the 3 ~ acetoxymethyl-7- [C2- (2-tritylaminothiazol-4-yl) -2 ~ hydro: xyimino] -acetyl] amino-ceph ^ -em - ^ - carboxylic acid diethylata salt (syn- Isomer) are suspended in 4 ml of methylene chloride with stirring. Then 0.335 S phthalimidoacetyl chloride are added. After 5 ^m in. At room temperature, it is precipitated by adding 10 ml of isopropyl ether, suction filtered, made into a paste with water and dried. The crude product obtained is then at 35 *> is QG ° C for 20 min in 2 ral an aqueous formic acid solution {Ameisensä \ ire / water 2: stirred 1). After adding 10 ml of water, suction filtering, taking up again in ether and suction filtering again, it is dried. The product is then dissolved in 4 ml of acetone, after the insoluble anchoring has been separated off, it is precipitated with 10 ml of ether. 0.280 g of the desired product are obtained.

Element ar analysis: ^ 15 ^ 20 ^ 10 ^ 6 ^ 2 ^: ^ 8.6

% Ή % S

calculated: 13.77 10.20
found: 12.5 10.4.

UV spectrum (ethanol):

Maximum 217-218 nm E ^] = 782

Inflection point 230 nm έ \ = 844

ORIGINAL INSPECTED

Inflection point 238 nm E ₁ = 453

Turning point 260 217 nm A. = 242 Turning point 300 231 nm A. = 107 N / 10 HCl in ethanol: 239 maximum 258 - 218 nm A. = 773 Turning point nm A. = 429 maximum nm A. = 352 maximum nm = 286

Inflection point 280 nm E ₁ = 230.

UMR spectrum (DMSO):

7.18 ppm: thiazole proton.

Example 3: 3-Acetoxymethyl-7- £ [2 - (2-aminothiaEol-4-yl) - ^ -dimethylamino-carbamoj-loxylminoj -acetyl] amino-ceph-3-em-4-carboxylic acid (syn isomer)

»75 g of the 3-acetoxyraethyl-7- produced in Example 1 | _C, 2- (2-tritylaminothiazol-4-yl) -2-hy (1roxyimino]] -acetylJamino-ceph ^ -em ^ -carboxylic acid diethylamine salt (syn-isomer) are suspended in 4 ml of methylene chloride with stirring.

Then 0.2 ml of pyridine and 0.2 nil of dimethylcarbamoyl chloride added. After dissolving, it is first treated with water

and then washed with 2 acidified water to pH, "The organic phase is dried and evaporated sv.r dryness and the residue is charged with Xther irerrie" ben. shall see After Abnut received ₃ O 600 g crude "This product is then "Stirred at 40 ° for 5 min with 2 ml of an aqueous formic acid solution (formic acid / water 2 si). Thereafter, 5 ml of ethanol are added, whereupon raid evaporated to Sroekn® resumed with Ätligrlacetat

Ss tierdsa G ₀ 334- gr crude product obtained, ei as aurcii dissolve in sdaea AcetcSi-lfetnanol-Geiiiscii (1s1) _s subsequent addition

toe, Ätlier * äS.s she easy Ausfloekea «, Abnutscliea des umelieE. Bäckst wads n & ä, fällusg äes IFiIt rats with lth © r iigt ^ iIrS ₃ Ss wes & @ n. 0.213 g of eagestrebtsn product

obtain"

iMB ^ jgggBglgsQ ^ ^s i ^ 2oOg% S ₂ s 511.52

15th

1724 esT ¹
166? ea """ ¹

1532 e @ r ¹ _o

(Ethanol) s

230 ma E ^ s 357 2 _s 18 _O 3

90 98 4 0VO '

Turning point 251 nm E. 256 nm E \ = 261 Maxi room 300 nm E 280 nm E \ = 87. Ethanol, N / 10 HCl: EMR-S spectrum (DMSO): maximum ^ = £ 270 = 13,800 Turning point \ = 218.

10.3 ppm: proton of the thiazole ring.

Example 4: 3-Acetoxymethyl ~ 7- £ [2- (2-aminothiazol-4-yl) ~ 2-phthalimidomethyloxyimi «oJ-acetylj-aminoceph ^ -em - ^ - carboxylic acid trifluoroacetate (syn isomer)

Stage_Aj_ 3-Acetoxymethyl-7- [[2- (2-tritylaminothiazol-4-yl) -2-phthalimidomethyloxyimino] -acetylj -aminoceph-3-em-4-carboxylic acid diphenylmethyl ester

0.085 g of the 3-acetoxymethyl-7-j_C2- (2-tritylaminothiazol-4-yl) -2-hyclx-oxyimino] acetyl] amino-ceph ^ -em ^ -carboxylic acid diphenylmethyl ester, 0.12 g bromomethylphthalimide , 0.069 g of potassium carbonate and 0.4 ml of dimethyl sulfoxide are stirred vigorously at room temperature for 15 minutes. Then 10 ml of 0.1 Έ hydrochloric acid are added. The precipitate formed is filtered off with suction, washed with water and dried, after which 0.121 g of crude product is obtained, which is dissolved in 1 ml of ethyl acetate and coated with activated charcoal

O3T-: ■:. :,. ., *, ....-, · ;. 909840/0886

29128

is treated. After separation of the solvent -will the residue is allowed to disintegrate in JLther and suction filtered; 0.075 S of the acylated product is obtained.

" J -1
cm NH 3408 ρ -lactam
Phthalimide I ^ 1782 Phthalimide II
Ester ' I73O Amide 1665 C = C, C = N 1614 Aromatics
supply 1599 Amide II 1511 NH 1493 C = N-OR 1033

NMR spectrum (CDCl ₃ ):

7.03 ppm: arom. H of the trityi groups, diphenylraethyl groups 7.8 ppm: phthalimide

0 9 8 '. fi /; ■ ·

ORIGINAL INSPECTED

2912823

6.9 ppm: COpCH

3.4- ppm: CH ₂ S

phthalitnidomethyloxyiminoj -acetyl] -amino-ceph-3-

0.32 g of the product from step A are 3 nil trifluoroacetic acid added, whereupon ΊΟ min at room temperature vigorously stirred wiz'd. Thereafter, at 30 ° C under reduced Pressure evaporated, whereupon 30 ml of isopropyl ether are added; after the product has disintegrated, it is suctioned off and washed with isopropyl ether.

0.21 g of the desired product are obtained.

The inserted top 3 - A ^c ötoxyiuethyl-7-j [2- (2-trityl aminothiazol-4-yl) -2-hydro3qyimino3 -acetylj - amino-ceph-3-em-ή ~ carboxylic acid dipheriylmethylesber (syn 'Isomer) is made as follows:

ORIGINAL INSPECTED

- 455

291

A): 3-acetoxymethyl-7- £ [2- (2-tritylaminothiazol ~ 4-yl) -2-C.1-methyl-1-methoxyethO3y] -imino] -acetyl] -amino-ceph-

4 · j ^"1 5 S Diäthylaminsalzes of the product obtained in Stage B of Example 1 are introduced 0.1 IT hydrochloric acid in AO ml of methylene chloride and 55 ^m l.

After stirring for 10 min at room temperature, it is decanted off,
whereupon the organic phase is washed twice with 25 ml of water. The organic phase is then dried.

Then 15 ml of an 8% solution of diazodiphenylmethane in benzene are added over the course of 10 minutes. After stirring for 15 min at room temperature, the solvents are ^{evaporated off at 30 °} C. under reduced pressure. After the product has been taken up in isopropyl ether and allowed to disintegrate, the solvent is evaporated off under reduced pressure
sucked off and washed. After drying, 4.41 g of the desired product are obtained.

Nuclear Magnetic Resonance Spectrum _{(CDCl 3} ; 60 MHz):
(n) J ₃ C -NH

0
S.

9098 ^ 0/0888

ORIGINAL INSPECTED

a = ¹ J53 ppm
b = 2.01 ppm
c = 3 j 26 ppm
d = 6.78 ppm
e = 7133 ppm.

B): 3-acetoxymethyl-7- [C2- (2- tritylaminothiazol-4-yl) -2 (hydroxy) -imino] -acetylj -amino-ceph - ^ - em - ^ - carbon-

2.775 g of the product obtained above are in 14 ml Acetone and 4.5 ml of 1N hydrochloric acid were introduced. After stirring for 2 hours at room temperature, the acetone is reduced under reduced pressure Pressure evaporated.

Tray addition of 20 ml of ethyl acetate is stirred and then decanted. The organic phase is washed four times with 10 ml of slightly salty water. The United Wash water is extracted with 5 ml of ethyl acetate. The organic fractions are combined and dried. After suction filtration and washing with ethyl acetate is the solvent evaporated under reduced pressure. The residue crystallizes after being taken up in ether. After disintegrating, it is suction filtered and washed with ether. After drying, 1.88 g of the desired Product received.

Nuclear Magnetic Resonance Spectrum (ODOL ,; 60 MHz):

6.88 ppm: proton of the thiazole ring

rl; ' >J' ». '! Μ

909840/0886

ORIGINAL INSPECTED

Ί5Ψ-

2912823

7> 33 ppm: protons of the phenyl nuclei. Rf = 0.5 (eluent: ether with 20 % acetone).

Example 5: Sodium salt of 3-acetoxymetbyl-7 ™ j_C2- (2-

aminothiazol ~ 4 ~ yl) -2-phbhalimido-mebh, yloxyiminqj-acebylj -amino ~ ceph-3-em-4-carboxylic acid (syn isomer)

0.21 g of the trifluoroacetate obtained in Example 4 has been obtained dissolved in 0.4 ml of methanol, whereupon 0.6 ml of a 1 M sodium acetate solution in methanol was slowly added with stirring will. Then 2 ml of ethanol are slowly added. The precipitated sodium salt is abgenutscbb and washed with ethanol and then with ether.

0.127 g of the desired product will be obtained. UV spectrum (ethanol, N / 10 HCl):

nm £ maximum 217 46,500 Turning point 237 20,000 maximum 252 16,300 Turning point 301 7,400 Turning point 320 5.85O. NMR spectrum (DMSO):

8 »05 ppm: aromatic protons 2 ppm: OAc

9 0 9 8 U 0/0 PB δ

ORIGINAL INSPECTED

IR-Spekbrum (in no time ₁ JoI):

-1
cm G = O 1776-1764-1724 Amide 1689 O = G, C = N ) 1659 Aromatherapy
worked )
1611 Amide II I545 CO " I525

Example 6: 3-Aceboxymebhyl-7- [C2- (2-aminobhiazol-4-yl) -2 - ((cl -carboxy) -pbenvlmebhoxyimino) -acetyl] amino j -ceph-3-em-'l-carboxylic acid- brifluoroacetate (syn isomer)

i "Di-ethylamine salt of 3-acetoxymethyl-7 - [[2- {trifcyLaiiiLtiothLnzol-4-yl) -2- ( (Ot -tbutoxycarbonyL) -benzyhoxyimino) -acetyl] -

1 »37 S dei 'as an intermediate product in fibufe G from example 1 erhalbeneri 3-aceboxymebhyl-7 - [_ [2- (2-brif; ylaminothiazol ~ 4-yl) -2-hydro: xyimino] -8cebylJ-aιnilιo-ceph-3-em-4-carboxylic acid are agitated at room temperature ία 20 ml metal chloride. Then 20 ml of water and then slowly 2.8 ml of triethylamine are added. To the emulsion obtained a solution of 4.8 g of et-D romp hen ;. I acetate-t-butyl-

Ο f'i π ρ. ·! / ^ '"8 p

ORIGINAL INSPECTED

291282

ester in 5 ml of methylene chloride is added, after which the mixture is stirred for 23 hours at room temperature. It is then acidified to pH 1 by adding 10 ml of 2I hydrochloric acid. It is extracted with chloroform, washed with water, dried and evaporated at a maximum of JO ⁰ C under reduced pressure Print to dryness

6.1 g of a brown oil are obtained, which is dissolved in 5 ml Ethyl acetate is dissolved. After adding 0.25 ml of diethylamine, 50 ml of isopropyl ether are added. After sucking off 1.11 g of the diethylamine salt are obtained.

The mother liquors yield a further 0.1 g of a product identical to the previous one.

The two fractions are combined and dissolved in 5 wl ethyl acetate solved. After filtering the solution, the solvent is evaporated to dryness. The residue will be resumed in ether. " Ether washed and then dried at room temperature under reduced pressure. 0.96 g of the desired product obtained in dej? present Form is used for the following stage.

IR spectrum (CHCl _x ):

+ Associates -1
cm NH -Lactam 3372 ß I78I

909840/0888

ORlGiNAL INSPECTED

cm 230 nm mm (Shoulder) • A- 2912829 1738 260 nm A- AcO 1729
1681 303 nm E ₁ « C ester
It
⁰ amide 1602
1526
1493 447 nm E / i - COO ")
Amide II) 1063. C = N-OH UV spectrum (Xthanol): Turning point Turning point Turning point = 304 maximum - 189 »9,700 χ £ 60 8th

Inflection point 515 nm E ₁ s 3 N / 10 HCl, ethanol:

Maximum 267 nm E ₁ = 160 £ = 15,000

KMR spectrum:

6.8 ppm: proton of the thiazole ring.

909840/0886

3-acetoxymethyl-7- [L2- (2-aminotliiazol-4-7l) -2- ( (CL -carboxy) -phenylmethoxyimino) -acetyl] -amino J. ceph.-3-em-A ~ carbonsäiire-trif luoracetab

0.882 g of the diethylamine salt obtained in stage A are in 8.9 Μ. Trifluoroacetic acid stirred at room temperature for 10 min. After dissolution, G is up to a volume of about 3 ml evaporated under reduced pressure at a maximum of 30 ^0th After cooling, the residue is taken up in 30 ml of isopropyl ether and stirred at room temperature for a further Ί0 min. After suction filtration and washing with isopropyl ether ⁰ C under reduced pressure at 20 to 25 dried, after which 0.512 product traffic.

The product is taken up again in 2 ml of acetone with 1 % water, stirred for 5 min at room temperature and then slowly diluted with 20 ml of ether while stirring. After 10 min it is suction filtered, washed with ether and dried under reduced pressure at room temperature.

This gives 0.443 S of the purified product.

Example 7: Sodium salt of 3-acetoxymethyl-7-j ~ [.2- (2-aminothi azol-4-yl) -2- ((d. -Carboxy) -phenyl- methoxyimino ) -acetyl] -aminoj - ceph-3-em-4 ~ carboxylic acid (syn isomer)

0.421 g of the trifltioracetate obtained in Example 6

at room temperature in 2.1 ml of a 1 M solution of sodium acetate in methanol and 2.1 ml of methanol · After treatment with 40 rag activated charcoal and suction filtered through silica, the filtrate under reduced pressure at a maximum of 30 ⁰ O to a volume of 1 ml evaporated. Then 10 ml of 100% ethanol are added to precipitate the sodium salt. After suction filtration, it is washed first with ethanol and then with ether, whereupon it is dried under reduced pressure at room temperature.

0.275% of the desired product is obtained.

% C 260 nm 1761 U 7 7 C-
% H •
• C.
% N % S. calculated: 44.59 276 nm 1532 3.09 -1
cm 11.3 10, 35 found: 44.8 395 nm 1027 3.5 cm"" 11.3 10, 2. UV spectrum (N / 10 HCl, IR spectrum (in Nu.1ol) Ethanol) cm ". *
• maximum β- lactam E ₁ = 266 = 16,500 Turning point Amide II t? 1
E ₁ = 222 ε ■ 13,700 Turning point C = N-OR τρ1
E ₁ » 8th

9098 40/0

Example 8; 3-Acetoxymethyl-7 - (_ £ 2- (2-aminothiazol-4-yl) -2- £ [C2-oxo-3-tetrahydrofuranylD -oxy] -imino] acetyl] -amino] -ceph-3 ~ em- 4-carboxylic acid (syn isomer)

Stage_A: mixture of the Δ 2 " ¹ ^ ^ χ-isomers of 3-acetoxymet] ayl-7- £ [2- (2-tritylaminothiaz ol-4 ~ yl) -2 LQ2-oxo-3-tetrahydrofuranyl] - oxy] -iminoj acetyl] -aminoj -ceph ^ em - ^ - carboxylic acid diphenyl

1.7 g of the 3 ~ acetoxyraethyl-7 - {_ [2- ( 2-tritylaminothiazol - ^ - yl) -2- £ hydroxyimi no] -acetyl] amino] -ceph ^ -em- ^ l -carboxylic acid diphenylmethyl ester dissolved in 8.5 ml of dimethylformamide at room temperature. Then 0.69 g of anhydrous potassium carbonate are added with stirring and then 3 * 2 ml of OC-bromo-y-butyrolactone added. The suspension is then 4-5 min at room temperature and stirred further under an inert atmosphere. Afterward 20 ml of water, 12 ml of 1N hydrochloric acid and 30 ml of ethyl acetate are added. Then it is decanted, whereupon the organic phase with NaCl-containing water up to is washed to neutrality. After drying, the solvent is reduced under reduced pressure at a temperature below 35 ° C ^ is removed to dryness.

6.6 g of a light brown oil are obtained. This oil is taken up in 20 ml of isopropyl ether and 5 min stirred at 40 ° 0, decanted off before the isopropyl ether and the above procedure is repeated, after which a dry extract of about 2.5 6 results, which in

909 8 4 0/0886

treated in the same way with ethyl ether. The residue is taken up again in 20 ml of ether at room temperature with stirring for 15 · The insoluble residue is suction filtered, washed with ether and dried under reduced pressure, after which 1.513 g yellow, amorphous product can be obtained, which is used in this form for the following stage.

IR spectrum;

cm" 3395 HH 1785 β- lactam )
Υ -lactone \ 1744 OAc + ester 1691 Amide 1655 C = C, C = N 1599 Amide II 1588 Aromatic
vibrations 1515 14-93 NMR spectrum (CDCl,)

6.80 ppm: proton of the thiazole ring

903840/0886

1-Oxo-3-aceto3qyTethyl-7 - [[2- (2-trityXaminthiazol-4-yl) -2-CCC2-oxo-3-tetrahydrofuranylI | - oxyj -imino] -acetyl] -amino] -ceph-3-βm-4-carbon-

1.525 6 of the mixture obtained in the previous stage the Δ2 and Δ, isomers are dissolved in 8 ml of methylene chloride under an inert atmosphere and with stirring. After cooling to 0 to +5 ° C in an ice-water bath, the 20 min 0.420 g of la-chloroperbenzoic acid in 8 ml of methylene chloride at 0 to +5 ° 0 was added. At this temperature is stirred for 1 h, after which it is evaporated under reduced pressure without heating and then in 20 ml of ethyl acetate is resumed. Then, first with a sodium hydrogen carbonate solution and then a Sodium chloride solution washed to neutrality

After drying the organic phase has been under reduced pressure at a temperature below 30 ⁰ O is evaporated to dryness. The residue is taken up again in 10 ml of ether. After the insoluble residue has been removed at room temperature, it is washed with ether.

1.390 g of yellow product are obtained.

IR spectrum (CHCl,):

cm""

NH 3386

C = O γ -lactone +

-Lactam

1797

909840/0888

OAc

conjugated ester

Amide
C = O, C-CIi

Aromatic vibrations

Amide II

S = O (possibly)

+ Oxime ether

cm "1737

1691

1634 - 1599 - 1587 - 152> - 1595 1044-1035-1023

W spectrum (ethanol):

Turning point 257 nm 265 nm E ₁ Äs 196 ε » j 5OOO Turning point 305 nm 300 nm A. κ 53 N / 10 HCl, ethanol: £ ~ 19,000 maximum Ί as 200 8,100 Turning point 1
EGG Λ; 85

NMR spectrum (CDCI,): 2 ppm: OAc

6.73 and 6.77 ppm: thiazole ring 6.7 ppm: -CO ₂ CH 7.3 ppm: aromatic protons

909840/0888

Stuf e_G £ 3-Acet oxymethyl-7- £ [2- (2-1 r ityl aminothiaz ο 1-4--

yl) -2-QLC2-oxo-3-tetrahydrof uranyll -oxy] -imino] acetyl] -aminoj -ceph - ^ - em - ^ - carboxylic acid dipheiiylmethjlester

1.328 6 of the product obtained in the previous step are dissolved in 6.6 ml of dimethylformamide. After cooling to -20 ⁰ C under an inert atmosphere 0.6 ml of phosphorus trichloride in 30 s are added. Tray 5 min stirring at -20 ⁰ C 30 ml of ethyl acetate, 30 ml of a saturated sodium bicarbonate solution and 15 g of ice are added. Compartment extraction and decanting is extracted again with 20 ml of ethyl acetate, whereupon it is washed with a sodium chloride solution until neutral. After drying, it is evaporated to dryness under reduced pressure at a temperature below .40 ^{0 O.} The product is taken up in 10 ml of ether, whereupon it is suction filtered, washed and dried under reduced pressure at room temperature.

1.039 g of product are obtained, which is purified by chromatography on silica using methylene chloride with 10% ether as the eluent.

After evaporation to dryness and taking up again in ether, it is suction filtered at room temperature and dried.

0.751% of product are obtained.

NMR spectrum (CDCl,):
2 ppm: OAc

909840/0886

291282S

6.8 ppm: proton of the thiazole ring

6.9 ppm: COp-CS

7.3 ppm: aromatic protons.

StTJLf e_Dj_ 3-Acetoxymethyl-7-Q | l2- (2-aminothiazol-4-yl) -2-CQC2-oxo-3-tetrahydrofuranyl] -OxyJ -iminoj -

7.2 ml of trifluoroacetic acid and 0.720 g of the 3-acetoxymethyl-7- | .E2- (2-tritylaminothiazol-4-yl) -2-CCC2-oxo-3-tetrahydrofur8nylJ -οχχ] -imino] obtained in the previous step -acety IJ -amino] -ceph ^ -em - ^ - carboxylic acid diphenylmethyl ester (syn isomer) are ^{stirred at 20 to 25 0} C for 10 min. It is then evaporated to a volume of about 2 ml at a temperature below 30 ^{° C. under reduced pressure.} The product is taken up again in 30 ml of isopropyl ether while cooling with an ice-water bath. The mixture is then stirred for 10 min at room temperature and suction filtered, whereupon 0.483 g of product are obtained.

0.480 g of the product are taken up in 0.5 ml of anisole and 4.8 ml of trifluoroacetic acid like the, and taken up for 5 minutes at room temperature touched. It is then evaporated to about 1 ml and taken up in 20 ml of isopropyl ether. In the case of the Abnutsehen 0.472 g of product are obtained. to 0.458 g of the product are 1.8 ml of 50% aqueous formic acid admitted.

This is followed by 10 min under an inert gas atmosphere

909840/0886

291282!

50 ° C heated · Thereafter, a slight insoluble product filtered hot, evaporated the filtrate under reduced pressure and without exceeding an outside temperature of 30 ⁰ C to dryness. It is then taken up in 3 ml of water. After suction filtration, washing is carried out with very little water and then with ether.

0.283 g of product are obtained which in this form for the example below is used.

Example 9: the sodium salt of 3-acetoxymethyl-7- [| j? - (2-

aminothiazol-4-yl) -2-nCll2-oxo-3-tetrahydrofuranyX] -oxy] -imino] -acetyl] -aminoj ~ ceph-3- em-4-carboxylic acid (syn isomer)

0.283 6 eggs obtained in Example 8 3-acetoxymethyl-7-j_ [2- (2-amino thi azol-4-yl) -2-CC G2-oxo-3-tetrahydrofuran anyl oxy] -imino] -acetyl] -aminoj -ceph-3-em-4-carboxylic acid dissolved in 1 ml of a 1 M solution of sodium acetate in methanol and 1 ml of methanol. The solution is made with 30 mg of activated charcoal treated, then filtered through silica and washed three times with ethanol. The filtrate is then taken under evaporated to 1 ml under reduced pressure at a temperature below 30 ° 0. Then with 10 ml 100% Ethanol diluted, suction filtered and first with 100? 6 igem Ethanol and then washed with ether.

0.165 g of product are obtained. Elemental analysis:

% G % H% N % S % Na

calculated: 41.68 3.31 12.79 11.72 4.1 found: 43.8 3.5 11.8 10.7 4.2

UV spectrum (N / 10 HCl, ethanol): inflection point 220 nm E ^ J = 255 maximum 260 nm E ^ j = 302 £ = 16,500

IR spectrum (in Nujol):

β- lactam
f -lactone ) 1765 cm" Amide 1673 cm ~ C = C, C = N
COO " } 1611 cm"" Amide II 1535 cm" NMR spectrum (DMSO): 1.98 ppm: OAc 6.78 ppm: Proton of the thiazole ring 4.33 ppm: CO ₂ CH ₂

909840/0886

2912823

Example 10: Disodium salt of 3-acetoxymethyl-7- £ [2- (2-aminothiazol-4-yl) -2- ££ [; 1.4- dihydroxy-1-oxo-2-butyU -oxy] -imino] -acetyl] -amino] -ceph-3- em-4-carboxylic acid (syn-isomer)

0.257 6 of the sodium salt obtained in Example 9 are stirred with 2.7 ml of an aqueous 0.0865 M sodium carbonate solution for 4 h at room temperature. After 16 h C is evaporated to dryness under reduced pressure at a maximum of 30 ^0th The residue is taken up again in 2 ml of methanol, after which the filtrate is evaporated to dryness after the brown, insoluble constituents have been separated off. The residue is taken up in 2.5 ml of ethanol. After the insoluble material has been filtered off with suction, washing is carried out first with ethanol and then with ether.

0.226 g of the desired product are obtained.

Elemental analysis: % ^ 1Q nm H ₁ q ( H SoNc: 587, 5 % N / A calculated: 38, C. ¹ S.
% , 26 % S. 7, 82 found: 39, 84 3. , 7 11.92 10, 91 7, 6th 8th Ethanol) 10.7 10, 1 UV spectrum (N / 10 HOl, •
* Turning point 224 E ₁ - 198

Maximum 262 nm & \ = 225 £ = 15,000

NMR spectrum (D ₂ O):

7 »03 ppm: proton of the thiazole ring

909840/0888

IR spectrum :

β- lactam 1763 cm "

Amid 1667 cm "" ¹

COO "1575 cm"" ¹

Example 11: 3-Acetoxymethyl-7- £ [2- (2-aminothiazol-4-yl) .2-CQ; 2-oxo-3-tetrahydrofuranyX] -o: xy] -imino] ■ acetyl] -aminoj -ceph ^ -era- *! - carboxylic acid (syn isomer)

Diethylamine salt of the S-yy I [2- (2-tritylaminothiazol-4-yl) -2- [[[2-OXO-3-tetrahydrofuranyl] -oxy] -imino] -acetyl} -amino] -

S of the 3-acetoxymetbyl-7- £ 2- (2-tritylaminothiazol-4-yl) -2-hydroxyimino-acetyl] -amino] -ceph-3-em-4-carboxylic acid obtained as an intermediate in stage B of Example 1 are dissolved in 20 ml of methylene chloride with stirring and under an inert atmosphere. After adding 20 ml of water and 2.8 ml of triethylamine and then 1 ml of oi-bromo-y-butyrolactone, the mixture is stirred at room temperature for 17 hours; then another 1 ml of al-bromo-ν-butyrolactone and after 3 ti 1.4 ml of triethylamine are added, whereupon the mixture is stirred for 5 h; then 1.5 ml of oL-bromo- γ- butyrolactone and 1.4 ml of triethylamine are added, whereupon stirring is continued for 16 hours.

It is then acidified with 20 ml of 2N hydrochloric acid and decanted off and washed with water until neutral.

909840/0886

The organic phase is then dried and evaporated to dryness under reduced pressure. The residue is taken up in 10 ml of ethyl acetate and the insoluble material is filtered off with suction and washed, and the filtrate is dried and evaporated to dryness; the residue is taken up in 10 ml of ethyl acetate, whereupon 0.2 ml of diethylamine are slowly added. The diethylamine salt of the starting product is filtered off with suction at room temperature and washed with ethyl acetate and then with ether. The mother liquors are turned to dryness _; evaporated, whereupon the residue is taken up again in 2 ml of ethyl acetate and treated with 20 ml of isopropyl ether. After removing it, 0.500 g of product are obtained.

UV spectrum (N / 10 HCl, ethanol):

Maximum 265 nm &} = 1? 9 £ = 15,000

NMR spectrum (CDCl ₃ ):

⁶ »76 ppm: proton of the thiazole ring

3-acetoxymethyl-7 - [[2- (2-aminothiazol-4-yl) -2-Q ^ C2-oxo-3-tetrahydrofuranyIT-oxy] -imino] -acetyl] -aminoj -ceph ^ -em - ^ - carboxylic acid-trif luor-

0.5 g of the diethylamine salt obtained above are in 5 ml of trifluoroacetic acid introduced, followed by 15 min at Room temperature is stirred. After that, under

909840 / 08SS

ORIGINAL INSPECTED

evaporated to about 2 ml under reduced pressure, whereupon 20 ml isopropyl ether are added all at once. After 15 min stirring at room temperature, the product is suction filtered and washed five times with 2 ml of isopropyl ether. After this Drying under reduced pressure gives the aimed product.

3-acetoxymethyl-7- [ [2- (2-aminothiazol-4-yl) -2-2-oxo-tetrahydrofuranyl] -oxy] -imino] -acetyl] -

The trifluoroacetate obtained as above is introduced into a mixture consisting of 2 ml of a 1: 1 solution of methanol and methylene chloride and 0.5 ml of a 1 M solution of pyridine in ethanol; subsequently made into a paste at room temperature I5 ^m i ^n. Then it is diluted in 2 min with 8 ml of ether with a content of 2 % ethanol. After stirring, viewing, washing with ethyl ether and drying under reduced pressure, the desired product is obtained.

Example 12; Sodium salt of 3-acetoxymethyl-7- £ 2- (2-

aminothiazol-4 ~ yl) -2- (tetrazol-5-yl) -methyI-oxyiminoj-acetylamino-ceph-3-em-4-carboxylic acid (syn-isomer)

Level Jl: 2- (2-Tritylaminothiazol-4-yl) -2- (tetrazol-5-yl) -

2.43 g 2- (2-tritylaminothiazol-4-yl) -2-cyanomethyloxy-

9 0 9 8 A 0/0 8 8 S ORIGINAL INSPECTED

2912823

imino-acetic acid, the preparation of which is explained below, are stirred in 12 ml of dimethylformamide. Then 1.5 g of sodium azide and 1.5 g of ammonium chloride are added. After 5 hours heating at 75 ⁰ C is allowed to cool to Eaumtemperatur, after which. 120 ml of distilled water, 40 ml of ethyl acetate and 30 ml of formic acid are added. The precipitate formed is filtered off with suction, washed with water, ethyl acetate and then with ether and dried.

1.275 g of the desired product are obtained. the end 0.127 g of product are obtained from the filtrate.

Elemental analysis: C ₀ ^ -Hp ₁ H ff ^ p % : 511 , 55 % G % 1 19th N % S calculated: 61.0 4, 6th 17th , 2 6.3 found: 61.1 4, DMSO): ,8th 5.8 UV spectrum (ethanol) (+

Inflection point 259 nm

Turning point 265 at £ = 11,000

Inflection point 27I nm

Inflection point 294 nm £ = 6,600

N / 10 HGl, ethanol:
Inflection point 270 nm
Maximum 275 nm ί = 13,700

909840/0886

-JlG-

- in -

KMR spectrum (DMBO):

7 »28 ppm: protons of the trityl group 6.86 ppm: proton of the thiazole ring

IR spectrum :

Aromatic vibrations 1608 cm

"* ¹

1491 cm " ¹

UH 1624 eof ¹

1580 cm "

GOO " ^ 57 ^cm

Level JBj. 3-Acetoxymethyl-7-j_2- (2-tritylaminothiazol-4-yl) -2- (tetrazol-5-yl) -methylo3qyiminoj-acetylamino-ceph-3-em-4-carboxylic acid t-butyl ester

To 1.024 g of that made in the previous step 2- (2-Tritylaminothiazol-4-yl) -2- (tetrazol-5-yl) -methyloxyimino-acetic acid 0.656 mg of 7-amino-3-acetoxymethylceph-3-em-4-carboxylic acid t-butyl ester and 2 ml of pyridine were added. After adding 0.5 g of dicyclohexylcarbodiimide in 5 ml of methylene chloride is stirred for 1 h at room temperature, whereupon the precipitate formed of dicyclohexylurea is sucked off. Then 25 ml of 1N hydrochloric acid are added to the filtrate, after which the mixture is stirred for 5 min. decanted off and washed with 25 ml of water; after drying the organic phase and distilling off the solvent the residue is taken up in isopropyl ether under reduced pressure. After the disintegration

9Q9B4Q / Ü8S6

,,. lMsen is suction filtered and washed with isopropyl ether; washed.

After drying, 1.778 g of crude product are obtained.

The crude product is dissolved in 4 ml of ethyl acetate with activated charcoal treated and filtered through silica. Thereafter, 20 ml of isopropyl ether are added to the filtrate in 5 minutes while drilling added, which is followed by stirring for a further 5 min; after suction filtration, it is washed with isopropyl ether. After this Drying gives 1.412 g of white product; 158 ° C,

Elemental analysis: * σ % H % N % 8th calculated: 58 , 5 4.8 15, 3. 7th ,8th found: 58 , 5 5.0 14, 7th 7th , 6 UV spectrum (N / 10: HCl, Ethanol):

Maximum 267-268 nm £ - 19,400

Inflection point 290 nm

m VB7 cn "" ¹ 1738 c »" ¹ AmUL ti ** β · " ¹

1C73 ca "' ¹

NHRHBpektruB (CDCl,). ·

7.2 ppm: protons of the trityl group ^ f75 ppm: proton of the thiazole ring

90 9 8 4 0/0888

BAD ORtGlNAL

1.5 ppm: t-butyl group
2.05 ppm: aoyl group

Stage e_Cj; 3-Acet 02 ^ ethyl-7-f2- ^ -amijiothiazol- ^ - yl) -2- (tetrazol-5-yl) -metiiyloxyimino / 1-acetylaminoceph-3-em-4-carboxylic acid trifluoroacetate -

1.226 g of 3-aceto3tymethyl-7- £ 2- (2-tritylaniinothiazol-4-yl) -2- (tetrazol-5-yl) -methyloxyiminoJ-acetylamiiio-cepli-3-em-4-carboxylic acid t-butyl ester and 12 ml of trifluoroacetic acid become stirred at room temperature for 30 min. Then the The acid is partially evaporated under reduced pressure, after which is precipitated with 120 ml of isopropyl ether. After sight, Wash with isopropyl ether and dry Obtained 1.061 g of product which still contains starting product as an impurity, which was only partially converted. After repeating the reaction twice with irifluoroacetic acid 0.879 g of the desired product are obtained. '

Stuf * _Dj_ NatriumsalE der 3-Acetoaymethyl-7- |] 2- (2-aeiiiothiazol-4-yl) -2- (t et r ft »ol-5-yl > -met ojlooqrieino J-

The trifluoroacetate obtained in the previous step is dissolved in 1.8 ml of methanol. Then be at tree temperature slowly with stirring 2.8 ml of a 1 K sodium acetate solution in methanol and then within

90984 0/0885

18 ml of ethanol were added for 5 min. After stirring for a further 15 min is cooled in an ice-water bath. After sight, Washing with alcohol and then with ethyl ether and drying gives 0.447 g of crystalline sodium salt.

Elemental analysis t C ₁ r ^, -, CUNgB ₂ : 525 »5

% G% E% N % S • calculated: 37.4-3.0 25.1 11.8 found: 37.8 3.2 21.1 11.1

EHR-8 spectrum

δ, 73 ppm: proton άβε thiazole ring 7.25 ppm: trityl group protons

The 2- (2-tritylaminothiazol-4-yl) -2 - {_ [Qcyanomethyl] used as starting material in Example 12 -oxy] -iminoj acetic acid (syn isomer) was prepared as follows:

1) 2- (2-Tritylaminothiazol-4-yl) -2 - [_ [[cyanomethyl] -oxy] iminoJ-acetic acid cyanomethyl ester (syn isomer)

12.9 g of 2- (hydroxyamine) - 2- (2-tritylaminothiazol-4-yl) acetic acid (syn isomer), 9.12 g potassium carbonate, 60 ml dry dimethylformamide and 7.6 ml chloroacetonitrile are mixed and stirred under an inert atmosphere. After solidification, it is kept in a sealed container for 65 hours Vessel left standing. Thereafter, in a mixture of 750 ml of water, 130 ml of 1N hydrochloric acid and 150 ml of ethyl acetate

909840/0

poured and stirred, whereupon the insoluble residue suctioned off and washed with ethyl acetate and with water; then it is decanted.

After washing with 100 ml of water, it is re-extracted three times with 100 ml of ethyl acetate each time, whereupon the organic phase is dried will; after viewing and washing as well as evaporation to dryness a residue is obtained which can be dissolved on silica using ether as the eluent is chromatographed. After the ether has been driven off, 8.69 g of the desired product are obtained in the form of an oil obtain.

Nuclear Magnetic Resonance Spectrum (ODCI ,; 60 MHz):

6.8 ppm: proton of the thiazole ring 71.37 ppm: protons of the trityl group.

2) 2- (2-Tritylaminothiazol-4-yl) -2-Qjcyanomethyl] -oxy] - iminoj-acetic acid (syn-isomer)

8.69 g of the product obtained under 1) are in 52 ml Dioxane was introduced and cooled in an ice bath, whereupon 17.1 ml of 1N NaOH were added dropwise over 20 min will. The mixture is then allowed to warm up spontaneously and 10.5 ml of 2N hydrochloric acid are added; then the dioxane becomes practical as well the entire amount of water evaporated.

After adding 20 ml of water and 30 ml of ether, the mixture is stirred for 15 minutes, after which the crystals are suction filtered, washed with water and with ether and dried; 4.32 g of the desired product are obtained; P. about 180 ⁰ C

909840/0886

-AtA--

(with decomposition).

ME spectrum (ODOL ,; 60MHz):
4.7 ppm: 00H ₂ ON
6.7 ppm: proton of the thiazole ring 7 * 34 · ppm: protons of the trityl group

Example 13 : 3-Acetoxymetbyl-7- [X2- (2-aminothiazol-4-yl) -. 2- (phenylcarbonyloxyimino) -acetylJ -amino] ceph-S-em - ^ - carboxylic acid (syn-isomer)

Stage_Aj, diethylamine salt der 3-acetoxymethyl-7-Γ [[2- (2-tritylara ± nothiazQl-4-yl) -2- (phenylcarbönyl oxyimino) -acetylj -amino] -ceph'-S-ero-i-earboic acid

To a solution of 0.683 g of 5-

ceph-3-em-4-.cart> onsäiire (ayn-Isoaer) in 10 al chloriä 0.2 »1 pyiidin tanä Ö" 2 ml BeÄaoylchlori4 are added " After stirring for 10 min at tree temperature, the Separating funnel washed with "water acidified to pH 1", dried, sucked off and dry aiagödaapft.

Ex will 0.737 S Äohpredidct erMltea-j ias is -5; ^v ml ".- ithyl- '" acetate is dissolved.- Dara ^ if will. 0.1 al liiat ^ lslsiü '. admitted; after 10 minutes, 0.27 g of the aspired diethylamine gel are obtained by using ateutse.

909840/0888

S tuf e_B ι 3-Acet oxyme ttxyl-7 - \ _ [2- (2-aminothiaz ol-4-yl) -2- (phenylcarbonyloxyimino) -acetylj -aminoj -ceph-3-em-4-carboxylic acid_ (syn- Isomer2

The above 0.27 g of the diethylamine salt are kept at 45 ° C 10 min with 2 ml of a 50% aqueous formic acid solution touched. Then it is evaporated to dryness and with Ether triturated, whereupon 0.155 g of crude product are separated off, which is dissolved in 0.5 ml of methanol and precipitated with 5 ml of ether.

0.14 g of the desired product are obtained.

Element ar analysis ■ %: CppILjo O ₆ N ₁ -S ₂ 13th D Z> C- calculated: 13th , 64 found: 4th

Example 14 : 3-Aceto2ymethjl-7- [2- (2-aminothiazol-4-j'l) -2- (2-aminoethoxyimino) -acetamidoJ -ceph-3-em-4-carboxylic acid-bis-trifluoroacetate (syn- Iso mer) ■

§ £ B £ fLAjL 2- (2-Srit7laminoäthosyitriino) -2- (2-tritylamlno-

Under an inert atmosphere, 12.2 g of 2- (2-iodethoxyimino) -2- (2-tritylaminothiazol ~ 4-yl) -acetic acid ethyl ester (syn isomer) in 80 ml of anhydrous dimethylformamide and 12.4 g

SS 4 "0/0888

COPY

2912823

Triethylamine introduced. Thereafter, whereupon 6.2 g of 5 tritylamine is heated to 100 ⁰ C h, are added; then 7 η is kept at 100 ^° C. After cooling to room temperature, it is poured into 1.6 l of distilled water, extracted six times with 250 ml of benzene and washed with water and then with a saturated sodium hydrogen carbonate solution and then with a saturated sodium chloride solution. After drying, 23.5 g of a resin are obtained which is ^{chromatographed on silica using a benzene-ether mixture (95:} 5). The main fraction is then chromatographed on silica using pure methylene chloride as the eluent.

3.6 g of leg product are obtained.

NMR spectrum (CDCl,):

6.46 ppm: proton of the thiazole ring ..

Triplet centered at 2.45 ppm: CH ^ -NH J - 5 Hz

Stuf e_B ι 2- (2-Tritylaminoäthoxyimino) -2- (2-t rityl amino-

Isomer) _

2 g of the ethyl ester prepared in stage A are introduced into 10 ml of dioxane and 66 ml of absolute ethanol under nitrogen. Then 3 ml of 1 l NaOH are added. After 65 h, the precipitate formed is filtered with suction and washed three times 3 »5 nil with a $ e ithanol dioxane mixture (1: 6.6) and dried. A first amount of 1.445 g

S098A0 / 0885

Obtain sodium salt.

The mother liquors are saponified again under the same conditions and yield 0. VK) g of sodium salt. The 1,445 6 The first amount of the sodium salt is dissolved in 30 ml of water and 30 ml of chloroform are introduced, whereupon 1N hydrochloric acid is added to pH 2 with vigorous stirring (about 1.9 ml).

After decanting off the organic phase, it is washed four times with 10 ml of water each time until neutral. Each fraction of the wash water is re-extracted with 3 ml of chloroform. The combined chloroform phases are then dried and evaporated to dryness. The white powder obtained is made into a paste with 2 × 2 ml of dichloroethane and then with 2 × 2 ml of isopropyl ether. It is then dried under reduced pressure to constant weight, 1.202 g of product being obtained. F. 176 ⁰ C (with decomposition).

The second portion of 0.440 g is treated in the same way and provides a further 0.325 g of the desired product. F. 176 ⁰ C (with decomposition). A total of 1.527 g of product, mp 176 ⁰ C

NMR spectrum (CDCl,):

6.65 ppm: 5-proton of the thiazole ring 2.95 ppm: CH ₂ -N.

909840/0888

3-acetoxymethyl-7 - (_ L2- (2-tritylaminoethoxyimino) 2- (2-tritylaminothiazol-4-yl) -acetyl] -amino] ceph-3-em-4-carboxylic acid ~ diphenylmethyl ester

0.286 g of the acid prepared in stage B are under Nitrogen introduced into 2 ml of methylene chloride. Of the 0.4 ml of a suspension are added dropwise with stirring immediately beforehand by mixing 1.4 ml of triethylamine and one to make a final volume of 10 ml of solution sufficient amount of methylene chloride prepared solution added.

The solution is then cooled in an acetone-dry ice bath to -20 ⁰ C and 5 min for equilibration allowed to stand, whereupon 0.4 ml of a sufficient immediately above by mixing 1.25 ml of pivaloyl chloride with a 10 ml to obtain solution amount Methylene chloride solution is added dropwise with stirring.

The bath is then ^{heated to -10 0} C; it is left at this temperature for 30 minutes.

The solution is then within 10 min at 10 ⁰ C is heated, after which 0.176 g of 7-aminocephalosporanic acid, diphenylmethyl ester aufjeinmal be added; then allowed to warm to room temperature. After 1 h 20 min, a further 17> 6 mg of the same ester are added. After stirring for 30 min at room temperature, the mixture is left to stand in the refrigerator for 15 h and then allowed to warm to room temperature again; then it is evaporated to dryness under reduced pressure and eluting with a

9098 U 0/08 88

Benzene-ethyl acetate mixture (8: 2) chromatographed on silica.

0.208 g of the desired product are obtained.

NMR spectrum (GDGl ^);

1.99 ppm: OG-CH,
6th

4 »38 ppm: NO-CH ₂

6 »7 ^ ppm: 5-proton of the thiazole ring 6.88 ppm:

Step D: 3-Aceto ^ methyl-7-r2- (2-aminothiazol-4-yl) -2- (2-aminoethoxyimino) -acetamidoJ-ceph-3-em-4-carbon-

186 mg of the 3-acetoxymethyl-7- Γ 2- (2-tritylaminothiazol-4-yl) -2- (2-tritylaminoethoxyimino) acetamido] -ceph ^ -em - ^ - carboxylic acid diphenylmethyl ester prepared in stage C are in 1 , 8 ml of pure trifluoroacetic acid introduced. The yellow solution obtained is stirred for 3 min at tree temperature and then under an inert atmosphere in an ice-water bath, after which 18 ml of isopropyl ether are quickly added. After stirring for 10 min, suction filtration, washing with isopropyl ether and then with ethyl ether and drying, 100 mg of a white powder are obtained; i ¹ . about 21Ö ⁰ G (with decomposition).

909840/0888

NMR spectrum (DMSO):
2.03 ppm: 0-0-CH,

3.1? ppm: NO-CH ₂

6 »85 ppm: 5-proton of the thiazole ring.

The 2- (2- - Iodethoxyimino) -2- (2-tritylaminothiazol-4-yl) -acetic acid ethyl ester (syn isomer) was made as follows:

a) 2- (2-Bromoethoxyimino) -2- (2-tritylaminothiazol-4-yl) -acetic acid ethyl ester (syn isomer).

4.94 g of 2-hydro: ^ imino-2- (2-tritylaminothiazol-4-yl) -acetic acid ethyl ester hydrochloride (syn isomer) are introduced into 10 ml of dimethylformamide under an inert atmosphere, whereupon 4 · 14 g of potassium carbonate in 3 min at room temperature can be added.

After stirring for 20 min at 20 ⁰ C. 8.65 ml of 1,2-dibromoethane are added. The mixture is then stirred for 30 h, after which it is poured into a mixture consisting of 100 ml of distilled water and 20 ml of methylene chloride; it is then decanted, re-extracted with methylene chloride, washed with distilled water and re-extracted again; After the organic solutions have been dried, filtered off with suction and washed, the mixture is evaporated to dryness.

A crude product is obtained which is chromatographed on silica using benzene containing 5% ether as the eluent. A first fraction is obtained, which after dissolving at 50 to 60 ⁰ C and

909840/0888

Is recrystallized with suction at 0 to +5 ⁰ C in methanol.

1.16 g of a creamy white product are obtained; F. 117 ⁰ C

Thereafter, a homogeneous fraction is obtained in an amount of 1.258 g.

MMR spectrum (CDCl,):

Triplet at 3.55 ppm: J = 7 Hz: CH ₂ Br

Triplet at 4.51 ppm: J = 6 Hz: FO-CH ₂ singlet at 6.55 ppm: proton of the thiazole ring.

b) 2- (2-iodoethoxyimino) -2- (2 ~ tritylaniinothiaz.ol ~ 4-yl) ethyl acetate (syn isomer).

6 g of the 2- (2-bromoethoxyimino) -2- (2-tritylaminothiazol-4-yl) ~ acetic acid ethyl ester (syn isomer) prepared under a) are introduced into 60 ml of methyl ethyl ketone together with 2.141 g of sodium iodide, after which 1 h Is refluxed for 10 min. It is then evaporated under reduced pressure. The residue is taken up again in 120 ml of methylene chloride and washed five times with 40 ml of water each time. The wash water is re-extracted with 2 ml of methylene chloride, whereupon the organic phases are dried and evaporated to dryness. Ether is added to the resin obtained and drying is carried out under reduced pressure. 6.22 g of product are obtained; F. 110 ⁰ C.

909840/0886

NMR spectrum (CDCl,):

! Triplet with center at 3.31 ppm: CH ₂ JJ = 7 Hz 6 »53 ppm: 5-proton of the thiazole ring.

Example 15 : 3-Acetoxymethyl-7- [2- (2-aminothiazol-4-yl) -2- (2-aminoethoxyimino) -acetamidoJ-ceph-3-em- 4-carboxylic acid (syn isomer) _:

220 mg of the bis-trifluoroacetate prepared in Example 14 are placed in a test tube and 1.6 ml of a 1 M solution of I sodium acetate in methanol are added will. The mixture is stirred until it is completely dissolved and the glass wall is then rinsed with 0.66 ml of methanol. Afterward 18.6 ml of absolute ethanol are added. Thereby precipitation occurs, whereupon the same thing, in the same way Way from 100 mg of bis-trifluoroacetate obtained mixture is added. After 1 hour 50 minutes, suction is applied, whereupon the insoluble material is washed with ethanol and then with ether and dried under reduced pressure to constant weight.

181 mg of a white powder are obtained; F. 270 ⁰ C (with decomposition).

R _f = 0.12 (ethyl acetate-ethanol-water 60:25:15). The product is cleaned as follows:

120 mg of the above product are distilled in 1 ml Brought in water. After stirring for 5 min, pyridine slowly becomes up to pH 7 »0 to 7» 2 added. Tray will stir for 15 min

9840/0888

-490-

sucked off and washed with 0.5 ml of water. The filtrate 40 ml of acetone are then added, whereupon the mixture is stirred for 5 min and left to stand for 20 min, then suction filtered, washed three times with acetone and dried.

99 »5 mg of a white powder are obtained.

UV spectrum ;

Maximum 261 nm κ \ = 348

Example 16; 3-acetoxymethyl-7 - [[2- (2-aminothiazol-4-yl). 2- (2-amino-2-t hioxoethoxyimino) -ac etyl] aminoj-ceph-3-em-4-carboxylic acid (syn isomer)

0.502 g of the sodium salt of 3-acetoxymethyl-7- | _ [2- (2-aminothiazol-4-yl) -2- (cyanome thoxyimino) -acetylJ -aminoj ceph-3-em-4-carboxylic acid (syn isomer) are introduced into 2 ml of dimethylformamide and 0.14 ml of triethylamine. subject complete dissolution becomes more gaseous for 15 min Introduced hydrogen sulfide and then left to stand for 30 min at room temperature with stirring. Thereafter 20 ml of isopropyl ether are added and the mixture is stirred; after separation of the isopropyl ether phase, the am In the bottom of the vessel, 7 ml of ethanol were added to the remaining oil, whereupon is stirred; an insoluble product is obtained which is filtered off with suction, washed with ethanol and dried will.

0.388 g of crude product are obtained, which is purified as follows.

909840/0886

O »309 g of the crude product are dissolved in 1.5 ml of water, whereupon 30 mg of activated charcoal are added; then it is stirred and sucked off and washed with water; thereafter 5 drops of pure formic acid are added to the JFiltrate, The precipitated product is washed with water and dried.

0.195% of purified product is obtained. CHR spectrum (EMSO):

J ^NiI 2
, As
S ^V N
(d) (e) (c> ^CH 2, (f) W (b) 02 ppm ) <? - N
NII ₂ I ^ ⁿ 2 ^C
CO ₂ H (a) Singlet 2, 55 ppm 0>) Singlet 3, 75 ppm (c) Singlet 4-, 83 ppm (d) Singlet 6, 25 ppm (e) Singlet 7,

O (a)

(f) Doublet centered at 9.73 ppm J »8 Hz

UV spectrum (N / 10 HCl, ethanol): maximum 265 nm E ^ = 468 I = 24,100

90984Q / 088S

The sodium salt of 3-acetoxymethyl-7- £ used in Example 16 Q2- (2-aminothiazol-4-yl) -2- (cyanomethoxyimino) -acetyl] -amino] -ceph-J-em - ^ - carboxylic acid (syn-isomer) vrarde produced as follows:

A) 3-Acetoxymethyl7fC ² ^ ^tt y ^lanothiaf 3 ^{: L} ^ ² CC (cyanomethyl) -oxyJ -imino] -acetyl] -aminoj -ceph-5-em - ^ -

^ » ⁸ 75 B of the 2 - {_ [CCyanoaiethyl] oxy] iminoj -2- (2-tritylaminothiazol-4-yl) acetic acid (syn isomer) obtained as in Example 12 and 1.312 g of 7-aminocephalosporanic acid t-butyl ester are mixed under an inert atmosphere in 12 ml of dry methylene chloride.

A solution of 950 mg of dicyclohexylcarbodiimide is then added with stirring added in 12 ml of dry methylene chloride. It is then stirred and at room temperature for 1 hour Left to stand for 45 min; then the formed dicyclohexylurea sucked off and in an amount of 457 mg isolated.

The filtrate is evaporated to dryness, leaving a residue obtained on silica using methylene chloride and then from Ither as Eluent is chromatographed.

The product-rich fractions are collected; after the ether has been expelled, it is taken up again into ether. After crystallization has started, the product slowly crystallizes in the refrigerator. After the removal is seen

909840/0886 COPY

washed at ⁰ ° C. by pasting with ether and then dried.

Ea, 776 mg of the desired product are isolated. P. 180 ⁰ C (with decomposition).

KMR spectrum (CDCl,; 60 MHz): 4.9 ppm: 0-CH ₂ -CN 6.8 ppm: proton of the thiazole ring 7-31 ppm: protons of the trityl group

B) 3-acetoxymethyl-7 - [[2- (2-aminothiazol-4-yl) -2-

C [(cyanomethyl) -o:>: y3 -imino] -acetyl] -amino] -ceph-3-em

779 mg of the product obtained under A) are in 4 ml Trifluoroacetic acid introduced. After that, until the dissolution stirred and 17 A left to stand, whereupon 40 ml Isopropyl ether is poured. After stirring, look away and drying, 525 nag of the desired product are isolated.

C) Sodium salt of 3-acetoxymethyl-7 - [[2- (2-aininothiazole · 4-jl) -2 - [[[(cyEaoBiethyl) -ox5rJ -ieinoj -acetyl] -amino} -

The 523 mg of the trifluoroacetate obtained under B) are dissolved in 2 BtI of a 1 N solution of NaOH in methanol. Then it is diluted with 6.6 El ethanol and stirred for 10 A,

8098A0 / 088S

whereupon the insoluble material sucked off with ethanol washed and dried.

226 mg of the desired sodium salt are obtained. F. about 200 ⁰ C (with decomposition).

NMR spectra (QJXiIy 60 spleen); 4.98 ppm: O _{-CH 2 -CN}

6.86 ppm: proton of the thiazole ring

Element ar analysis ; C ^ ^ H ^ COr ₇ NgS ₂ Na

% C % H% Na: y

calculated: 40.64 3.01 4.57 found: 40.2 3.3 4.5

Example 17 : 3-Acetoxymethyl-7 - [[2- (2-aininothiazol-4-yl) -2- (2-amino-2-thiioxoethoxyimino) -acetyl3 aminoJ -οβρίι-3-βΐη-4-οαχ ^ οη3αιΐΓΘ (syn isomer)

Level_A: 2- (2-Tritylaminothiazol-4-yl) -2- (2-amino-2-

2.814 g of the 2- ^ 2, -tritylaminothiazol-4-yl) -2- ^ cyanomethoxyioiino) -esßi ^ ß ^ ure obtained in Example 12 are in 12 ml of a solution of 1.6 ml of triethylamine and 20 ml of dimethyl xormamide

Stnacb becomes more gacX-shaped at Säum tcp eratu r 30 nin laAfr

909840 / 088S

Hydrogen sulfide initiated. The vessel is then closed and left to stand with stirring for 2 hours 10 minutes. It is then poured into 100 ml of water and 14.4 ml of 1N hydrochloric acid. It is then vigorously stirred, after which the insoluble material is suction filtered and washed with water; then methylene chloride is added, with crystallization is observed; then it is sucked off again, washed and dried.

2.47 g of the desired acid are obtained; P. about 180 ⁰ C.

NMR-S spectrum (DMSO):

6.96 ppm: protons of the trityl group 7 »33 ppm: 5-proton of the thiazole ring

Level_B: J-acetoxymethyl -? - ^ [2- (2-tritylaminothiazol-4-yl) -2- ( 2-amino-2-thioxoethoxyimino) -acetylj -

1.01 g of the acid obtained in step A and 0.656 mg of 7-aminocephalosporanic acid are placed in 2 ml of pyridine .

After dissolution, 0.5 g of dicyclohexylcarbodiimide is added in 5 ml Methylene chloride was added and the mixture was stirred at room temperature for 1 h. After the precipitation is sucked off and with Washed methylene chloride. It is then dried, after which about 0.5 g of dicyclohexylurea is isolated.

The filtrate is poured into 25 ml of 1N hydrochloric acid. To Stir for 5 min and decant with 25 ml of water

909840/0886 COPY

washed. After drying, suction filtering and driving off the solvent, it is taken up again in isopropyl ether. After it has been allowed to disintegrate, it is again suction filtered and washed.

In this way, the desired product is obtained in an impure form. The product is then dissolved in 4 ml of ethyl acetate dissolved, after which 0.18 g of activated carbon are added; then it is suction filtered and washed with ethyl acetate.

The filtrate is stirred with 20 ml within 5 minutes Isopropyl ether added. Then another 5 units are stirred, whereupon it is suction filtered and washed with isopropyl ether. After drying, the purified product is obtained.

Stage_C: 3-acetoxymethyl-7-j ^ [2- (2-aminothiazol-4-yl) -2- (2-amino-2-thioxoethoxyimino) acetyl] -aminoj -

The product obtained in stage B is introduced into 12 ml of trifluoroacetic acid. After stirring for 30 min at room temperature the acid is partially evaporated off under reduced pressure, whereupon it is precipitated with 120 ml of isopropyl ether will. After it has been allowed to disintegrate, it is suction filtered and washed with isopropyl ether.

The product obtained after drying is identical to that of Example 16.

909840 / 088B

2912823

Example 18 : 3-Acetoxymethyl-7 - [[2- (2-aminothiazol-4-yl) -2- £ C (2-oxopropyl) -oxy] -imino] -acetyl] -aminoj eeph-J-em ^ - carboxylic acid trifluoroacetate (syn isomer) _: ~ -

Stage_A: 3-Acetoxymethyl-7 - [[2- (2-tritylaminothiazol-4-y -) - 2-LC (2-oxopropyl) -oxyj-imino] -acetyl] -

7.6 g of the diethylamine salt of 3-acetoxymethyl-7 - [[2- (2-tritylaininothiazol-4-yl) -2- (hydroxyimino) -acetyl] -amino] -ceph-J-em prepared in Example 1 - ^ - carDonic acid (syn-isomer) are introduced into 114 ml of methylene chloride and 114 ml of distilled water. Thereafter, 14 ml of triethylamine are added at 20 ° C. with buzzing. After 5 min stirring, a temperature of oil to 25 ⁰ C are added 8.45 bromoacetone, while maintaining, is followed by stirring for 5 hours at 25 ⁰ C} then is acidified by addition of 6 ml of hydrochloric acid at 15 ⁰ O at pH 1 to the second After decanting, it is re-extracted twice with 50 ml of methylene chloride each time. It is then washed with water, whereupon the wash water is re-extracted; it is then dried and evaporated to dryness, whereupon 8.48 g of a resin are obtained. After the extract has been dissolved in 8.5 ml of methylene chloride, it is precipitated by adding 85 ml of ethyl ether. The mixture is then stirred for 2 hours at room temperature, suction filtered, washed three times with 10 ml of ether each time and dried, whereupon 6.27 g of the desired product are obtained.

909840/0886

-49t-

Purification via the diethylamine salt;

The above reaction product is taken up in 62 ml of ethyl acetate and made into a paste at room temperature for 5 minutes. The insoluble fraction is then filtered off with suction and washed with ethyl acetate

The filtrate is then concentrated to 50 ml and all at once 0.6 ml of diethylamine are added. After stirring, the resulting gummy substance is added three times with 5 ml each Washed ethyl acetate. The filtrate is diluted with 130 ml of isopropyl ether. Then the precipitate is stirred for 15 minutes, sucked off and washed with isopropyl ether. To 3.27 6 of the aimed salt are obtained on drying.

3.25 g of the salt are dissolved in 25 ml of distilled water and 98 ml of ethyl acetate dissolved. Then 50 ml of a saturated sodium chloride solution are added. Sine The gummy substance that separates out is obtained with the aqueous phase. After acidification to pH 1 to 2 in the presence of 50 ml of methylene chloride by adding 2.5 ml of concentrated hydrochloric acid is twice with 50 ml Re-extracted methylene chloride. It is washed with water, dried, dried, washed and the filtrate is distilled.

In this way 1.79 g of product are obtained. The resin is dissolved in 4 ml of methylene chloride and diluted with 40 ml of ether. After removing it, it is washed again with ether.

After drying, 1.22 g of the desired product are obtained obtain.

909840/0888

MMR spectrum (CDCl,):

2.03 ppm: OO-CH *
6th

2.13 ppm: CH ₂ -C-CH,

0.

6.8 ppm: 5-proton of the thiazole ring

Step_B: 3-acetoxymethyl-7- [[2- (2-aminothiazol-4-yl) -2-EC (2-oxopropyl) -oxy3 -imino] -acetyl] -amino] -ceph-

1.22 g of the product obtained in step A are introduced into 12 ml of trifluoroacetic acid, whereupon 15 min at 20 to
22 ⁰ C is stirred. It is then concentrated in vacuo to 6 ml and diluted with 60 ml of isopropyl ether. Of the
The precipitate is then stirred at room temperature for 15 minutes, then suction filtered and washed five times with 5 ml of isopropyl ether each time. Subsequently, under reduced
Pressure dried, after which 0.97 g of crude product are obtained.

The cleaning is done as follows:

The product is first dissolved in 4 ml of acetone with a content of 1 % water. Then after adding 0.2 g
Activated charcoal was stirred at 20 to 22 ^° C. for 5 min. Afterward
is filtered and washed five times with 1 ml of acetone with 1 % water. Then 90 ml of ethyl ether are added at 20 to 22 ^{° C.} The mixture is stirred for another hour at 20 to 22 ⁰ C, then suction filtered, washed with Ithyläther and dried.

909840/0888

291282S

In this way, it becomes 0.57 g of the desired product obtain.

Example 19 : Sodium salt of 3-acetoxymethyl-7 - [[2- (2-aminothiazol-4-yl) -2- £ [X 2-oxopropyl) -oxy] -imino] -acetyl] -amino! -ceph ^ -em - ^ - carboxylic acid (syn isomer)

0.57 S of the trifluoroacetate obtained in Example 18 is dissolved in a mixture of 0.25 ml of distilled water, 2.3 ml of methanol and 2.3 ml of a 1N solution of sodium acetate in methanol. The slightly insoluble fraction is filtered off with suction and washed with 2.3 ml of methanol. It is then concentrated to about 3 ^ l, whereupon a colored solution is obtained which is diluted with 20 ml of ethanol. The mixture is then stirred at 20 to 22 ⁰ C, filtered off under suction and washed three times with 3 ml of ethanol 10th After drying, the sodium salt is obtained in an amount of 0.38 g.

By evaporation of the mother liquors and removing a second amount of 0.12 g of product is obtained, which is at 20 ° 0

Is made into a paste in 0.6 ml of methanol for 5 min. Then with

6 ml of ethanol diluted and washed. In this way 0.07 g of product is finally obtained.

The product is cleaned as follows:

The two portions, ie 0.45 g, are at room temperature dissolved in 2 ml of distilled water. Then 12 ml of acetone are slowly added with stirring at 20 °. the

909840/0886

Excreted rubber-like substances are filtered off with suction, whereupon the I-filtrate is evaporated to dryness. The treatment is repeated with 1.5 ml of distilled water and 10 ml of acetone. Then in 5 n & pure "ethanol is. Resumed and filtered off with suction at 20 ⁰ O and washed three times with 1 ml of ethanol. After drying under reduced pressure to 0.26 g of the expected product are obtained.

MMR spectrum (DMSO):

2 ppm: OC-CEU
0

2.13 ppm: CS ₂ -C

6.78 ppm: 5-proton of the thiazole ring

Example 20 : 3-Methyl-7- £ | J2-C2-aminothiazol-4-yl) -2- (2-aminoethoxyimino) -acetyl] -amino] -ceph-3-em-4-carboxylic acid-bis-trifluoroacetate (syn-iso mer)

Step e_A: 3-methyl-7- [[2- (2-tritylaminothiazol-4-yl) ~ 2- (2-tritylaminoät hoxyimino) -ac etyl] -amino] -c eph-3-em-4-carboxylic acid diphenylmethyl ester

0.923 g of the 2- (2-tritylaminothiazol-4-yl) -2- (2-tritylaminoethoxyimino) acetic acid prepared by the procedure of step B in Example 14 (syn isomer) are dissolved in 6.5 nil methylene chloride and 1.3 ml of a triethylamine solution

90 9 84 0/0886

291282S

solved. The triethylamine solution is through. Mixing 1.4 ml of triethylamine and a sufficient amount of methylene chloride to achieve 10 ml of solution.

After dissolution is cooled to -20 ⁰ C, after which 1.3 ml of a Pivaloylchloridlösung be added, which had been prepared by mixing 1.25 ml of pivaloyl chloride and a 10 ml solution of zur'Erzielung sufficient amount of methylene chloride.

It is then allowed to ^{warm to -10 0} O, after which this temperature is maintained for 35 min. After warming Leave to +10 ⁰ C 0.494 g · 7-Aminodesacetoxycephalosporahsäurebenzylester be added. After warming to room temperature, the mixture is stirred for 1 hour 20 minutes. A further 77 mg of 7-aminodesacetoxycephalosporanic acid diphenylmethyl ester are then added. The mixture is then stirred for 1 h, evaporated to dryness under reduced pressure and chromatographed on silica using a benzene-ethyl acetate mixture (8: 2).

504 mg of the desired product are obtained.

NMR-S spectrum (CDG1,);
2.1 ppm: 3-methyl

6 »93 ppm: proton of the diphenylmethyl group CHT

909840/088 6

- 3 03 -

291282 ¹

Stage_B: 3-methyl-7- [[2- (2-aminoethoxyimino) -2- (2-aminothiazol-4-yl) -acetyl] -aminoj -

357 mg of the product obtained in step A are introduced into 3 ml of trifluoroacetic acid. The resulting solution is then 2.5 h. stirred and then placed in an ice-water bath, followed by rapidly stirring 40 ml under a 50: 50 mixture of Isopropylather and petroleum ether (fraction 64-75 ⁰ C) is added. After stirring for 10 minutes, the product is filtered off with suction, washed with isopropyl ether and then with ethyl ether and dried to constant weight. 200 mg of white powder are obtained. F. about 250 ° 0 (with decomposition).

lüMR spectrum (DMSO):
2.03 ppm: 3-methyl
6.88 ppm: 5-proton of the thiazole ring

Example 21 ; 3-Acetoxymethyl-7- {~ [J2- (2-aminothiazol-4-yl) -2 - [(2-bromoethoxy) -iminq] -acetyl] -aminoj ceph-3-em-4-carboxylic acid trifluoroacetate (syn -Isomer)

Step e_A: 3-Aceto3ςymethyl-7 - [_ [ß ~ (. 2-tritylaminotbiazol-4-yl) -2 - [(2-bromoethoxy) -imino] -acetyl] -aminoj 2§efez§m-4 ^ carboxylic acid -t-butyl ester_ £ syn isomer)

1.185 g 2- (2-bromoethoxyimino) -2- (2-tritylaminothiazol-4-yl) -

909840 / 088S

acetic acid (syn isomer) and 0.725 g of 7-aminocephalosporanic acid t-butyl ester are introduced into 20 ml of methylene chloride. After cooling, a 0.5 M solution of dicyclohexylcarbodiimide are added in 4.75 ml of methylene chloride was slowly un ter inert gas atmosphere, whereupon stirred at 0 to +5 ⁰ C 1.5, which dicyclohexylurea euskristallisiert. It is stirred for 1 h at 20 to 25 ⁰ C, nutseht off at 20 ⁰ C and washed with methylene chloride and 0.293 g of product. The filtrate is evaporated to dryness under reduced pressure, whereupon 2.09 g of product are obtained, which is purified by chromatography on silica using a benzene-ethyl ether mixture O: "I) as the eluent.

1.129 g of the desired product are obtained.

Stage e_B: 3-acetoxymethyl-7- [[2- (2-aminothiazol-4-yl) -2-

l2 (2-bromoethoxy) -imino] -acetyl] -aminoj -ceph-3-em-

" ¹ J 301 g of the product obtained by the process of step A are introduced into 13 ml of trifluoroacetic acid. The mixture is then stirred at room temperature for 10 minutes. After stirring for 1 minute under an inert gas atmosphere, complete dissolution is observed. The trifluoroacetic acid is then placed in a water bath under reduced pressure distilled off at a temperature below 35 ^° C. until a remaining volume of about 5 ml is achieved, cooling the compartment in an ice bath while stirring, adding 42 ml of isopropyl ether all at once, resulting in a yellow precipitate which is stirred at room temperature for 30 min

909840 / 088S

is suction filtered and three times with 2.6 ml of isopropyl ether each time washed. The product obtained is under reduced Print "dried at room temperature.

0.893 g of the desired product are obtained.

The 2- (2- -Bromät hO2iyimino) -2- (2-t r i t yl amino thi az ο 1-4-y 1) ~ e s si gic acid e (syn isomer) was made as follows:

a) 2- (2-Bromoethoxyimino) -2- (^ -tritylaminothiazol-il-yl) ethyl acetate (syn isomer).

4-, 94 g of 2-Hydro3qyimino-2- (2-tritylamino-4-thiazolyl) -acetic acid ethyl ester hydrochloride (syn isomer) are introduced under argon into 10 ml of dimethylformamide, whereupon 4, 14 g of potassium carbonate in 5 min to be added. After stirring for 20 minutes at 20 ° C., 8.65 ml of 1.2- dibromoethane are added. The mixture is then stirred for 30 h and poured into a mixture of 100 ml of distilled water and 20 ml of methylene chloride; it is then decanted off, re-extracted with methylene chloride, washed with distilled water and re-extracted again; After the organic solutions have dried, they are filtered off with suction, washed and evaporated to dryness. The crude product obtained is chromatographed on silica using benzene containing 5% ether as the eluent. There is obtained a first fraction which is recrystallized by dissolution at 50 to 60 ⁰ C and filtration with suction at 0 to + 5 ° 0 in methanol.

In this way 1.16 g of a creamy white product are obtained; P. 117 ⁰ C.

909840/0886

- «DG-

Thereafter, a homogeneous fraction is obtained in an amount of 1.258 g.

b) 2- (2-Bromoethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetic acid (syn isomer).

2.88 g of the 2- (2-bromoethoxyimino) -2- (2-tritylaminothiazol-4-yl) -acetic acid ethyl ester (syn isomer) obtained as above under a) are introduced into 4.3 ml of dioxane under argon. The mixture is stirred under an inert atmosphere at room temperature until it is dissolved. Subsequently, the solution in 3 min 30.6 mL of a 0.5 M solution of potassium hydroxide in ethanol at 20 to 25 ⁰ C was added, followed 24 h under an inert atmosphere is stirred at tree temperature. The potassium salt crystallizes after a reaction time of 2 to 3 hours. The salt formed is then removed at room temperature and washed with 1 ml of ether and then three times with 2 ml of methylene chloride each time. 1.6 g of the desired salt are obtained. The salt is taken up in a mixture of 10 ml of distilled water, 10 ml of methylene chloride and 1 ml of 2 IT hydrochloric acid. It is shaken for a few minutes in a separating funnel and then 10 ml of distilled water, 10 ml of methylene chloride and 1 ml of 2N hydrochloric acid are added. The methylene chloride phase is then washed three times with 20 ml of distilled water each time until neutral. The wash waters are then re-extracted with 10 ml of methylene chloride. It is then dried, suction filtered, washed and evaporated to dryness.

1.465 6 resin are obtained.
The cleaning is done as follows:

909840/0886

The dry product is taken up in 15 ml of 1,2-dichloroethane. Then it is dissolved by heating to about 40 ^° C. After cooling to 20 ⁰ C, the crystallization is initiated, wherein 3 is stirred at 20 ⁰ C. It is then filtered off with suction, washed with 0.5 ml of 1,2-dichloroethane and dried, whereupon 1.185 S white product is obtained. F. I50 ⁰ C, R ^ »0.65 (acetone with 5% water).

Elemental analysis:

% C OjL tr
/ O SX % N % S. ° / o Br calculated: 58.21 4.13 7th , 82 5 , 98 14.89 found: 58.0 4 2 7th "8th 5 , 9 15.2 NHR spectrum (( 3DCl,):

Triplet at 3.44 ppm: -CH ₂ -Br J >> 7.5 Hz triplet at 4.3 ppm: -HO-CH ₂ - J = 7 Hz

Singlet at 6.55 ppm: 5-P ^ oton of the thiazole ring

Example 22 : Sodium salt of 3-acetoxymethyl-7-j ~ [2- (2-aminothiazol-4-yl) -2- ^ 2-bromoethoxy) -iminol acetyl] -amino] -ceph-3-em-4-carboxylic acid (syn isomer)

893 S of ^the trifluoroacetate obtained in Example 21 are introduced into 3 »5 ml of a 1 M solution of sodium acetate in methanol.

At room temperature under an inert atmosphere until dissolution touched. It is then filtered off and initially with

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1 ml and then twice with 0.5 ml of pure, anhydrous Methanol washed. Then 40 ml of absolute ethanol are added, whereupon initially a cloudiness and subsequent precipitation of the sodium salt is observed. After stirring for 2 h at room temperature, the formed is Salt sucked off and three times with 1 ml of absolute. Ethanol and then three times with 3 μl of ethyl ether each time washed. It is then dried at room temperature under reduced pressure.

0.545 g of product are obtained. R ^ = 0.6 (acetone with 10 % water).

+ 1.5 ° (c = 1 % in H ₂ O)

Elemental analysis ι

calculated: 35.80 3.00 12.28 11.24 14.01 found: ₇ 36.0 3.1 11.9 11.2 '13.7

Nuclear Magnetic Resonance Spectrum ((CD ₃ ) ₂ SO):

2.0 ppm: -O-C-CH * Ö

Triplet at 3.62 ppm: -CH ₂ -Br J = 6 Hz

Triplet at 4.33 ppm: = N-0-0H ₂ J = 6 Hz

6 »75 ppm: 5-J ³ JFOtOn <3, es thiazole ring

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Example 2 3: 3-Acetoxymetbyl-7-r £ 2-f £ 2- (2-aminophenylthio) -ethoxy-imino.] -2- (2-aminothiazol-4-yl) -acetyl] -amino] -ceph -3 ~ em-4-cart) onic acid (syn-isomer) __ '. ·

Stage_A: 3-Acet03qFmethyl-7 - [[2- [Q2- (2-aminophenylthio) -ät hoxyj -imino] -2- (2-tritylamlnothiazol-4-yl) acetyl] -amino] -ceph ^ -em - ^ - carboxylic acid

790 mg of 3-AcetO3q7methyl-7-r [2- [[2-t »rom-ethoxyJ-ißiino-2> - (2-tri-tylaminothiazol-4-yl) -acetyl] -amino] -ceph ^ -era ^ - carboxylic acid 8 ml of benzene and 0.28 ml of a priethylamine are brought together one after the other. After complete dissolution, 0.14 ml of 2-aminothiophenol, 5 ml of distilled water and a few mg of methyltriqaprylammonium chloride are added. The mixture is then stirred vigorously overnight. After adding 2 ml λ Ν hydrochloric acid, the mixture is extracted with ethyl acetate, washed with water, dried and evaporated to dryness. The residue is taken up again in ethyl ether. After suction filtration, the 690 mg of 3-acetoxymethyl-7- £ | (2- [C2- (2-aminophenylthio) -ethO3iy] -imino] -2- (2-tritylaminothiazol-4-yl) -acetyl] amino] - ceph-3-em-4-carl3onic acid.

Step e_B: 3-ethoxymethyl-7- [[2- [[] 2- (2-aminophenylthio) ethoxyj -imino] -2- (2-aminothiazol-4-yl) acetyl] -

To the above product are added 5j3 ml of aqueous, 66? 6%

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-840-

Formic acid added; then it is heated to 55 ° C for 15 minutes, cooled and suction filtered, whereupon the solvent by distillation under reduced pressure from the "filtrate be separated. The residue is taken up in ethanol and then under reduced pressure to Evaporated to dryness. This results in the desired product, which is in the present form for the following example is used·

The 3-acetoxymethyl-7- £ [2- (2-tritylaminothiazol-4-yl) -2- £ used as starting material in Example 3 2- (bromoethoxy) -imino] -acetyl] -amino] -ceph - ^ - em - ^ - carboxylic acid (syn isomer) was made as follows!

26.85 β of the 3- (2-tritylaminothiazol-4-yl) -2- [2- (bromoethoxy) -imino] prepared in Example 1 acetic acid (syn isomer), 7.25 g i-hydroxy-IH-benzotriaaol, 12 g dicyclohexylcarbodiimide and 350 ml of anhydrous methylene chloride are mixed, after which the mixture is stirred at room temperature for 23 h will. After filtering off the picyclohexylurea formed the Eiltrat is washed with water, an aqueous, 1 M sodium hydrogen carbonate solution and then with water. The filtrate is dried and then evaporated to dryness under reduced pressure. The residue is taken up in 150 ml of ether.

There are 25.4 g of crystalline substance obtained in ml of anhydrous methylene chloride are dissolved. Then 10.56 g of 7-aminocephalosporanic acid, 200 ml of anhydrous Methylene chloride and 10.9 ml of triethylamine were added, whereupon the mixture was stirred for 65 hours. Then 350 ml of water and 45 ml of 2N hydrochloric acid were added, followed by extraction is stirred. The organic phase is washed and

90984Q / 0886

then dried and evaporated to dryness under reduced pressure. The residue is dissolved in 75 ml of ethyl acetate resumed and diluted with 520 ml of ethyl ether. After suction filtration, 24.75% of product are obtained.

Example 24 ; Sodium salt of 3-acetoxymethyl-7 - [[2- [Q2- (2-aminophenylthio) -ethoxyI-imino] -2- (2-aminothiazol-4-yl) -acetyl] -aminoj -ceph-3-em- 4 -Carboxylic acid (syn isomer)

1.5 ml are added to the product obtained in Example 23 a 1 M solution of sodium acetate in methanol and 1 ml of methanol were added. After mixing, add 6 ml of ethanol diluted. The precipitated product is filtered off with suction, washed with alcohol and then made into a paste with ether.

235 mg of the desired product are obtained.

Element ar analysis ;

calculated: found:

% G% R

44.94 3.77
44.8 3.7

: 614.65

% N % B

13.67 15.65 13.3 ^ 4.8

Nuclear Magnetic Resonance Spectrum ((CD ₃ J ₂ SO):
1.99 ppm: -0-0-

ppm: = NO-CH ₂ -6.73 ppm: 5-proton of the thiazole ring

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Example 25 : 3-Acetoxymethyl-7- [£ 2- (2-aminothiazol-4-yl) -2 - [(2-amino-1,3.4-thiadiazol-5-yl) -thioethoxy] -imino] -acetyl] carboxylic acid (syn isomer)

Step e_A: 3-acetoxymethyl-7- £ (2-tritylaminothiaz; ol-4-yl) 2- £ (2-amino-1.3.4-thiadiazol-5-yl) -thioethoxy-

a) 1.9 g of 2-amino-5-thiol-1.3.4-thiadiazole are mixed with 15 ml mixed with a 1 M solution of lithium methylate in methanol. After complete dissolution is under reduced Pressure evaporated to dryness, the lithium derivative of 2-amino-5-thiol-1.3.4 ~ thiadiazole in the form a resin is obtained, which is used in this form.

7 »91 S α ^ ^Γ 3-acetoxymethyl-7 - [[2- (2-tritylaminothiazol-4-yl) -2-]] 2-bromoethoxyimino) -acetylamino-ceph-3-em- ^ ~ prepared in Example 3 carboxylic acid (syn isomer) and 670 mg of lithium iodide are placed in 30 ml of anhydrous dimethylformamide. After the mixture has dissolved, the lithium derivative obtained above and 15 ml of dimethylformamide are added. After stirring for 5.5 hours at room temperature, 4-50 ml of water and 1 ml of formic acid are added. It is extracted with ethyl acetate, dried and evaporated to dryness under reduced pressure. The residue is chromatographed on silica, eluting with an ethyl acetate-methanol-water-triethylamine mixture (70: 20: 10: 1) as the eluent.

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2.36 g of the desired product are obtained.

Stage_B: 3-acetoxymethyl-7- £ [2- (2-aminothiazol-4-yl) - | - (2-amino-1.3.4-thiadiazol-5-yl) -thioethoxy-

843 mg of the tritylated product obtained as above and 6.4 ml of aqueous, 66% formic acid are 15 min at 55 ° C stirred. Thereafter, under reduced pressure to Evaporated to dryness, whereupon the residue in 5 rol ethanol and 50 ml of ether is reabsorbed. After viewing 606 mg of the desired crude product are obtained.

Example 26 : Sodium salt of 3-Aceto3qinnethyl-7-j] [2-g2-aminothiazol-4-yl) -2-U-2-amino-1,3.4-thiadiazol-5-ylJ-thioethoxyiminoj-acetylaminoce ph-5- em-4-carboxylic acid (synrlsomer)

The product of Example 25 is mixed with 1.5 ml of a 1 M solution of sodium acetate in methanol and 0.5 ml of dimethylformamide. After adding 5 ml of ethanol, the precipitate formed is filtered off with suction, which is taken up again in 7 ώ methanol, heated to reflux and cooled; then the impurities are sucked off. The filtrate is evaporated to dryness under reduced pressure; the residue is allowed to disintegrate in ethanol, suction filtered and dried, whereupon 146 mg of the desired product are obtained.

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Elemental analysis ; C ^ gH ^ gOrfNgS ^ Na: 622.66

% G% E% Ή% S

calculated: 36.65 3.08 17.99 20.60 found: 37.0 3.7 17.5 19.8

HMH spectrum ((CD ₃ J ₂ SO):

1.99 ppm: -0-0-Cll
Ö

^ 4.25 ppm: = N-O-CH ₂

6.76 ppm: 5-piOton of the thiaz oil ring

Example 27 : 3-Acetoxymethyl-7-Γ ^ 2-C2-aminothiazol-4-yl) .2-C2-C 5-nitro-2-pyriainylJ-thiOL1-ethoxy iminoj ^

: 3-acetoxymethyl-7 - [[2- (2-trityiatftinothiazol-4-yl) -2-C2-E 5-nitro-2-pyridinylJ-thioj-ethoxy-

396 mg of the 3-Acetoxymethy.l - 7-L prepared in Example 3 [2-Tl ~ 2-bromoethoxy] -iminoj -2 -] - 2-tritylaminothiazol-.4-yl) -acetylJ-afflino-ceph-3-em-4-carbonsä \ ire, 4 ml of benzene and 0.14 ml of triethylamine are brought together one after the other.

After dissolution, 92 mg of 2-thiol-5-nitropyridine, 5 ml distilled water and a few mg of methyltricaprylammonium chloride were added, followed by 72 h at room temperature is stirred. Then 1 ml of 1 N hydrochloric acid is added

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added and extracted with ethyl acetate. The organic phase is dried and then under reduced Pressure evaporated to dryness. The residue is taken up in ethyl ether and suction filtered.

416 mg of tritylated product are obtained.

Step_B: 3-Acetoxymethyl-7 - [[2- (2-aminothiazol-4-yl) -2-C2-CC (5-nitro-2-pyridinyl) -thio3 -ethoxy] -imino]

3 »2 ml of aqueous are added to the product obtained above 66% formic acid was added, whereupon 15 mxn to 55 ° C is heated. After seeing the triphenylcarbinol formed the piltrate is evaporated to dryness under reduced pressure. It is then taken up again in ethanol and again evaporated to dryness, whereupon the desired product is obtained.

Example 28 : Sodium salt of 3-acetoxymethyl-7 - [[2- (2-aminothi8Zol-4-yl) -2- [2- [C (5-nitro-2-pyridinyl) -thioj -ethoxy] -iminol-acetyl ] - aminoj -ceph-3-em-4-carbonsä ^ Γe (syn isomer)

Some methanol and then 2 ml of a 1 M solution of sodium acetate are added to the product obtained in Example 27 added in methanol. Traces of insoluble substances are suctioned off, whereupon the filtrate is reduced Pressure is evaporated to dryness. The residue is taken up again in ethanol. After sucking off

909840/0 8 86

153 mg of the desired sodium salt are obtained.

Element ar analys e; 022B ^ oQgNr ₇ S ^ Na J 645.63

% C% H % JS% S

calculated: 40.93 3.12 15, ^ 9 14.90 found: 39.0 3.3 13.2 12.9

mR spectrum ((CD ₃ ) ₂ SO):
2.0 ppm: -0-C-CH *

.- ^ 3.86, 4.3 and 4.4 ppm: -IT-O-OH ₂ -6.76 ppm: ^ - "proton of the thiazole ring

Example 29 : 3-Acetoxymethyl-7- | ^ [2- (2-aminothiazol-4-yl) -2- [2-C [l (3-cyano-6-methyl-2-pyridinyl) thio] ethoxy ] -imino] -acetyl] -aminoj-ceph-3-em-4- carboxylic acid (syn isomer)

Stage_A: 3-acetoxymethyl-7- [[2- (2-tritylaminothiazole-4-

yl) -2- [2-CC (3-cyano-6-methyl-2-pyridinyl) -thioJ ethoxyJ -imino] -acetyl] -amino] -c

791 mg of the 3-acetoxymethyl-7- [" [2- (2-tritylaminothiazol-4-yl) -2-C 2- (bromoethoxy) -iminoJacetyl] -aminoj -ceph-3-em-4-carboxylic acid, 326 mg 2-thiol-3-cyano-6-methylpyridine, 10 ml benzene, 0.42 ml triethylamine,

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10 ml of water and a few mg of methyltricaprylammonium chloride are mixed, whereupon the mixture is stirred for 44 h at room temperature
will. It is then acidified with 3 ml of 1 IT hydrochloric acid and
extracted with ethyl acetate. The organic phase is dried and evaporated to dryness under reduced pressure. The residue is taken up in ether and removed, whereupon 877 mg of crude product are isolated.

Stage_B: 3-Acetoxymethyl-7 - [[2- (2-aminothiazol-4-yl) -2-C2-CC (3-cyano-6-methyl-2-pyridinyl) -thioJ-ethoxy] -imino] -acetyl] -amino] -

To the product obtained above are 7 aqueous nil,
66% formic acid was added, whereupon the mixture was ^{heated to 55 °} C. for 15 min with stirring. It is then cooled and suction filtered, whereupon the solvents are separated off from the filtrate by distillation under reduced pressure; then it is taken up again in methanol and evaporated to dryness, whereby a crude product is obtained that can be purified using the sodium salt and subsequent treatment with formic acid.

Element ar analysis ; C ^^ HgiOr ^ T ^ S,: 617.69

calculated: 46.67 3.75 15.87 15.57
found: 46.2 3.8 15.2 14.5

imR spectrum (DMSO):
2.0 ppm: -OC-ΟΗχ

90 9 8 40/0 88 δ

4.2, 4.3 and 4.4 ppm: = -NO-CH ₂ -6.8 ppm: 5-proton of the thiazole ring

Example 30 : Sodium salt of 3-acetoxymethyl-7- £ [2- (2-

aminothiazol-4-yl) -2- [2 ~ QQ (3-cyano-6-methyl-2-pyridinyl) -thioJ -ethoxy] -imino] -acetyl] aminoj -ceph-3 ~ em-4-carbonsätire (s .yn isomer)

The product of Example 29 is 5 ml of methanol and then 4 ml of a 1 M solution of sodium acetate in methanol were added; then is under reduced pressure evaporated to dryness, treated with ethanol and nutted, whereupon 505 mg of the desired sodium salt are obtained

Example 31 : 3-Acetoxymethyl-7 - [[2- (2-aminothiazol-4-yl) -2- [2-C (1-methyltetrazol-5-yl) -thiojethoxy] -imino] -acetylJ-amino- ceph-3-em-4- carboxylic acid (syn isomer)

Step e_A: 3-Acetoxymethyl-7- [[2- (2-tritylaminothiazol-4-yl) -2- [2-C (1-methyltetrazol-5-yl) -thioJ-ethoxylcyj -imino] -acetyl] -amino -ceph-3-em-4-carboxylic acid

432 mg of the diethylamine salt of 3-acetoxymethyl-7 - [[2- (2-tritylaminothiazol-4-yl) -2 - ['2- (bromoethoxy) -imino] -acetyl] aminoj-ceph-3-em-4- carbonsäui ⁱ e (syn isomer), 64 mg

909840/0888

1-methyl-5-mercapto-i.2.3.4-tetrazole and 2.2 ml of anhydrous dimethylformamide are mixed. The mixture is heated for 1.5 hours in a water bath at 50 ° 0 and then stirred for 1.5 h "at room temperature and finally 1 h 10 min at 55 ⁰ C. Then it is cooled, diluted with 20 ml of water and stirred, whereupon the precipitate formed is filtered off by suction will.

406 mg of crude product are obtained.

Step e_B: 3-Acetoxymethyl-7- £ [2- (2-aminothiazol-4-yl) -2-C2-Q (1-methyltetrazol-5-yl) -thiq] -äthoxyj iminoj -acetylj -amino-ceph-3-em-4-carboxylic acid

406 mg of the product obtained above are (33% water) dissolved in 3.2 ml of aqueous formic acid, followed by 15 min in the water bath is heated to 55 ⁰ O. After filtering off the triphenylcarbinol with suction, the aqueous formic acid is removed by distillation under reduced pressure, after which the residue is taken up in ethanol and again evaporated to dryness. After adding 3 ml of methanol to dissolve the residue, it is diluted with 30 ml of ether, whereupon the precipitate formed is filtered off with suction.

201 mg of crude product are obtained, which is dissolved in 1 ml of warm methanol and precipitated by adding 5 ml of ether will. After suction filtration, 17I mg of the target are obtained Product received.

Elemental ^analysis t ^ ^/ ^ \ α ίί ο ^^ 'η "α ^ χ

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- 8Ä0-

% C% E% N% S

calculated: 39 , 10 3 : , 63 21, 6th 16.48 found: 38 , 6 3 , 7 20, 9 16 NMR spectrum ((CD ₃ ) ₂ so) 2.03 ppm: -0-0-GH 3 0 ~

Triplet at 4.33 ppm: = H-0-GH ₂ ~ J = 6 Hz

6j76 ppm: ^ proton of the thiazole ring

Singlet at 3.91 ppm: -N-GH,

The diethylamine salt of 3-acetO3qyTethyl-7- | _ £ 2- (2-tritylaminothiazol-4-yl) -2-T 2- (bromoethoxy) -iminol-acetylaminoJ-ceph-3-em-4-carboxylic acid (syn isomer) was made as follows:

0.79 g of 3-AcetO3cymethyl-7 - [[2- (2-tritylaminothiazol-4-yl) -2- £ 2- (bromoethoxy) -iminq] -acetyl] -amino] -ceph-3-em-4-carboxylic acid are dissolved in 5 ml of ethyl acetate; after complete Dissolution, 0.12 ml of diethylamine are added. After stirring, suction filtration and washing with ethyl acetate, is Obtain the desired salt after drying.

Example 32 : 3-Acetoxymethyl-7 - [^ [2- (2-aminothiazol-4-yl) · 2- (2-azidoethoxy) -imino] -acetylj -amino - ceph-3 ~ em-4-carboxylic acid Csyn- Isomer)

Step e__A: 2- [2-Tritylaminothiazol-4-yl [-2- (2-azidoethoxy) -

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291282 '

iminoj -acetic acid

24.8 g of the sodium salt of 2- (2-iritylaminothiazol-4 ~ yl) -2- (2-bromoethoxy) -iminoacetic acid, 125 ml of dimethylformamide and 7 »6 g of tetramethylguanidiyazide are placed in a water bath for 1 h stirred at 50 ° 0. Then 0.8 g Tetramethylguanidiri / azide added; after stirring for 45 min get a clear brown solution. After cooling to room temperature 500 ml of water and 50 ml of 2N hydrochloric acid are added added. It is then filtered off with suction, made into a paste three times with water and then triturated with methylene chloride. The filtrate is decanted off, washed with water and then dried. It is then concentrated to 50 ml under reduced pressure, after which 250 ml of ethyl ether are slowly added can be added. After suction filtration, 15> 58 S become acid obtain.

The sodium salt of 2- (2-Bromätho3ryimino) -2- (2-tritylaminothiazol-4-yl) -acetic acid (syn isomer) was made as follows:

6 g of NaOH pellets are dissolved in 280 ml of absolute ethanol. Then wex ^ the 28.2 g of that described in Example 21

Ethyl 2- (2-bromoethoxyimino) -2- (2-tritylaminothiazo1-4-yl) -acetic acid ester (syn isomer) added.

After 65 hours of stirring at room temperature, the sodium salt separates out. It is suction filtered, washed with ethanol and dried in vacuo.

There are 29.82 g of the desired product with 12%

90984 0- / 0886

Received solvate content.

Stage_B: Diethylamine salt of 3-acetoxymethyl-7 - [[2- (2-tritylaminothiazol-4-yl) -2 - [(2-azidoäth.o: xy) -imlnq] -acetyl] -aminoj -ceph-3-em-4-carboxylic acid: e

2.54 g of 7-aminocephalosporanic acid, 25 ml of anhydrous Methylene chloride and 2.6 ml of triethylamine are at room temperature Stirred for 15 min.

Then 6.02 g of the ester of 2- (2-tritylaminothiazol-4-yl) -2- (2-azidoethoxy) -imino-acetic acid with 1-hydroxy-1H-benzotriazole are added, after which the mixture is stirred for 4-5 h at tree temperature will. Then 25 ml of water and 5 ml of 1N hydrochloric acid are added. After decanting, the organic phase is washed with water, dried and evaporated to dryness under reduced pressure. The residue is taken up in 30 ml of ethyl acetate. After dissolution, 2.4 ml of diethylamine are added. After cooling to 0 ⁰ C 5) 9 g Diäthylaminsalz be äbgenutscht.

The ester of 2- (2-tritylaminothiazol-4-yl) -2- (2-azidoethoxy) iminoacetic acid used as starting material in stage B using 1-hydroxy-IH-benzotriazole was as follows manufactured:

9.84 g of 2- (2-tritylaminothiazol-4-yl) -2- (2-azidoethoxy) -imino-acetic acid, 2.93 S 1-hydroxy-IH-benzotriazole, 4.88 g Dicyclohexylcarbodiimide and 130 ml of anhydrous methylene chloride are mixed and then stirred for 20 h at tree temperature, after which the dicyclohexyl-

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2912823

urea is sucked off. The filtrate is then washed with water containing sodium hydrogen carbonate and then with pure water. It is then dried and evaporated to dryness under reduced pressure. The residue is taken up again in ethyl acetate. After 0.5 h, cooling to 0 ⁰ C is filtered with suction.

7.31 g of product are obtained. A further 1.5 g are also obtained from the mother liquors.

Step e_ (h 3-Acet o: xymethyl-7- £ [2- (2-aminothiazol-4-yl) -2-C (2-azidoethoxy) -imino] -acetyl] -aminoj -ceph-3-

1.2 / 8 g of the product obtained in the previous step and 6 ml of 70% formic acid are 15% hot 50 ° 0 stirred. Thereafter, the formed triphenylcarbinol suction filtered and the filtrate evaporated to dryness under reduced pressure. The residue is in water again absorbed and disintegrated therein. Then it is suction filtered and dried.

0.358 g of acid are obtained.

Example 33 : Sodium salt of 3-acetoxymethyl-7 - {_ [2- (2-aminothiazol-4-yl) -2 - [(2-azidoethoxy) -iminoj -acetyl] -aminoj -ceph ^ -em - ^ - carbon acid (syn isomer)

0.385 g of the acid obtained in Example 32 and 1 ml of a 1 M solution of sodium acetate in methanol are mixed.

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291282

5 ml of ethanol are slowly added to the clear solution obtained. After viewing, Vaschen with A "thand> l and then with ethyl ether 0.215 g of sodium salt are obtained.

Element ar analysis ; C ₁ ^ oOJSgS ₂ Na * 532.49

% G% E % N % S

calculated: 38.4 3.2 21.0 12.0 found: 38.3 3.2 20.4 12.1

Nuclear Magnetic Resonance Spectrum ((CD ₃ J ₂ SO):

1.98 ppm: -O-C-CH,

Triplet at 4.18 ppm: = NO-CH ₂ - J = 5 Hz

6.76 ppm: 5-3? Rotons of the thiazole ring

Example 34 : 3-Acetoxymethyl-7- [2- (2-aminothiazol-4-yl) 2- (2-aminoethO3qy) -imino] -acetylamino-ceph-3- em-4-carboxylic acid (syn isomer)

Step e_A: 3-Acetoxymethyl-7 - [[2- (2-tritylaminothiazole-4-

yl) -2- [2-aminoethoxy] -iminoj -acetylamino-ceph-J-

0.752 g of the 3-acetoxymethyl-7- [2- (2-tritylaminothiazol-4-yl) -2- [2-azidoetho: xyJ -iminoj acetylamino-ceph-3-em-4-carboxylic acid, 4 ml of dimethylformamide and 0.7 ml of anhydrous triethylamine are mixed.

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291282 '

Hydrogen sulfide is then bubbled through the mixture for 15 minutes. Thereafter, 40 ral ■ water, and then 0.7 ^m l of acetic acid are added.

After suction filtration, 0.707 g of crude product are obtained.

Step JB: 3-AcetO27metbyl-7 - [[2- (2-aminothiazol-4-yl) -2- (2-aminoetho33r) -imino] -acetyl] -amino-ceph-3-em

1 * 054 g of the product obtained above are heated in 5 ml of 70% formic acid for 15 min at 50 ⁰ C. The triphenylcarbinol formed is then filtered off with suction and the filtrate is evaporated under reduced pressure. The dry residue is taken up in water and separated from the insoluble portion. The filtrate, which has evaporated to dryness, is taken up again in ethanol. After it has been allowed to disintegrate, it is suction filtered, after which 0.125 g of acid are obtained.

Example 35 ? Sodium salt of 3-acetoxymethyl-7- [Q2- (2-aminothiazol-4-yl) -2-C2-caminoethoxyJimino]] -acetyl] -aminoj -ceph ^ -em - ^ - carboxylic acid (syn isomer)

The product of Example 34 is dissolved in 0.2 ml of a 1 M Dissolved sodium hydrogen carbonate solution. After careful Addition of 0.4 ml of ethanol, the insoluble fraction is suction filtered, whereupon the piltrate under reduced pressure to Dry is evaporated. The residue is taken up in ethanol and left to disintegrate.

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-gSG-

291282S

After removing it, 0.047 g of the desired salt are obtained obtain.

Example 36 ; 3 - [(1-Methyl-iH-tetrazol-5-yl) -thiomethyl [7- [C2- (2-aminothiazol-4-yl) -23- (2-azidoethoxy) -imino] -acetyl] -amino] carboxylic acid (syn isomer)

Level A:

3- [O-methyl-1H-tetrazol-5 ~ yl) thiomethyl: { _: 7- [[2 (2-tritylaminothiazoi-4-yl) -2] - (2-azidoethoxy) imino] acetyl] - aminoj -ceph ^ -em - ^ - carbonsäxire

0.652 g of 7-amino-3-f (1-methyii ^ etrazol-5-yl) -thiomethyl] -ceph-3-em-4-carbonsätire, 6.5 ml of methylene chloride and 0.56 ml of triethylamine are stirred for 15 min at room temperature, after which 1.29 g of the ester of oL- £ (2-azidoethoxy) imino prepared by the method of Example 32, stage B J-2- (2-tritylaminothiazol-4-yl) acetic acid with 1-Hydroxy-iH-benzotriazole can be added. After that, will Stirred h at room temperature, whereupon 10 ml of water and 3 ml of 2N hydrochloric acid are added. After decanting, vaschen the organic phase with water, drying and evaporation to dryness under reduced pressure is obtained The residue was taken up in 5 ml of ethyl acetate and washed with 10 ml of ethyl ether are added. The mixture is then stirred for 0.5 h at room temperature and suction filtered, whereupon 1.416 g of crude product can be obtained.

909840 / 088S

2912823

_B: 5-Γ (1-methyl-iH-tetrazol-5-yl) -thiomethyl- [7- [C2- (2-aminothiazol-4-yl) J -2- (2-azidoethoxy) -iminp] -acetyl] -amino] -ceph ^ -em - ^ - carboxylic acid

Ί "336 g of the product obtained above are stirred for 15 min in 7 ml of formic acid at 50 ⁰ C. The triphenylcarbinol formed is then filtered off with suction and the filtrate is evaporated to dryness under reduced pressure. The residue is taken up again in water, allowed to disintegrate and suction filtered, after which 0.77 g of crude product is obtained, which is dissolved in as little 10% sodium hydrogen carbonate solution as possible. Then 0.07 g of activated charcoal are added, whereupon the filtrate is suction filtered and formic acid is added to pH 2. After removing the purified acid, 0.171 g of the desired product are obtained »

Example 57 ; Sodium salt of 3-r (1-methyl-iH-tetrazol-5-yl) -thiomethyl-Q7- [£ 2- (2-aminothiazol-4-yl) J 2- (2-azidoethoxy) -iminq] -acetyl] -aminqj-

^ -em - *! - carboxylic acid (syn isomer)

0.362 g of the purified acid obtained in Example 36 are dissolved in 0.3 ml of 1 M sodium hydrogen carbonate solution, after which 1 ml of ethanol is added. After the insoluble material has been removed, the filtrate is reduced under reduced pressure Pressure evaporated to dryness, whereupon the residue is taken up in ethanol. After disintegrating and suction filtration, 0.09 g of sodium salt are obtained.

909840/0886

291282!

Element ar analysis: C ₁ nB. " . ι ·
% G i ^ cN ₁ oS _x Na: 588 584 34.7 {
% H % N % S calculated: 34.5 2 , 9 28.5 16, 3 found: ((CD ₃ ) ₂ so) 3 , 2 25.3 3 NME spectrum T-GH _x •
• 3.9 ppm: 1

6.76 ppm: 5-proton of the thiazole ring 9.35 to 9.48 ppm: -COBH-

Example 38 : 3 - [(1-Methyl-iH-tetrazol-5-yl) -thiomethyl- [7-CC ² - (2-aminothiazol-4-yl) J -2- (2-aminoethoxy) -imino] - ac θtylj -amino J -c eph-3 -em-4- carboxylic acid (syn isomer)

Stage_A: 3 - [(^ - methyl- ^ H-tetrazol-5-yl) -thiomethyl- [7 - [[2- (2-tritylaminothiazol-4-yl > J -2- (2-aminoethoxy) -imino} -acetyl] -aminoj -ceph-3-em-4-

3.91 g of the sodium salt of 3 - ^ (1-methyl-iH-tetrazol-5-yl) -thiometbyl- [7- [C2- (2-tritylaminothiazol-4-yl) J-2- (2-azidoethoxy) -iminq] -acetyl} -aminoj -ceph.-3-βm-4-carboxylic acid are dissolved in 39 ml of dimethylformamide, whereupon slowly ml of water and then 9.75 nil of triethylamine were added will. Hydrogen sulfide is then passed into the mixture in bubbles. After 45 minutes, 3 »9 ml of triethylamine are added admitted, whereupon the passage still 15 niin

909840/0888

9 291282 '

- 095 -

continued · The mixture is then poured into a dilute hydrochloric acid solution at 10 ^{° C.} Thereafter, it is heated for 15 min with stirring to 30 ⁰ G; after cooling and suction filtration, the precipitate is washed until neutral and rinsed with ethyl ether, whereupon 2 g of the desired product are obtained.

The sodium salt of 3- £ (1-methyl-iH-tetrazol-5-yl) -thiomethyl- [7 - [[2- (2-tritylaminothiazol ~ 4-yl)] used as starting material in the present example -2- (2-azidoethoxy) -imino] -acetyl] -amino] -ceph-3 ~ em-4-carboxylic acid was prepared as follows:

8.47 g of the 2- (2-tritylaminothiazol-4-yl) -2- (2-azidoethoxy) imino-acetic acid (syn isomer) obtained in Example 32, 50 ml of methylene chloride and 1.93 g of dieyelohexylcarbodiimide are added for 1 hour stirred at room temperature; the dicyclohexylurea formed is then filtered off with suction. The filtrate is added to a mixture of 3.07 g of 3- (1- -Methyl-iH-tetrazol-5-yl) -thiomethyl-7-amino-ceph-3-em-4-carboxylic acid, 40 ml of anhydrous in 20 min Methylene chloride and 3.9 ml of triethylamine were added. The mixture is then stirred for a further 1 hour and then evaporated to dryness under reduced pressure. The residue is taken up in 50 ml ethyl acetate at 20 ⁰ C and acidified with 0.2 ml of acetic acid. It is then filtered off with suction and the filtrate is washed with 1 N hydrochloric acid and then with water until neutral. The organic phase is dried and concentrated to a volume of 50 ml, whereupon 1.7 ml of diethylamine are added. After the salt of the starting acid has crystallized out, it is filtered off with suction, whereupon the filtrate is used for precipitation with 115 ml of isopropyl ether. After removal, 7-62 g of the diethylamine salt are obtained.

909 84 0/0888

5.9 g of this salt are dissolved with stirring in a mixture of 60 ml of water, 60 ml of methylene chloride and 3.5 ml of 2N hydrochloric acid; After decanting and washing the organic phase with water, it is dried and evaporated to dryness under reduced pressure. The residue is taken up in 20 ml of isopropyl ether; after suction filtration, 5.6 g of free acid are obtained, which is dissolved in a mixture of 9.5 ml of methanol and 6.7 ml of a 1 M sodium acetate solution in methanol. The sodium salt is precipitated by adding 27 ml of isopropanol with 25 % ethanol, whereupon it is diluted with 270 ml of isopropanol.

4.21 g of the desired product are obtained.

Step e_B: 3 ~ [O -Methyl-iH-tetrazol-5-yl) -thiomethyl- [7- [[2- (2-aminothiazol-4-yl)] -2- (2-aminoethoxy) -imino] -acetyl] -aminoj-ceph-3-em-4-carboxylic acid (syn-isomerjl

2 g of the product obtained above and 5 ml of formic acid are heated ^{to 40 to 45 ° C. with stirring.} Then 5 ml of water are added while maintaining the temperature for 15 minutes. After cooling, the triphenylcarbinol formed is filtered off with suction, whereupon the piltrate is evaporated to dryness under reduced pressure. The residue is taken up in 10 ml of ethanol, left to disintegrate, suction filtered and washed with ethanol and then with diethyl ether.

1.36 g of crude product are obtained, which in 15 ml of 2N Hydrochloric acid again — is taken on. After filtering off the insoluble part of the piltrate with 3 ml of an aqueous,

909840/0888

2912828

1 M lithium acetate solution and then with an aqueous lithium hydroxide solution are adjusted to pH 4. Then is suction filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is in 30 ml Ithanol reabsorbed, disintegrated therein and sucked off.

5 ^ 5 mg of the desired product are obtained.

A further 133 mg are recovered from the mother liquors « Both products are treated again in the same way as above, whereupon 430 mg of white product are isolated.

HMR-fipectrum ((CDj) ₂ SO):

6.86 ppm: 5-P ^ oton of the thiazole ring

Example 39: 3-Aceto3cymethyl-7-Q [2- (2-aminothiazol-4-yl) · 2-C (2- $ odäthoxy) imino] -ac etyll amino] ceph-3-em-4-carboxylic acid -trifluoroacetate (syn isomer) -

Stage_A: Benzhydryl ester of 5-AcetO3 £ ymethyl-7 - [[2- (2-tritylaminothiazol-4-yl) -2-C (2-iodätho3q5r) -imino] -acetyl] -aminoj -ceph ^ -em - ^ - carboxylic acid

1.28 g of 2- (2-Jodätho3q5Timino> -2- (2-tritylaminothiazol-4-yl) acetic acid (syn isomer) in Sorm the solvate with Dlchloräthan (ie, corresponding 1 _r Q $ lg pure product) and 1, 45 g of 7-aminocephalosporanic acid benzhydryl ester are dissolved in 22 ml of anhydrous methylene chloride under an inert atmosphere

9-0984α / 0886

291282!

brought in.

It is then placed in an ice bath, whereupon 5 ml of a 0.5 M solution of dicyclohexylcarbodiimide in methylene chloride (corresponding concentration 103 g / l) are added dropwise. Mixture is then stirred for 1.5 hours at 0 to +5 ⁰ C and then for 1 h at 25 ⁰ C. The precipitated Dicyelohexylharnstoff is suction filtered, washed with methylene chloride and the filtrate and washings are evaporated at a temperature below 40 ⁰ C under reduced pressure to dryness.

2.98 g of product are obtained, which is obtained by chromatography on silica using a methylene chloride-ethyl acetate mixture (92: 8) is purified as an eluent.

1.12 g of white product are obtained.

UV spectrum (ΕΓ / 10 HCl in ethanol): maximum 269 nm E ^ - 209

IR spectrum (chloroform):
β- lactam I79I cm "" ¹
CF-OR 1042 cm " ¹
C = C 1638 cm * " ¹

MMR spectrum (CDCl ₅ ):

6i? 5 ppm: 5-PrOtOn of the thiazole ring

& 09840 / -0888

2912823

Level_B: 3-Acefcoxymet; hyl-7 - [[2- (2-aniinotliiazol-4-yl) -2-Q (2-iodoethoxy) -iminoj -acetyl] -aminoJ -ceph-3-eQi-

960 mg of the product obtained in stage A are in IQ ml pure trifluoroacetic acid introduced. Then 3 min stirred at room temperature, cooled in an ice bath for 1 min and then precipitated by adding 100 ml of ice-cold isopropyl acid. After stirring for 10 min, at room temperature the precipitate is nebulized with isopropyl ether and then washed with diethyl ether and under dried under reduced pressure.

460 mg of the desired product are obtained;

Element ar analysis : C ₁ ^ H ₁₈ NcOr ₇ SJ '

% N % S

calculated: 9.87 9.04 - found: 9.7 9.2

UV spectrum (N / 10 HGl in ethanol): maximum 262 nm e | = 290

NMR spectrum

6.83 ppm: 5-proton of the thiazole ring

The 2- (2- -Iodethoxyimino) -2- (2-tritylaminofchίazol-4-yl) acetic acid (syn isomer) was made as follows:

9 on π A-n / ΟΒδδ

ORIGINAL INSPECTED

291282?

a) 2- (2-iodoethoxyimino) -2- (2-tritylaminothiazol-4-yl) ethyl acetate (syn isomer).

6 6 of the 2- (2-bromoethoxyimino) -2- (2-tritylaminothiazol-4-yl) -acetic acid ethyl ester (syn isomer) prepared in Example 1 are introduced into 60 ml of methyl ethyl ketone with 2.141 g of sodium iodide. The mixture is then refluxed for 1 hour 10 minutes, after which it is evaporated under reduced pressure. The residue is taken up in 120 ml of methylene chloride and washed five times with 40 ml of water each time. Each Vaßchwasser is re-extracted with 2 ml of methylene chloride, whereupon the organic phase is dried and evaporated to dryness; will. Ether is added to the resinous product obtained. After drying under reduced pressure, 6.22 g of product are obtained; F. 110 ⁰ C.

b) 2- (2-iodo-bhoxyimino) -2- (2-tritylaminothiazol-4-yl) -acetic acid (syn isomer).

6.7 g of the ethyl ester prepared in stage a) are introduced into 5 »5 ml of dioxane and 44 ml of absolute ethanol under an inert atmosphere. Then 5 »5 ml of a 2N NaOH solution are added dropwise. After adding 7 ml of absolute ethanol, the mixture is stirred overnight at room temperature, whereupon the sodium salt formed is filtered off with suction. Then it is washed twice with 3 ml each of an ethanol-dioxane mixture (4: 1) and then made into a paste with ether. The product obtained is treated in a separating funnel with 100 ml of water and 100 ml of chloroform, whereupon the pH is adjusted to 2 with 1N hydrochloric acid. The organic phase is decanted off, washed with a saturated NHCl solution, dried and evaporated to dryness under reduced pressure. The resin obtained is at 40 ^° C. in 35 ml of di-

90984n / 0R88

- ORIGINAL INSPECTED

chloroethane dissolved; after initiation of crystallization is left to stand for 72 h at tree temperature, whereupon the The precipitate formed is filtered off with suction, washed and dried.

5 »4 g of white product solvated with dichloroethane (corresponding to 4.61 g of pure product) are obtained. F. 161 ⁰ C.

Elemental analysis ; C ₂₆ H ₂₂ OjNjSJ: 583.35

% N % S

calculated: 6.56 4.70
found: 5.9 4.8

UV spectrum (N / 10 HOl in ethanol): 278 nm E ^] - 235

NMR spectrum j

6.58 ppm: 5-proton of the thiazole ring

Example 40 : N- [2- [Q2-C C2-carboxy-3-methyl-8-oxo-5-thia-1-aazabicyclo [4.2.θ] oct-2-en-7-yl.l -aminoj - 1 (2-aminothiazol-4-yl) -2-oxo-ethyljl-imino] oxyj -ät hy IJ-pyrid inium-d oppe 1 salt (Jo did and trifluoroacetate) (syn-isomer)

3-methyl-7 - [[2- (2-tritylaminothiazol-4-yl) -f2- (2-bromoethoxy) imino] -acetyl] -amino] -ceph-3-em-

2912823

- 2 & G -

536 mg of 2- (2-bromoetho: ^ imino) -2- (2-tritylaminothiazol-4-yl) acetic acid (syn isomer), 380 mg of 7-amino-3-deacetoxycephalosporanic acid benzhydryl ester and 6 ml of anhydrous methylene chloride are found under Inert atmosphere brought together. After cooling in an ice bath, 230 mg of dicyclohexylcarbodiimide are added after 5 minutes, followed by washing with 2 ml of methylene chloride. Thereafter, it is held for 2 h at 0 to +5 ⁰ C and then for 1 h at room temperature. It is then filtered off with suction and the insoluble product is washed three times with methylene chloride.

111 mg of product are recovered.

The filtrate is evaporated to dryness, whereupon 1.02 g a resin can be obtained. This product was purified as follows.

After loading onto 100 g of silica, the mixture is eluted with a benzene-ethyl acetate mixture (17: 3), whereupon 54-8 mg of resin are obtained. R _f = 0.27 to 0.28 (benzene-ethyl acetate mixture 17: 3).

NMR spectrum :

6 »75 ppm: 5-proton of the thiazole ring triplet with center at 3» 58 ppm: -CH ₂ -Br-

J = 7 Hz

909840/0886

ORIGINAL INSPECTED

Step_B: N- [2- [LL2-Cc2-l) iphenylmethylcarbOxy-3-methyl-8-oxo-5-thia-1-azabicyclo | 4 · .2.0] oc t -2-en-7-yl I amino] -1- (2-tri tylaminothiazol-4-yl) -2-oxo ~
ethyl] imino] oxyethyl] pyridinium iodide

500 mg of the product obtained in step A and 1 l ^ rag pyridine hydroiodide are under InertabmoBphere in 5> mL L'yridLn was introduced.

After 15 h heating to 50 ⁰ C under vermindertetu pressure at a temperature below 40 ⁰ G einRedaiupfU.

It is then taken up again in methanol and four times in succession to remove the pyridine which has remained as a residue pumped out. After drying under reduced pressure, 620 mg of crude product are obtained; receive.

The purification is carried out by chromatography on silica using a chloroform-riebhanol mixture
(85:15) as an elution device.

3 ^ 8 mg of product are obtained in the form of a resin.

NMR Spectrum ((CD ^) ₂ SO):

6.81 ppm: 5-product of the thiazole ring

azabicycloj_4.2.o] oct-2-en-7-yH-aminoI-1- (2-aminothiazol-4-yl) -2-oxoethyl -imino] -oxy j äbhylj-pyridinium double salt (iodide and trifluoroacetate) _ ^ sjn isomer2__ . .

300 mg of the product obtained in stage B are mixed with 3 ml

/ HBBS

ORIGINAL INSPECTED

- 23ß- '912821

pure trifluoroacetic acid added. The solution is 3 min stirred at room temperature and then cooled in an ice bath for 20 s.

Then it is ^{precipitated by adding 1} \ 0 ml of a Ί: 1 mixture of isopropyluther and I'mUo Lather (bp between 65 and 75 ° C); After the precipitate obtained has slipped off, it is washed with isopropyl ether and then with ethyl ether and dried.

E3 ¹ mg of fiLne3 powders are obtained. E '. ~ 222 ° G. K _f = C), 05 (EnaLKoüiire-iithylacel.ab-Vaaser 70: 35: '10).

ti ν-S ρ akb film (ti / IC) HUL in ÄbhauoL): HaKLinuni JbO um KJ = - ■ 3 ^r > 5

IR-Hpekbru m:

ß-Lncbam. ! ^r / 6B cm " ¹

O = N-OtJ 10. ^ fI cm "' ¹

NMli-Spect.riiüi ((CJI) /). £ 0):

6.76 ppm: ^£ > -Probori den 'Phiazo Lfings

Example ^ l : 3-Aceboxymethyl-7- [[2- (2-amLnobhiazol-4-yL) - £. ⁾ - | J (2- (liraebliyLanii.noäl; hoxy) -iinino] -acety L am int)] -ceph-i-em - ^ - carboxylic acid-trL Cluoracie- tfib (syn-Iaomer)

- (2-1) LrntibhyLarainoäthoxy LmLno) -2- ( d-hν Lbyl-

! i Π ^; ) [) '■ Π f Π?} 3 5

- 239- ²⁹ I ²⁸

aminothiazol-4-yl) -acetic acid-hydro; iodide

120 ml of a chloroform-dimethylamine mixture (9: 1) and 10 g 2- (2-iodoethoxyimino) -2- (2-tritylaminothiazol-4-yl) ~ acetic acid (syn isomer) become about 3 h at tree temperature touched.

Thereafter, a temperature of 40 ⁰ G is evaporated to dryness and again added to 100 ml of isopropyl ether without exceeding. Then it is triturated, stirred for 15 min at room temperature, suction filtered and washed. Then it is taken up again in 50 ml acetone, refluxed for 5 min and then suction filtered and dried at room temperature, whereupon the solvents are evaporated off under reduced pressure.

9.33 g of product are obtained, which is taken up again in 46 ml of water, stirred, filtered off with suction and washed. It is then taken up again in 80 ml of acetone, stirred, suction filtered and dried under reduced pressure. F. 208 to 210 ⁰ C (with decomposition).

MMR spectrum (DqO

Triplet centered at 4.55 ppm: = N-0-CH ₂ -

J = 5 Hz

Singlet at 6.98 ppm: 5-proton of the thiazole ring Singlet at 7.33 ppm: -C0 ₃

UV spectrum (N / 10 HCl in ethanol): inflection point 270 nm E ^ »271

90984 07 088 * ORIGINAL INSPECTED

Maximum 275 nm E ^ > 280 £ = 14,000 inflection point 284 nm έΙ = 260

Stage JB: 3-Acetoxymethyl-7- | _ [2- (2-tritylaminothiazol-4-yl) -2 - ['(2-dimethylaminoethoxy) -iminq] -acetyl] aminoj-ceph ^ -em ^ -carboxylic acid-b enzhydryl e st er

1 g of the acid prepared in stage A is dissolved in a mixture of 15 ml of chloroform and 1.5 ml of methanol, whereupon 304 mg of triethylamine hydrochloride are added. After 5 minutes of heating to 60 ^° C., it is evaporated to dryness. After resuming in 15 'al of chloroform and cooled in an ice bath to 0 to +5 ⁰ C a PivaloylchloridlÖsung is treated dropwise with 2 ml was added, which had been prepared by filling of 1.25 g of pivaloyl chloride with chloroform in ml.

It is then allowed to warm to room temperature. After 2 h 1.1 g of 7-aminocephalosporanic acid benzhydryl ester are added.

After 1.5 h, the mixture is evaporated to dryness and chromatographed on silica using chloroform with 5% methanol as the eluent.

430 mg of the desired product are obtained.

909840/0886

Step e_C: 3-Acetoxymethyl-7- [[2- (2-aminothiazol-4-yl) -2-

[^ 2-dimethylaminoethoxy] -imino] -acetylj -aminoj c eph-3-e m-4-carboxylic acid e-t r i f luo r ac e t at (syn-I ε ο -

A mixture of 100 mg of the product obtained above in Step B with 1 ml of trifluoroacetic acid is made for 3 minutes at room temperature touched. Then it is precipitated with ether, taken up again in 0.2 ml of methanol and again through Addition of 2 ml of ether precipitated. After pasting with chloroform is suction filtered and with chloroform and then washed with ether.

40 mg of the desired product are obtained. F. 230 ⁰ C.

NMR spectrum

Singlet at 6.8 ppm: 5-proton of the thiazole ring

UV spectrum (ethanol):

Maximum 234 nm & \ = 305 ί = 15,600

Inflection point 254 nm E ^ = 247 £ = 12,650 inflection point 296 nm E ^ J = 103 t = 5,300

N / 10 HCl in ethanol:

Maximum 260 nm E ^ j = 279 £ = 14,300

Inflection point 276 nm έΙ = 243

SQ9840 / G88S

Example 42 : 3-Acetoxymethyl-7 - [[2- (2-aminothiazol-4-yl) -2- £ (2-pyridylethoxy) -iminoJ -acetyl] -aminoj ceph-J-em - ^ - carboxylic acid trifluoroacetate ( syn isomer) in the form of the inner pyridine salt

Stage_A: 2- (2-Tritylaminothiazol-4-yl) -2 - [(2-pyridyl-

ethoxy) -iminoj-acetic acid (syn isomer) in the form of the inner pyridinium salt

5 g of 2- (2-iodoethoxy) imino-2- (2-tritylaminothiazol-4-yl) acetic acid (syn isomer) in the form of the dichloroethane solvate (corresponding to an amount of pure substance of 4.27% as in Example 39) ^{) are heated to 60 0} O in 30 ml of pyridine for 24 h and then left to stand at room temperature for 56 h. After the precipitate formed is filtered off with suction, it is washed with pyridine and then with ether and dried.

1.66 g of product are obtained. F. 250 ⁰ C (with decomposition).

NflR spectrum (OD ^ COCDz, D ₂ O 1: 1):

6.8 ppm: 5-proton of the thiazole ring 7i5 to 8 ppm: pyridyl protons 4.58 to 5.08 ppm: = Ν-Ο-σΗ ₂ -0Η ₂

UV spectrum (N / 10 HCl in ethanol): maximum 260 nm έ \ = 324

909840 / 088S

IR spectrum (Nu (JoI):
CO ₂ "1639 cm" ¹
C = O 1583 cm " ¹
C * N 1523 cm " ¹

Stage B: 3-Aceto2ymethyl-7-rC ² - ( ² - ^> ' ^fcrit y ^laiaino ' ^{bl: iiazo} - ^L - ^{/ |} · yl) -2- (2-pyridylethoxyimino) -acetyl] -aminoj ceph-J- em ^ -carboxylic acid benzhydryl ester iodide

540 mg of the product obtained above, 210 mg of pyridinium iodide, 420 mg dicyclohexylcarbodiimide, 350 mg 7 ~ -Ä.mino-3-acetoxymethyl-ceph-3-em-4-carboxylic acid benzhydryl ester and 5 ml of anhydrous dimethylformamide are 20 min at room temperature touched. Thereafter, the precipitate formed clay dicyclohexyl urea is suction filtered and mixed with dimethylformamide washed, whereupon the filtrate is poured into 60 ml of ether will; a gummy substance is formed in the process. After stirring for 5 minutes at room temperature, it is decanted off and the supernatant removed. The gummy substance is reabsorbed in 60 ml of ether and rubbed in. To If the precipitate formed is observed, 754 mg of crude product are obtained.

The product is cleaned with 1.6 g of magnesium silicate for 20 minutes stirred in 7 »5 nil dichloroethane; after that it will insoluble material is suction filtered and washed with 0.5 ml of dichloroethane, whereupon the filtrate is evaporated to dryness will.

Ee 368 mg of the desired product are obtained.

909840/0886

- on -

Step e_C: 3-Acetoxymethyl-7- | _ [2- (2-aminothiazol-4-yl) -2 - [(2-pyridylethoxy) -imino] -acetyl] -amino] -ceph-3-

The 368 mg of the product obtained above are stirred in 3 ml of pure trifluoroacetic acid at room temperature for 3 minutes. After the insoluble fraction is quickly seen, the filtrate is mixed with 40 ml of ether for precipitation and stirred for 5 minutes, after which it is suction filtered and washed with ether. The hygroscopic product is taken up in 0.35 ml of methanol and precipitated by adding 4 ml of ether. After viewing and washing with ether, 140 mg of the desired product are obtained. F. 205 ⁰ C (with decomposition).

NMR spectrum (DHSO):
2.06 ppm: OAc

6.86 ppm: 5-piOton of the thiazole ring 8.9 Ms 9.1 ppm: 2-H and 6-H 8.55 to 8.78 ppm: 4-H
8.03 to 8.26 ppm: 3-H and 5-H

UV spectrum (N / 10 HCl in ethanol): maximum 260 nm e2 = 318

IR spectrum (Nu ^ oI):
β- lactam 1777 cm
OAc H74O cm "" ¹

ν \

309840 / Οδδδ

CO ₂ "1633 cm" ¹

O = NO-E 1037 cm "* ¹

Example 43 : 3-Acetoxymethyl-7-j_ [2- (2-aminotbiazol-4-yl) -2- [(2-imidazol-1-yl-ethoxy) -imino] -acetyl] amijioJ-ceph-3-em -4-carboxylic acid trifruorace tat (syn isomer)

Stage_A: 2- (2-Tritylaminothiazol-4-yl) -2- (2-imidazol-1 yl-etho2q5rimino) -acetic acid (syn isomer) in the form

3 g of 2- (2-tritylaminothiazol-4-yl) -2- (2- _t iodethoxyimino) acetic acid (syn isomer) in a form solvated with dichloroethane (corresponding to 2.56 g of the pure compound), 4.2 g of imidazole and 10 ml of dimetbylacetamide are 3 h. stirred at room temperature. A further 10 ml of dimethylacetamide are then added, whereupon stirring is continued for 40 hours at room temperature. It is then poured into 200 ml of isopropyl ether, stirred for 30 minutes and allowed to decant, whereupon the supernatant is removed and the gummy substance thus obtained is taken up in 200 ml of isopropyl ether and stirred therein; this treatment is repeated with 300 ml of diethyl ether. After stirring for 30 minutes, suction is filtered off, washed with ether, taken up in 30 ml of acetone, stirred for 1 h, suction filtered, washed with acetone and then with ether and dried, whereupon 1.243 g of product are obtained. F. 280 ⁰ C (with decomposition).

909840/0886

- 2A6 -

NMR spectrum (DMSO):

4-135 PP ^m : N ^ O-CH ₂ -CH ₂ -N ^

6.8 ppm: 5-PiOtOn of the thiazole ring

7.82 ppm:

II

UV spectrum (N / 10 HCl in ethanol): maximum 277 um E ^] = 259

IR spectrum (Nujöl):

-1

CO ₂ 161 ^ cm

I chromate oscillations 1492 cm Heterocycle oscillations 1527 cm

Step e_B: 3-Acetoxymethyl-7- [[2- (2-tritylaminotniazol-4-yl) -2 - [(2-imidazol-1-yl-ethoxy) -iminoJ acetyl]

780 mg of the product obtained above, 3 ^ 5 mg of pyridine hydroiodide, 630 mg dicyclohexylcarbodiimide, 600 mg 7-amino-J-acetoxymethyl-ceph-J-em - ^ - carboxylic acid benzhydryiester and 6 ml of anhydrous dimethylformamide are stirred vigorously in an ice bath, during which dicyclohexylurea precipitates. After warming to room temperature, the mixture is stirred for a further 20 minutes. Then the insoluble part is sucked off and washed with dimethylformamide. The filtrate becomes

0/0888

120 ml of ether are added to the precipitation. Tray and stir for 20 min Allowing to decant, the supernatant is removed and the gummy substance obtained is taken up again in 100 ml of ether and rubbed in it. After stirring for 10 minutes at room temperature, the product is filtered off with suction, washed with ether and dried, whereupon 1.3 g of product are obtained, which is silica using an ethyl acetate-ethanol-water mixture (8: 1: 0.5) is chromatographed as the eluent.

332 mg of the desired product are obtained.

MMR spectrum (CDCl ₂ ):
2 ppm: OAc
6> 75 ppm: 5-proton of the thiazole ring (syn)

IR spectrum

ß- lactam 1788 cm

Ester and OAc 1759 cm

Het ero cyclus oscillations 1525

Step_C: 3-Acetoxymethyl-7 - [[2- (2-aminothiazol- ^ - yl) -2-C (2-imidazol-1-yl-ethoxy) -iminol-acetyl] -aminoJ-ceph ^ -em- ^ -carboxylic acid trifluoroacetate

230 mg of the product obtained above and 2 ml of pure rifluoroacetic acid are stirred for 3 min at room temperature. The solution obtained is then dissolved in an isopropyl ether-diethyl ether mixture (1: 1) poured in and 20 min at

909840/0888

Stirred at room temperature; then the precipitate formed is removed, washed with diethyl ether, in 0.4 ml Methanol was taken up again and again with 4 ml of diethyl ether failed; After stirring for 10 min at room temperature, it is suction filtered, washed with Ither and dried.

140 mg of the desired product are obtained. P. 205 ⁰ G (with decomposition).

HMR spectrum (DMSO):
2.03 ppm: OAc
6.8 ppm: 5-proton of the thiazole ring (syn)

7.66 and 7.71 ppm: 4-H and 5-H)

) des imidazole 8.95 ppm: 2-H)

UV spectrum (IT / 10 HCl in ethanol): maximum 260 nm έ \ = 271

Example 44 : 3-Acetoxymethyl-7 - [[2- (2-aminothiazol-4-yl) 2- U (ethooqycarbonyloxy) -iminoj -acetyl] aminoj-c eph-3-em-4-carboxylic acid trifluoroacetate ( syn isomer)

Stage_A: Diethylamine salt of 3-acetoxymethyl-7 - [[2- (2-tritylaminothiazol-4-yl) -2- [(ethoxycarbonyloxy) iminoj -acetyl] -aminoj -ceph ^ -em ^ -carboxylic acid

1 * 67 g 3-aceto3cymethyl-7 - [[2- (2-tritylaminothiazol-4-yl) -

909840 / 088S

291282:

2-hydroxyiminoacetyl] -aminoJ-ceph ^ -em ^ -carboxylic acid (syn isomer) are dissolved in 25 ml of methylene chloride and 0.37 ml of pyridine while stirring and under an inert atmosphere. The solution is cooled in an ice bath. Then, a 2.7 min "VM ml solution of ethyl chloroformate in methylene chloride was added over 5. After 10 a temperature between 0 and +5 C ⁰ min 20 ml of water and 2.7 ml of 1 N hydrochloric acid are added while maintaining. After stirring The organic phase is washed with water until neutral and dried. The solvent is then distilled off under reduced pressure and the residue is taken up in 10 ml of ethyl acetate and treated with 0.23 ml of diethylamine. The diethylamine salt precipitates after the addition of 10 ml of isopropyl ether After suction filtration, it is washed with an isopropyl ether-ethyl acetate mixture (1: 1) and then with isopropyl ether.

1.60 g of product are obtained in 5 ml of methylene chloride and 10 ml of ethyl acetate is dissolved. Then under reduced pressure to a final volume of c «6 ml concentrated and diluted with 5 ml of isopropyl ether. After this Filtering off with suction and washing as above, 1.47 g of product are obtained.

NMR spectrum (CDCl ^):
2.03 ppm: OAc

695 ppm: 5-piOton of the thiazole ring 7 »66 ppm: protons of the trityl group 4.13-4.25-4.36-4.48 ppm: CH _{2 of} the group CO ₂ Et

909840/0886

- $. 50-

2312823

A-

IR spectrum (CHCl,);

-Lactam I78I cm
OAc 1740 cm "" ¹
Amid 1694 cm " ¹
COo "1634 cm" ¹

Stage_B: 3-acetoxymethyl-7- [[2- (2-aminothiazol-4-yl) -2 - [(ethoxycarbonyloxy) -imino] -acetyl] -amino] ceph-3-em-4-carboxylic acid trifluoroacetate

1.43 6 of the product obtained above and 5 »7 tnl trifluoroacetic acid are stirred for 20 min at room temperature. Then 57 nil isopropyl ether are quickly added, whereupon stirred for 15 min, suction filtered and with isopropyl ether is washed.

1.04 g of crude product are obtained, which is dissolved in 4 ml of acetone with 1 % water. Thereafter, 12 ml of ither are added for precipitation, whereupon 0.69 g of the desired product are obtained.

A further 0.11 g of identical product are obtained from the mother liquors.

Example 45 : Sodium salt of 3-acetoxymethyl-7- [[2- (2-aminothiazο1-4-yl) -2 - [(ethoxycarbonyloxy) imino] -acetylj -aminoj -ceph-3-em-4-carboxylic acid (syn -Isomer)

0.8 g of the product obtained above are in 4 ml of a

909840/0886

- # 54-

1 M solution of sodium acetate dissolved in methanol and 2 ml of methanol. The solution is treated with activated charcoal, diluted with 20 ml of anhydrous ethanol and then ^{concentrated by distillation under reduced pressure at a maximum of 30 °} C. to a final volume of 10 ml. The resulting precipitate is filtered off with suction and washed with ethanol and then with ether, whereupon # 20 mg of product are obtained.

580 mg of the product prepared as above are taken up in 5 »8 ml of methanol, and 1.2 ml of ethanol are slowly added while stirring. After the precipitate formed has been removed, the filtrate is diluted with 10 ml of ethanol and then ^{concentrated by distillation under reduced pressure at a maximum of 30 °} C. to a final volume of 5 ml. After sniffing and washing with ether, 460 mg of product are obtained, which is treated again as above, whereupon 4-20 mg of the desired product are finally isolated.

NMR spectrum (DMSO):

" ¹ » ' ¹ 3 - 1.25 - 1.36 ppm; ") Protons of the group

} CO ₀ Et 4.03-4.16- #, 28-4.4- ppm:) ^

1.98 ppm: OAc

7.03 ppm: 5-proton of the thiazole ring

UV spectrum (N / 10 HGl in ethanol):

Maximum 259 nm E ^ j = 324 £ = 17,350

Inflection point 278 nm E ^ j = 252

90984G / 088S

IR spectrum (Nujol):

β- lactam 1763 cm " ¹
OAc 1726 cm " ¹
CO ₂ "1609 cm" ¹
1038 cm " ¹

Example 46 : 3-Acetoxymethyl-7- [[2- (2-aminothiazol-4-yl) .2 - [(2-morpholinoethoxy) -imino] -acetylJaminoj -ceph ^ -em - ^ - carboxylic acid (syn-isomer ) in the form of the inner salt

Aj. 2- (2-Tri1; ylaminothiazol-4-yl) -2- (2-morphplinoethoxy) -imino-acetic acid (syn-isomer) in the form of the_inner_salt

2 g of 2- (2-tritylaminothiazol- ^ yl) -2- (2-iodoethoxy) -iminoacetic acid (syn isomer) in the form of dichloroethane solvate (corresponding to 1.71 g of the pure compound) in 7 ml Dissolved morpholine. The solution is stirred for 1 h at room temperature and then evaporated under a stream of nitrogen. Then it is taken up again in 30 ml of ethyl acetate, Stirred for 20 min at room temperature, suction filtered and washed with ethyl acetate. The product is 15 min in 15 ml of dimethoxypropane stirred, then suction filtered and washed with the same solvent. Then in 15 ml of ether taken up again, stirred for 15 min, suction filtered and washed with ether, whereupon 2.3 g of product are obtained. M.p. 180 ° 0 (with decomposition).

909840/0886

- Q53-

2912823

The product obtained is in the form obtained for the next level used.

100 mg of this product are purified by recrystallization in 0.5 ml of ethanol, 46 mg of recrystallized product being obtained. F. 182 to 184 ⁰ O (with decomposition).

NMR spectrum (CDOL,)

7 »33 ppm: protons of the trityl group 6» 75 ppm: 5-proton of the thiazole ring

trV spectrum (N / 10 HOl in ethanol): maximum 276 nm E ^ = 172

IR spectrum ^

CO ₂ "and aromatic vibrations 1606, 1529 and 1495 cm" ¹ -NH 3399 cm " ¹

Stage_B | _ B-Acetoxymethyl-V- [2- (2-tritylaminothiazol-4-yl) -2- (J2-morpholinoethoxy) -iminoj -acetyl] aInino-ceph-3-em-4-carboxylic acid benzhydryl ester-

1 g of the product obtained above, 0.38 g of pyridine hydroiodide, 0.63 g of dicyclohexylcarbodiimide and 0.60 g of 3-acetoxymethyl-7-amino-ceph-3-em-4-carboxylic acid benzhydryl ester are dissolved in 5 ml of anhydrous dimethylformamide. The solution is stirred for 30 minutes at room temperature. After that, the educated Dicyclohexylurea suction filtered and the filtrate with 100 ml of ether added. After stirring for 10 min, suction is performed,

909840 / 088S

Washed with ether and on silica using an ethyl acetate-ethanol mixture (7 s Ό as the eluent chromatographed

0.524 g of product are obtained. M.p. 167 ° C (with decomposition).

HMR spectrum (CDCl,):
2.03 ppm: OAc
3.72 ppm: CH ₂ O
⁶ »75 ppm: 5-proton of the thiazole ring (

OT spectrum (N / 10 HCl in ethanol): maximum 268 nm E ^ J = 165 £ - ^ 5

IR spectrum (CHCl ^):

^ -Lactam I791 cm " ¹
Ester and OAc 1740 cm
Amid 1678 cm " ¹

Stage_C: 3-acetoxymethyl-7 - [[2- (2-aminothiazol-4-yl) -2-C (2-morpholinoethO3q7 -) - imino] -acetylj -aminoj ceph-3-em- "4-carboxylic acid (syn isomer) in the form of

0.42 g of the product obtained in step B and 3 ml of trifluoroacetic acid are stirred for 2 min at room temperature, whereupon the insoluble fraction is suction filtered and trifluoroacetic acid is washed. The filtrate is in 30 ml of ether

9098 ^ 0/0886

taken up and stirred for 15 min at room temperature. The precipitate formed is then filtered off with suction, washed with ether, dissolved in 0.5 ml of methanol and precipitated again by adding 5 ml of Ither. After stirring for 5 min and filtering with suction, 208 mg of the product are obtained as a salt with trifluoroacetic acid. F. 212 to 214 ⁰ C (with decomposition).

HMR spectrum (DMBO):
2.05 ppm: OAc
3.1? up to 4.66 ppm: CH ₂ -N and CH ₃ O

6.85 ppm: 5-PrOtOn of the thiazole ring (syn)

W spectrum (ΪΓ / 10 HCl in ethanol):

253

Maximum 260 nm 1797 E ₁ IR spectrum (CHCl ₂ ): 1634 β- lactam 1667 cm ~ CO ₂ " cm- Amide cm""

Example 47 : 3-Aceto3q5rmethyl-7-J ^ [2- (2-aminothiazol-4-yl) - 2- [2- (4-methylpiperazin-1-yl) -etho3; yJ -imino] acetylaminoj -ceph ^ - em - ^ - carboxylic acid trifluoroacetate (syn isomer) in the form of the inner salt

Step e_A: 2- (2-Tritylaminothiazol-4-yl) -2- [2- (4-methyl-

909840/0886

piperazin-1-yl) -etho: xyimino] -acetic acid (syn-isomer2_in_form_des__inneren_salzes

2.22 g of N-methylpiperazine in 15 ml of dioxane and 3j325 g of 2- (2- (dritylaminothiazol-4-yl) -2- (2-; iodoethoxy) -im: ino-acetic acid (syn- Isomer) in the form of the solvate with dichloroethane (corresponding to 2.84 g of the pure substance) are vigorously stirred for 16 hours at room temperature ml of isopropyl ether is added and the mixture is stirred for 30 min. The product is then suction filtered and the product is taken up in 10 ml dimethoxypropane; after stirring and suction for 30 min, it is taken up again in ml of water, stirred for 10 min and then suction filtered again. The insoluble material is poured twice in 100 ml an isopropyl ether-diethyl-g-emischs (1: 1). triturated and recrystallized in 100% ethanol are obtained 1.47 g of product F. 220 ⁰ C (with decomposition)..

HMR spectrum (CDCl ^):
2.52 ppm: -

3.0 ppm: CH ₂ N

6.7 ppm: 5-pi "oton of the thiazole ring

W-fi spectrum (N / 10 HOl in ethanol): maximum 277 nm E ^ j - 257 £ _s 14,300

909840 / 088S

-ζ * - 291282

IR spectrum (Nu ^ oI):

CO ₂ "" 1602 cm "" ¹

Heterocycle _{oscillation- Λ}
gung I529 cm "

CO ₂ H (missing)

Stage β JB: 3-acetoxymethyl-7- [T [2 - (2-tritylaminotliiazol-4-yl) -2- £ 2 - (^ Hoaethylpiperazin-1-yl) ethoxy] -iminoj acetylaainoj-ceph ^ -em- ^ carbonsätire-benz-

560 mg of the product obtained above and 140 mg of triethylamine hydrochloride are ^{heated to 60 °} C. for 10 minutes in 5 ml of chloroform and 5 ml of methanol; then the solvents are evaporated off under reduced pressure. The residue is taken up in 20 ml methylene chloride and cooled to -20 ⁰ C. Thereafter, 1 ml of a 12.5% solution of pivaloyl chloride in methylene chloride is added over the course of 10 minutes and the mixture is stirred at room temperature for 1 hour. Thereafter, the solution is cooled to -10 ⁰ C and in one portion with 550 mg p-Amino-i-acetosymethyl-ceph-J-eni - ^ - carboxylic acid benzhydryl ester was added. Thereafter, it is stirred 3 h and then evaporated under reduced pressure at 30 ⁰ C höchstesn to dryness. The residue is taken up in 50 ml of a benzene-ethyl acetate mixture (8: 2). The insoluble fraction is separated off and the solution is evaporated to dryness under reduced pressure. The residue is taken up in 25 ml of dichloroethane, 1.5 6 activated magnesium silicate is added and the mixture is stirred for 30 minutes. It is then filtered off with suction and washed with dichloroethane;

90984Π / 0886

-252-

the filtrate is under reduced pressure at a maximum of 30 ⁰ C e:

fall.

Evaporated to 30 ⁰ C, after which 870 mg of a white resin

NMR spectrum (CDCl,):

2.02 to 2.03 ppm: OAc

6.87 ppm: 5-proton of the thiazole ring

2.45 ppm: N-CH ₅

UV spectrum (N / 10 HCl in ethanol):

Maximum 267 to 268 nm £ * 14,700

Stage_C: 3-acetoxymethyl-7 - [[2- (2-aminothiazol-4-yl) -2- [2-

(4-methylpiperazin-1-yl) -etho3? YJ -iminoj acetylaminoJ-ceph-3-em-4-carboxylic acid-trifluoro-

524 mg of the product obtained above are dissolved in 3 ml of pure trifluoroacetic acid, whereupon the solution is stirred for 1 min at room temperature. Thereafter, by adding 30 ml Isopropylather and 5 ^m in precipitated and filtered off under suction, followed by 320 mg of incurred a hygroscopic product which is dissolved in 1 ml of methanol and precipitated by addition of 10 ml of diethyl ether; then it is stirred for 5 minutes, suction filtered, washed with diethyl ether and made into a paste with chloroform and then with ether, whereupon 220 mg of the salt (trifluoroacetate) are obtained. P. 245 ° C.

909840/0886

- ■■ 659 -.--

- 291282!

MMR spectrum (UMSO):
2.05 ppm: OAc
2.75 to 3.67 ppm: ₂

6.78 ppm: 5-proton of the thiazole ring

UV spectrum (M / 10 HCl in ethanol): maximum 262 nm £ r 14,200

IR spectrum (Nujol):

.-1

β- lactam 1773 cm "

OAc 1726 cm "" ¹

CO ₂ "1627 cm" ¹

C = NO- 1035 cm " ¹

Example 48 : 3-Acetoxymeth3rl-7- [2- (2-aminothia2iol-4-7l) -2- (2-aminoethoxyimino) -acetamidoj-ceph-3-em-4-carboxylic acid bis-trifluoroacetate (syn isomer)

A: 2- (2-Tritylaminoethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetic acid (syn isomer)

g tritylamine, 50 g 2- (2-BromoätliO3q5rimino) -2- (2-tritylaminothiazol-4-yl) -acetic acid ethyl ester and 100 ml bimetnyl sulfoxide are mixed under argon.

The suspension is ^{stirred at 60 °} C. for 82 h. It is then allowed to cool to room temperature and by adding the

909840/0886

ten times the volume of water precipitated. After removing it and washing it with water, the precipitate obtained is dissolved in 1 l of chloroform and washed first with water and then with a saturated NaCl solution. After drying, is evaporated under reduced pressure at a temperature below 40 ⁰ C. The crude product is taken up again in a mixture of 320 ml of dioxane, 2 liters of absolute ethanol and 200 ml of 2 N NaOH, stirred for 24 hours at room temperature and then evaporated to dryness under reduced pressure at a temperature of -40 ° C.

The product is mixed five times with 60 ml each of a dioxane-ethanol mixture (1: 7) made into a paste and taken up in a mixture of 1 liter of chloroform and 1 liter of water.

An amount of 1N hydrochloric acid sufficient to adjust the pH to 2 is added with stirring. After decanting off the organic phase, it is washed first with water and then with a saturated NaCl solution. Then it is evaporated and dried under reduced pressure at a temperature below 40 ⁰ C to dryness. The product obtained is suspended in 300 ml of dichloroethane and heated for 15 min at 50 ⁰ C. After returning to room temperature, it is dried under a slight vacuum. Then it is washed with dichloroethane, then with isopropyl ether and finally with diet hy lather and dried to constant weight.

40 g of powder are obtained. P. 176 ⁰ C.

NMR spectrum

¹¹¹ '•

6.68 ppm: 5-proton of the thiazole ring 2.95 ppm: CH ₂ -N

909840/0886

- 291282!

Stage_B: Esters of 2- (2-tritylaminoethoxyimino) -2- (2-tritylaminothiazol-4 ~ yl) ~ acetic acid with hydroxy

6.97 g of the acid obtained in stage A and 1.54 g of hydroxybenzotriazole are introduced into 35 ml of methylene chloride. It is then stirred in an ice bath and added dropwise with a solution of 2.44 g of dicyclohexylcarbodiimide in 35 ml Methylene chloride added.

It is then allowed to rewarm to room temperature and Stirred for 3.5 h, after which the dicyclohexylurea formed is suction filtered and washed with methylene chloride. That The filtrate is first made with sodium hydrogen carbonate, then with Water and finally with a saturated FaCl solution washed. It is then dried and evaporated to dryness under reduced pressure.

The resinous product obtained is dissolved in 50 ml of isopropyl ether resumed and vigorously for 1 h at room temperature touched. Thereafter, the resulting precipitate is filtered off with suction, washed with isopropyl ether and up to wt cht constancy dried.

8.046 g of product are obtained. F. 150 to 152 ° 0 (under Decomposition).

HMR spectrum ^

6.68 ppm: 5 - Pi ¹ OtOn des Thiazolx'ing 2.36 ppm: -CH ₂ -N

90 9 8 40/0886

ÜG2

Step e_C: 3-Acet03qsrmethyl-7-j ^ 2- (2-tritylaminoethoxyimino) 2- (2-tritylaminothi az ol-4-yl) -acet amido] -ceph-3-

H > 55 S of the activated ester prepared in stage B and the equivalent amount of 7.65 g of 7-aminocephalosporanic acid diphenylmethyl ester are introduced into 75 ml of methylene chloride. After stirring for 18 h at room temperature, the mixture is evaporated under reduced pressure and chromatographed on silica under pressure using a benzene-ethyl acetate mixture (85:15) as the eluent.

9.1 g of the desired product are obtained.

Step_D: 3-Aceto2ymethyl-7- [2- (2-aminothiazol-4-yl) -2- (2-aminoethoaqyimino) -acetamidoj -

186 mg of the J-acetoxymethyl ^ - Γ 2- (2-tritylaminothiazol-4-yl) -2- (2-tritylaminoethoxyimino) -acetamidoj -ceph ^ -em - ^ - diphenylmethyl ester prepared in stage C are in 1.8 ml of pure trifluoroacetic acid introduced. The yellow solution obtained is stirred for 3 min at room temperature and then in an inert atmosphere in an ice-water bath and then quickly mixed with 18 ml of isopropyl ether. After 10 minutes of stirring, removal of the watch, washing with isopropyl ether and then with diethyl ether and drying, 100 mg of a white powder are obtained. Έ, about 210 ⁰ C (with decomposition).

909840/0886

Example 49 : Composable compositions

Injectable compositions were made of the following formulation manufactured:

A - 3-yy7 (y) 2- (2-aminoethoxyimino) -acet amidoj-c eph-3-em-4-carboxylic acid (syn isomer) 500 mg

- aqueous, sterile excipient ad 5 ml

B -3-Acetoxymetbyl-7 - [[2- (2-aminothiazol-4-yl) -2-acetoxyimino] -acetyl] -amino-ceph-J-em- ^ carboxylic acid (syn isomer) 500 mg

- aqueous, sterile excipient ad 5 ml

Example 50 : Gelatin Capsules

Gelatin capsules of the following formulation were produced:

- 3-acetoxymethyl-7-r2- (2-aminothiazol-4-yl) -2- ( 2-aminoethoxyimino) -ac et amidoj-ceph-3-em-4-carboxylic acid (syn isomer) 250 mg

- Exöipiens on a capsule ad 400 mg

Example 5 ^ : Injectable Compositions

The following formulation were injectable compositions manufactured:

909840/0886

A - Sodium salt of 3-acetoxymethyl-7- £ [2-Q (2-bromoethoxy) -imino] -2- (2-aminothiazol-4-yl) -acetyl] -aminoj -ceph-3-em-4-cart > onsätu? e (syn isomer) 500 mg

- aqueous, sterile excipient ad 5 ml

B _ 3 - [(1-methyl-1.2.3.4-tetrazol-5-yl) thiomethyl-7 - [] 2- [; (2-aminoetho: jqr) -imino] -2- (2-aminothiazol-4-yl) -acetyl] -aminoj -ceph-3-em-4-carbonate (syn isomer) 500 mg

- aqueous, sterile excipient ad 5 ml - 3-Acetoxymetnyl-7-r | "2-r (2-Jodäthoxy) -iminq] -

_ - i

2- (2-aminotiiiazol-4-yl) -acetylJ -aminoj ceph ^ -em - ^ - carboxylic acid trifluoroacetate

(syn isomer). 500 ml

- Aqueous, sterile excipient ad 5 "ol

Example 52 ; Gelatin capsules

Gelatin capsules were produced with the following formulation :

- 3 - [(1-Methyl-1.2.3.4-tetrazol-5-yl) -thiomethyl-7- [2 - [(2-aminoethoxy) -imino] -2- (2-aminothiazol-4-yl) -acetyl] -aminoj -ceph-3-em-4-carboxylic acid (syn isomer) 250 mg

- Excipiens on a capsule ad 400 mg

909840/0886

Example 53 : Injectable Compositions

Injectable compositions of the following formulation were prepared:

A - 3-Acetoxymethyl-7 ~ [[2- (2-aminothiazol-4-yl) -2 - [(2-imidazol-1-yl-ethoxy) -imino-3-acetyl] -aminoj -ceph ^ -em - ^ - carboxylic acid (syn isomer) 500 mg

- aqueous, sterile excipient ad 5 ml '

B - sodium salt of 3-aceto: qyTnetliyl-7 - [_ [2- (2-aminothiazol-4 ~ yl) -2 ~ [(2-ethoxycarbonyl- oxy) -iminoj -acetyl] -aminoj ~ ceph-3-em-4-

carboxylic acid (syn isomer). 500 rag

- aqueous, sterile excipient ad 5 ml

Example 5 ^ i gelatin capsules

Gelatin capsules of the following formulation were produced:

- Sodium salt of 3-aceto2ymethyl-7 - [[2- (2-aminothiazol-4-yl) -2 - \ _ (2-ethoxycarbonyoxy) imino.] -Acetyl] -aminoj -ceph-3-em-4 ~ carbon-

acid (syn isomer) 250 mg

- Excipiens on a capsule ad 400 mg

909840/0886

291282S

Pharmacological investigation of the compounds according to the invention

Effectiveness in vitro

Method of dilution in a liquid medium, etc.

In this method, a number of tubes are prepared, each with the same amount of sterile culture medium is distributed · Subsequently, increasing amounts of the the product to be examined is distributed to the individual tubes, whereupon each tube is inoculated with a bacterial strain will.

After incubation for 24 or 48 h in the incubator at 37 ⁰ C, the inhibition of the bacterial growth is estimated by candling, whereby the minimum inhibitory concentrations (CiMi) of the product LL g can be determined ml /.

The following results were obtained:

909840/0886

Compound of Example 22

tribe CKE C / zg / ml) 48 h Staphylococcus auretis AIDCC 6 538,
Penicillin sensitive 24 hours 1 Staphylococcus aureus UC "1 128,
Penicillin-resistant 0.5 1 Staphylococcus aureus Erp, ffr. 54-146 1 1 Streptococcus pyogenes A 561 1 c 0.02 Streptococous faecalis 5 432 < 0.02 10 Streptococcus faecalis 99 F 74 2 > 40 Bacillus subtilis ATCC 6 633 10 1 Escherichia CoIi ATCC 9 637,
Tetracycline sensitive 0.2 1 Escherichia CoIi AICC 11 303,
Tetracycline resistant 1 0.2 Escherichia CoIi Exp. S ^ gBg 0.2 0.5 Escherichia CoIi E 55 123 D,
Gentamycin resistant,
lobrasnycin resistant 0.5 0.5 Elebsiella pneumoniae Exp. 52 145 0.5 0.5 Klebsiella pneumoniae 2 536,
Grentamycin resistant 0.2 2 Proteus mirabilis (indole -) A 235 2 0.2 Salmonella typhimurium 420 0.2 2 Enterobacter cloacae 681 1 10 Providencia Du 48 5 5 Serratia 2532, gentamycin resistant 5 5 5

909840/0886

~ 268-

Connection of example

tribe CMI (yug / ml) 48 h Staphylococcus aureus ATCG 6 538,
Penicillin sensitive 24 hours 1 Staphylococcus aureus UC 1 128,
Penicillin Resistant 1 1 Staphylococcus aureus Erp. Mr. 54 146 1 1 Streptococcus pyogenes A 561 1 <0.02 Streptococcus faecalis 5 432 <0.02 20th Streptococcus faecalis 99 P 74 2 10 Bacillus subtilis ATCC 6 633 10 0.5 Escherichia CoIi AOJCC 9 637,
Tetracycline sensitive 0.5 2 Escherichia CoIi AO) CC 11 303,
Tetracycline resistant 2 1 Escherichia Coil Exp.TOoiA
CD O 1 3 Escherichia CoIi R 55 123 D,
Gentamycin resistant,
Tobramycin resistant 2 2 Klebsieila pneumoniae Exp. 52 145 1 1 Klebsiella pneumoniae 2 536,
Gentamycin resistant 1 10 Proteus mirabilis (indole -) A 235 10 1 Salmonella typhimurium 420 1 3 Providencia Du 48 2 20th Serratia 2532, gentamycin resistant 20th 10 10

909840/0886

- & 9γ-

Compound of Example 26

tribe Cm (^ u.g / ml) 48 h Staphylococcus aureus AiDOC 6 538,
Penicillin sensitive. 24 hours 2 Staphylococcus aureus UC 1 128,
Penicillin Resistant 2 2 Staphylococcus aureus Exp. No. 54 146 2 2 Streptococcus pyogenes A 561 2 <0.02 Streptococcus faecalis 5 4-32 SUN, 02 > 40 Streptococcus faecalis 99 P 74 3 > 40 Bacillus subtilis ATCC 6 633 10 1 Escherichia CoIi ATCC 9 637,
Tetracycline sensitive. 1 2 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 2 2 Escherichia CoIi Exp.TOo ₆ Bg 1 2 Escherichia CoIi E 55 123 D,
Gentamycin resistant
Tobramycin resistant CVJ 2 Klebsiella pneumoniae Exp. 52 145 1 1 Klebsiella pneumoniae 2 536,
Gentamycin resistant 1 5 Proteus mirabilis (indole -) A 235 5 0.5 Salmonella typhimurium 420 0.5 2 Providencia Du 48 2 40 Serratia 2532, gentamycin resistant 40 10 10

909840/0886

2912823

Compound of Example 28

tribe CMI (/ Ug / ml) 48 h Staphylococcus aureus ATGC 6 538 »
Penicillin sensitive 24 hours 1 Staphylococcus aureus UC 1 128,
Penicillin Resistant o, 5 1 Staphylococcus aureus Exp. Mr. 5 ^ 146 1 1 Streptococcus pyogenes A 561 1 <0.02 Bacillus subtilis ATCC 6 633 ' <0.02 2 Escherichia CoIi ATCC 9 637,
Tetracycline sensitive 1 3 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 3 1 Escherichia CoIi Exp. TO ₂₆ Bg 1 2 Escherichia CoIi R 55 123 D,
Gentamycin resistant
Tobramycin resistant 2 2 Elebsiella pneuraoniae Exp. 52 145 2 1 Klebsiella pneumoniae 2 536,
Gentamycin resistant 1 10 Proteus mirabilis (indole -) A 235 10 ' 1 Salmonella typhimurium 420 1 2 Enterobacter cloacae 681 2 20th Providencia Du 48 20th 20th Serratia 2532, gentamycin resistant 10 5 5

909840/0886

Compound of Example 30

tribe CMI (/ Jg / ml) 48 h Staphylococcus aureus ATCC 6 538 »
Penicillin sensitive 24 hours 2 Staphylococcus aureus TJC 128,
Penicillin Resistant 2 2 Staphylococcus aureus Exp. No. 54 146 2 2 Streptococcus pyogenes A 561 2 0.05 Bacillus subtilis ATCC 6,635 0.05 1 Escherichia CoIi ATCC 9 637,
Tetracycline sensitive 1 5 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 5 2 Escherichia CoIi Exp.TOg ^ Bg 2 3 Escherichia CoIi R 55 123 D,
Gentamycin resistant
Tobramycin resistant 3 3 Klebsieila pneumoniae Exp. 52 145 3 1 Klebsiella pneumoniae 2 536,
Gentamycin resistant 1 20th Proteus airabilis <indole -) A 235 20th 2 Salmonella typhimurium 420 2 5 Providencia Du 48 3 20th Serratia 2532, gentamycin resistant 20th 10 5

909840/0886

-SW-

Link"; from Example 31

tribe CMI (μ. G / ml) 48 h Staphylococcus aureus ATCC 6 538,
Penicillin sensitive 24 hours 2 Staphylococcus aureue UC 1 128,
Penicillin Resistant 2 2 · Staphylococcus aureus Exp. No. 5 ^ 146 2 2 Streptococcus pyogenes A 561 2 <0.02 Streptococcus faecalis 5 4-32 <0.02 40 Bacillus subtilis ATCC 6 633 3 3 Esclierichia CoIi ATCC 9 637,
Tetracycline sensitive 2 3 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 3 3 Escherichia CoIi Exp. TO ₂₆ Bg 3 2 Escherichia CoIi R 55 123 D,
Gentamycin-resistant
Tobramycin resistant 2 2 Kleiella pneumoniae Exp. 52 145 2 0.5 Klebsieila pneumoniae 2 536,
Gentamycin resistant 0.5 10 Proteus mirabilis (indole -) A 235 10 1 Salmonella typhimurium 420 1 2 Providencia Du 48 2 20th Serratia 2532, gentamycin resistant 20th 5 3

909840/0888

- zn-

-257 -

Connection of example

tribe CMI (/ Xg / ral) 48 h Staphylococcus aureus ATCC 6 538,
Penicillin sensitive 24 hours 2 Staphylococcus aureus UC 1 128,
Penicillin Resistant 2 2 Staphylococcus aureus Έχρ. No. 54 146 2 2 Streptococcus pyogenes A 561 2 0.05 Streptococcus faecalis 5 432 0.05 40 Bacillus subtilis ATCC 6 633 3 2 Escherichia CoIi ATCC 9 637,
Tetracycline sensitive 2 2 Escherichia CoIi ATCC 11 3O3 ₉
Tetracycline resistant 1 0.5 Escherichia CoIi Exp.TQ _oa B (- 0.5 1 Escherichia CoIi E 55 123 D,
Gentamycin resistant
Tobramycin-re si st ent 1 1 Klebsiella pneumoniae Exp. 52 145 1 0.5 Klebsiella pneumoniae 2 536,
Gentamycin resistant 0.1 3 Proteus mirabilis (indole -) A 235 2 0.2 Salmonella typhimurium 420 0.2 1 Providencia Du 48 1 5 Serratia 2532, gentamycin resistant 5 3 2

909840/0886

Connection of example 3?

tribe CMI (/ X g / ml) 48 h Staphylococcus aureus JUCCC 6 538,
Penicillin sensitive 24 hours 1 Staphylococcus aureus UC 1 128,
Penicillin Resistant 1 1 Staphylococcus aureus Exp. No. 54 146 1 1 Streptococcus pyogenes A 561 1 0.05 Bacillus subtilis ATCC 6 633 0.05 2 Escherichia CoIi ATCC 9 637,
Tetracycline sensitive 1 2 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 2 0.5 Escherichia CoIi Exp. TO ₂₆ B ₆ 0.5 1 Escherichia CoIi R 55 123 D,
Gentamycin resistant
Tobramycin-resistant 1 2 Klebsiella pneumoniae Exp. 52 145 2 0.05 Klebsiella pneumoniae 2 536,
Gentamycin resistant 0.05 3 Proteus mirabilis (indole -) A 235 3 0.5 Salmonella typhimurium 420 0.5 . 3 Enterobacter cloacae 681 3 20th Providencia Du 48 10 10 Serratia 2532, gentamycin resistant 10 3 2

S08840 / 0886

Wt-S-

Link; of example

tribe CMI ( μ g / ml) 48 h; '' ' Staplaylococcus aureus ITOO 6 538,
Penicillin sensitive. 24 hours 3 Staphylococcus aureus UO 1 128,
Penicillin Resistant 2 LfN Staphylococcus aureus Exp. No. 5M- 146 3 5 Streptococcus pyogenes A 561 3 <0.02 Streptococcus faecalie 5 4-32 ^ 0.02 40 Streptococcus faecalis 99 F 74 2 > 40 Bacillus subtilis ATCO 6 633 40 2
0.5
0.1 Escherichia CoIi ATCC 9 637,
Tetracycline sensitive 1 0.5 Escherichia CoIi ATGC 11 303,
Tetracycline resistant 0.5
0.1 0.2 Escherichia GoIi Exp. TOggBg 0.2 0.05 Escherichia CoIi H 55 123 D,
Gent amycin-resist ent
Tobramycin resistant 0.2 2 Klebsieila pneumoniae Exp. 52 145 0.05 2 Klebsiella pneumoniae 2 536,
Gentamycin resistant 2 1 Proteus numbilis (indole +) A 232 1 0.5 Proteus mirabilis (indole -) A 235 0.2 3 Salmonella typhimurium 420 0.2 3 Enterobacter cloacae 681 2 1 Providencia Du 48 2 Serratia 2532, gentamycin resistant 1

809840/0886

Compound of Example 39

tribe CMI (/ ig / ml) 48 h Staphylococcus aureus ATCC 6 538,
Penicillin sensitive 24 hours 1 Staphylococcus aureus UC 1 128,
Penicillin Resistant 1 2 Staphylococcus aureus Exp. Ur. 54 146 1 1 Streptococcus pyogenes A 561 1 <0.02 Streptococcus faecalis 5 4-32 <0.02 10 Bacillus subtilis ATCC 6 633 2 5 Escherichia CoIi ATCC 9 637,
Tetracycline sensitive 1 5
0.5 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 3 2 Escherichia CoIi Exp. TO ₀ CBr- 0.5 2 Escherichia CoIi R 55 123 D,
Gentamycin resistant
Tobramycin resistant 2 0.2 Klebsiella pneumoniae Exp. 52 145 2 5 Elebsiella pneumoniae 2 536,
Gent amycin-resistant ent 0.2 0.5 Proteus mirabilis (indole -) A 235 5 1 Salmonella typhimurium 420 0.5 10 Providencia Du 48 1 10 Serratia 2532, gentamycin resistant 10 10

909840/0886

291282

Compound of Example 40

tribe CMI (μg / ml) 48 h Streptococcus pyogenes A 561 24 hours 0.1 Escherichia Ooli ATCC 9 637,
Tetracycline sensitive 0.05 3. Escherichia CoIi ATCC 11 303,
Tetracycline resistant 2 1 Escherichia CoIi Exp. TO ₂₆ B ₆ 1 2 Escherichia CoIi E 55 123 D,
Gentamycin resistant
Tobramycin resistant 2 3 Klebsiella pneumoniae Exp. 52 14-5 3 1 Klebsiella pneumoniae 2 536,
Gent amycin-resistant Λ 10 Proteus mirabilis (indole -) A 235 5 1 Salmonella typhimurium 420 1 5 Providencia Du 48 3 5 Serratia 2532, gentamycin resistant 5 20th 20th

909840/0888

291282:

Compound of Example 41

tribe CHI (/ xg / ml) 48 h Staphylococcus aureus ATCC 6 538,
Penicillin sensitive 24 hours 10 Staphylococcus aureus TJC 1 128,
Penicillin Resistant 10 10 Staphylococcus aureus Exp. No. 54-146 5 10 Streptococcus pyogenes A 561 10 0.02 Bacillus sübenilis ATCC 6 633 0.02 2 Escherichia CoIi ATCC 9 637,
Tetraeyclin sensitive 2 1 Escherichia Coil ATCC 11 303,
Tetracycline resistant 1 0.1 Escherichia CoIi Exp. TO ₂ ^ Bg 0.05 0.5 Escherichia CoIi B 55 123 D,
Gentamycin resistant
Tobramycin resistant 0.5 0.5 Klebsiella pneumoniae Exp. 52 145 0.5 0.2 Klebsiella pneumoniae 2 536,
Gentamycin resistant 0.2 2 Proteus mirabilis (indole -) A 235 2 0.2 Proteus mirabilis (indole +) A 232 0.2 5 Salmonella typhimurium 420 5 1 Enterobacter cloacae 681 0.5 20th Providencia Du 48 20th 3 Serratia 2532, gentamycin resistant 3 2 1

909840 / 088S

-ff? 9-

Connection of example .1

tribe CMI (.μ g / ml) 48 h Staphylococcus aureus ATCO 6 538,
Penicillin sensitive 24 η 1 Staphylococcus aureus UC 1 128,
Penicillin Resistant 0.5 1 Staphylococcus aureus Exp. No. 54 146 1 1 Streptococcus pyogenes A 561 1 0.1 Streptococcus faecalis 5 432 0.1 10 Streptococcus faecalis 99 3? 7 ^ · 5 20th Bacillus subtilis ATCC 6 633 10 2 Escherichia CoIi ATCC 9 637,
Tetracycline sensitive. 1 0.1 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 0.1 0.1 Escherichia CoIi Exp. TO ₂₆ B ₆ . 0.1 0.1 Escherichia CoIi R 55 123 D ,.
Gentamycin resistant
Tobramycin resistant 0.1 0.5 Klebsieila pneumoniae Exp 52 145 0.5 0.1 Klebsiella pneumoniae 2 536,
Gentamycin resistant 0.05 2 Proteus mirabilis (indole -) A 235 0.5 0.1 Salmonella typhimurium 420 0.1 0.2 Enterobacter cloacae 681 0.2 20th Providencia Du 48 20th 10 Serratia 2532, gentamycin resistant 5 20th 10

9 0 9 8 4 T ^ / 088 P.

Connection of example 2

tribe CMI (yu.es/ml) 48 h Staphylococcus aureus ATOO 6 558,
Penicillin sensitive 24 hours 0.5 Staphylococcus aureus UC 1 128,
Penicillin-resistant 0.5 1 Staphylococcus aureus Exp. ETr. 54-146 1 1 Streptococcus pyogenes A 561 0.5 0.05 Streptococcus faecalis 5 4-32 0.05 5 Streptococcus faecalis 99 I ¹ 74 5 20th Bacillus subtilis ATCO 6 633 10 1 Escherichia Ooli ATCO 9 637,
letracycline sensitive 1 0.2 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 0.2 0.1 Escherichia CoIi Exp. T0 _oc B _a 0.1 0.05 Escherichia CoIi E 55 123 D,
Gent amyc in-resistant
Tobramycin resistant 0.05 0.5 Klebsieila pneumoniae Exp. 52 145 0.5 0.05 Klebsiella pneumoniae 2 536,
Gentamycin resistant 0.05 0.5 Proteus mirabilis (indole -) A 235 0.5 0.1 Salmonella typhlmurium 420 0.1 0.2 Enterobacter cloacae 681 0.1 20th Providencia Du 48 20th 5 2

909840/0886

Compound of example 3

tribe CHI C ₁ UgZmI) 48 h Staphylococcus aureus AiEOG 6 538,
Penicillin sensitive 24 hours 2 Staphylococcus aureus ITC 1 128,
Penicillin Resistant 1 2 Staphylococcus aureus Exp. No. 54 146 2 2 Streptococcus pyogenes A 561 2 0.2 Bacillus subtilis ATOC 6 633 0.2 3 Escherichia Ooli ATCC 9 637,
Tetracycline sensitive 2 0.5 Escherichia Ooli ATCO 11 303,
Tetracycline resistant 0.5 0.2 Escherichia CoIi Exp. TO ₂₆ Bg 0.2 0.1 Escherichia CoIi R 55 123 D,
Gentamycin resistant
Tobramycin resistant 0.1 1 Klebsieila pneumoniae Exp. 52 145 0.5 0.2 Klebsiella pneumoniae 2 536,
Gentamycin resistant 0.1 1 Proteus mirabilis (indole -) A 235 1 0.2 Salmonella typhimurium 420 0.2 0.5 Enterobacter cloacae 681 0.5 40 Providencia Du 48 20th 5 Serratia 2532, gentamycin resistant 3 ' 5 3

9098AO / 0886

Compound of example 5

tribe CMI (.Ug / ml) 48 h. Staphylococcus aureus ATCC 6 538 »
Penicillin sensitive 24 hours 3 Staphylococcus aureus TJC 1 128,
Penicillin Resistant 2 5
3 Staphylococcus aureus Exp. No. 54 · 146 5
2 0.5 Streptococcus pyogenes A 561 0.5 10 Bacillus subtilis ATCC 6 633 10 0.5 Esoherichia CoIi ATCC 9 637,
Tetracycline sensitive 0.5 0.1 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 0.1 0.5 Escherichia CoIi Exp. ^ 2 ^ & 0.5 2 Escherichia CoIi R 55 123 D,
Gentamycin resistant
Iobramyein resistant 2 0.2 Klebsiella pneumoniae Exp. 52 145 0.2 2 Klebsiella pneumoniae 2 536,
Gentamycin resistant 2 0.2 Proteus mirabilis (indole -) A 235 0.2 0.5 Salmonella typhimurium 420 0.5

909840 / 088S

Link; of example 7

tribe CMI (µg / ml); 48 h Staphylococcus aureus ATCC 6 538,
Penicillin sensitive 24 hours 20th Staphylococcus aureus UC 1 128,
Penicillin resistant 10 Staphylococcus aureus Exp. No. 54 146 10 10 Streptococcus pyogenes A 561 10 1 Bacillus sübenilis ATCC 6 633 0.5 20th Escherichia CoIi ATCC 9 637,
Tetracycline sensitive 5 1 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 1 1 Escherichia CoIi Exp. TOocBc 0.5 1 Escherichia CoIi R 55 123 D,
Grentamycin resistant
Tobramycin resistant 1 1 Klebsiella pneumoniae Exp. 52 45 1 1 Klebsiella pneumoniae 2 536,
Grentamycin resistant 0.5 2 Proteus mirabilis (indole -) A 235 2 0.1 Proteus vulgaris (indole +) A 232 0.1 2 Salmonella typhimurium 420 1 1 Providencia Du 48 1 20th Serratia 2532, gentamycin resistant 20th 10. 10

909840/0886

Compound of Example 9

tribe CMI (^ g / ml) 48 h Staphylococcus aureus ATCO 6 538,
Penicillin sensitive 24 hours 2 Staphylococcus aureus UC 1 128,
Penicillin Resistant 2 3 Staphylococcus aureus Exp. No. 5 ^ 1 46 3 3 Streptococcus pyogenes A 561 3 0.2 Bacillus subtilis ATCC 6 633 0.2 2 Escherichia CoIi ATCC 9 637,
! Petracycline sensitive 1 0.5 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 0.5 0.1 Escherichia CoIi Exp. TOogBg 0.1 1 Escherichia CoIi R 55 123 D,
Grentamycin resistant
robramycin resistant 1 0.5 Klebsiella pneumoniae Exp. 52 145 0.5 0.1 Klebsiella pneumoniae 2 536,
Gentamycin-resistant 0.1 1 Proteus mirabilis (indole -) A 235 1 0.1 Proteus vulgaris (indole +) A 232 0.1 1 Salmonella typhimurium 420 1 1 Enterobacter cloacae 681 0.5 > 40 Providencia Du 48 20th 3
5 Serratia 2532, gentamycin resistant 3 3

909840/0886

2912823

Compound of example 10

tribe CMI ( μ. G / ml) 48 h. Staphylococcus aureus ATOO 6 538,
Penicillin sensitive 24 hours 20th Staphylococcus aureus UO 1 128,
Penicillin Resistant 10 20th Staphylococcus aureus Exp. No. 54 · 146 20th 20th Streptococcus pyogenes A 561 10 3 Bacillus subtilis ATOC 6 633 Λ 20th Escherichia CoIi ATCC 9 637,
Tetracycline sensitive 10 0.5 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 0.5 0.5 Escherichia CoIi Exp. TO ₂₆ B ₆ 0.5 0.5 Escherichia CoIi R 55 123 D,
Gentamycin resistant
Tobramycin re-resistant 0.5 1 Klebsiella pneumoniae Exp. 52 14-5 1 0.5 Klebsiella pneumoniae 2 536,
Gentamycin resistant 0.5 1 Proteus mirabilis (indole -) A 235 1 0.1 Proteus vulgaris (indole +) A 232 0.1 0.2 Salmonella typhimurium 4-20 0.2 1 Enterobacter cloacae 681 0.5 40 Providencia Du 48 20th 3 Serratia 2532, gentamycin resistant 2 10 10

909840/088 6

- 226-

Connection of example

tribe CMI ( μ g / ml)
3 48 h Staphylococcus aureus AIIICG 6 538,
Penicillin sensitive 24 η 20th Staphylococcus aureus UC 1 128,
Penicillin Resistant 10 10 Staphylococcus aureus Exp. No. 54 146 10 10 Streptococcus pyogenes A 561 10 0.1 Streptococcus faecalis 5 432 0.1 > 40 Bacillus subtilis AiDOO 6 633 20th 10 Escherichia CoIi ATCC 9 637,
T etr acyclin-sensitive. 10 0.2 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 0.2 0.05 Escherichia CoIi Exp. TO ₂₆ B ₆ 0.05 0.2 Escherichia CoIi E ^ 123 D,
Gent amycin-re eist ent
Tobramycin resistant 0.2 0.5 Klebsiella pneumoniae Exp. 52 145 0.5 0.1 Klebsiella pneumoniae 2 536,
Gentamycin resistant 0.1 0.2 Proteus mirabilis (indole -) A 235 0.2 0.02 Proteus vulgaris (indole +) A 232 0.02 1 Salmonella typhimurium 420 1 0.5 Enterobacter cloacae 681 0.5 40 Providencia Du 48 40 - Serratia 2532, gentamycin resistant 10 2

909840/0886

Compound of Example 13

tribe CMI (^ ag / mi; 48 h Staphylococcus aureus ATCC 6 538,
Penicillin sensitive 24 hours 1 Staphylococcus aureus UC 1 128,
Penicillin Resistant 1 1 Staphylococcus aureus Exp. No. 5 ^ " ¹ ^ -O 1 2 Streptococcus pyogenes A 561 1 0.05 Streptococcus faecalis 5 432 0.05 5 Streptococcus faecalis 99 F 7 ^ · 5 > 40 Bacillus subtilis ATCC 6 633 10 1 Escherichia CoIi ATCC 9 637,
Tetracycline sensitive 1 0.5 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 0.5 0.2 Escherichia CoIi Exp. TO ₂₆ B ₆ 0.15 0.5 Escherichia CoIi R 55 123 D,
Gentamycin resistant
Tobramycin resistant 0.5 0.5 Klebsieila pneumoniae Exp. 52 145 0.5 0.2 Klebsiella pneumoniae 2 536,
Gentamycin resistant 0.2 1 Proteus mirabilis (indole -) A 235 1 0.5 Salmonella typhimurium 420 0.5 0.5 Enterobacter cloacae 681 0.5 20th Providencia Du 48 20th 2 Serratia 2532, gentamycin resistant 2 5 5

9098A0 / 0886

Connection of example. 14th

tribe Cm (ytfs / ml) 48 h Staphylococcus aureus ATCC 6 538,
Penicillin sensitive 24 hours 10 Staphylococcus aureus UC 1 128,
Penicillin Resistant 10 10 Staphylococcus aureus Exp. ITr. 54-14-6 10 10 Streptococcus pyogenes A 561 10 _s 0.02 Streptococcus faecalis 5 4-32 <0.02 > 40 Streptococcus faecalis 99 F 74 10 2 Bacillus subtilis ATCC 6 633 1 0.2 Escherichia CoIi ATCC 9 637,
letracycline sensitive 0.2 0.2 Escherichia CoIi ATCC 11 303,
! Detracycline resistant 0.2 0.05 Escherichia CoIi Exp. ΤΟο, -Β ^ · 0.05 0.1 Escherichia CoIi R 55 123 D,
Gentamycin resistant
EDobramycin resistant 0.1 0.1 Klebsiella pneumoniae Exp. 52 14-5 0.1 0.1 Klebsiella pneumoniae 2 536,
Sent amycin-resistant 0.1 0.5 Proteus mirabilis (indole -) A 235 0.5 0.2 Proteus vulgaris (indole +) A 232 0.1 3 Salmonella typhimurium 420 1 0.1 Enterobacter cloacae 681 0.1 3 Providencia Du 48 3 1 Serratia 2532, gentamycin resistant 1 1 1

909840/0886

291282 ¹

Compound of Example 15

tribe CMI (yug / ml) 48 h Staphylococcus aureus ATCO 6 538,
Penicillin sensitive 24 hours 5 Staphylococcus aureus UC 1 128,
Penicillin Resistant 5 10 Staphylococcus aureus Exp. No. 5 ^ 146 10 10 Streptococcus pyogenes A 561 5 <0.02 Streptococcus faecalis 5 ^ 32 <0.02 > 40 Bacillus subtilis ATCC 6 633 10 2 Escherichia CoIi ATCC 9 637,
Tetracycline sensitive 1 0.3 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 0.1 0.05 Escherichia CoIi Exp. TO ₂₆ B ₆ 0.05 0.1 Escherichia CoIi R 55 123 D,
Gent amycin-re eist ent
Tobramycin resistant 0.1 0.1 Klebsiella pneumoniae Exp. 52 145 0.1 O, o5 Klebsiella pneumoniae 2 536,
G ent amycin-r esi st ent 0.05 0.2 Proteus mirabilis (indole -) A 235 0.2 0.2 Proteus vulgaris (indole +) A 232 0.1 2 Salmonella typhimurium 420 1 0.1 Enterobacter cloacae 681 0.1 2 Providencia Du 48 2 1 Serratia 2532, gentamycin resistant 1 1 0.5 ^

909840/0886

291282:

Compound of example 16

tribe CMI (μ g / ml) 48 h Staphylococcus aureus ATCC 6 538,
Penicillin sensitive. 24 hours 1 Staphylococcus aureus UC 1 128,
Penicillin Resistant 1 2 Staphylococcus aureus Exp. No. 54-146 1 2 Streptococcus pyogenes A 561 2 0.05 Streptococcus faecalis 5 4-32 0.05 40 Streptococcus faecalis 99 F 74 5 > 40 Bacillus subtilis ATCC 6 633 20th 3 Escherichia CoIi ATCC 9 637,
Tetracycline sensitive 2 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 0.5 0.05 Escherichia CoIi Exp. TO ₂₆ B ₆ 0.05 0.5 Escherichia CoIi R 55 123 D,
Gentamycin resistant
Tohramycin resistant 0.5 0.2 Klebsiella pneumoniae Exp. 52 145 0.2 0.2 Klebsiella pneumoniae 2 536,
Gentamycin resistant 0.2 1 Proteus mirabilis (indole -) A 235 1 0.1 Salmonella typhimurium 420 0.1 0.5 Providencia Du 48 0.5 10 Serratia 2532, gentamycin resistant 10 2 2

909840/0886

- 2S4-

Connection of example

tribe OMI (, μ g / ml) 48 h Staphylococcus aureus ATCC 6 538,
Penicillin sensitive 24 hours 1 Staphylococcus aureus UC 1 128,
Penicillin Resistant 1 2 Staphylococcus aureus Exp. Mr. 54 146 2 2 Streptococcus pyogenes A 561 2 0.1 Streptococcus faecalis 5 432 0.1 40 Bacillus subtilis ATCC 6 633 10 10 Escherichia CoIi ATCC 9 637,
Tetracycline sensitive 3 0.5 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 0.5 0.05 Escherichia CoIi Exp. TO ₂₆ Bg 0.05 0.2 Escherichia CoIi R 55 123 D,
Gentamycin resistant
Tobramycin resistant 0.2 0.5 Klebsiella pneumoniae Exp. 52 145 0.5 0.05. Klebsieila pneumoniae 2 536,
Gentamycin resistant 0.05 1 Proteus mirabilis (indole -) A 235 0.5 0.1 Salmonella typhimurium 420 0.1 0.1 Enterobacter cloacae 681 0.1 20th Providencia Du 48 10 5 Serratia 2532, gentamycin resistant 3 10 5

909840/0888

Compound of Example 42

tribe CMI (/ as / ml) 48 ii Staphylococcus aureus AiDCC 6 538,
Penicillin sensitive 24 hours 5 Staphylococcus aureus UC 1 128,
Penicillin Resistant ■ 5 10 Staphylococcus aureus Exp. No. 54 146 10 5 Streptococcus pyogenes A 561 5 £ 0.02 Streptococcus faecalis 5 432 <0.02 > 40 Bacillus subtilis ATCC 6 633 20th 2 Escherichia CoIi ATCC 9 637,
Tetracycline sensitive 1 1 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 1 0.2 Escherichia CoIi Exp. TO ₂₆ Bg 0.2 0.5 Escherichia CoIu R 55 ¹ 23 D,
Gentamycin resistant
Tobramycin resistant 0.2 0.5 Klebsiella pneumoniae Exp. 52 145 0.5 1 Klebsiella pneumoniae 2 536,
Gent amyc in-re s is ent 1 1 Proteus mirabilis (indole -) A 235 1 1 Salmonella typhimurium 420 1 1 Enterobacter cloacae 681 0.5 10 10 10 Providencia Du 48; 5 1 Serratia 2 532, gentamycin resistant 1

9 ü98- (0/0886

- £ 93-

-XFf-

Compound of Example 43

tribe CMI (/ ig / ml) 48 h Staphylococcus aureus ATCC 6 538 »
Penicillin sensitive. 24 hours 3 Staphylococcus aureus UC 1 128,
Penicillin Resistant 2 3 Staphylococcus aureus Exp. No. 54 146 3 3 Streptococcus pyogenes A 561 2 0.05 Streptococcus faecalis 5 432 0.05 > 40 Bacillus subtilis ATCC 6 633 10 2 Escherichia CoIi ATCC 9 637,
Tetracycline sensitive 1 1 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 1 0.05 Escherichia CoIi Exp. TO ₂₆ B ^ 0.05 0.2 Escherichia CoIi R 55 123 D,
Gentamycin resistant
Tobramycin resistant 0.2 0.2 Klebsiella pneumoniae Exp. 52 145 0.2 0.2 Klebsiella pneumoniae 2 536,
Gentamycin resistant 0.2 1 Proteus mirabilis (indole -) A 235 1 0.1 Salmonella typhimurium 420 0.1 1 Enterobacter cloacae 681 1 20th Providencia Du 48 20th 10 Serratia 2532, gentamycin resistant 10 1 1

90984Π / 0886

ORIGINAL INSPECTED

Link; from Example 45

tribe CMI (μκ / αιΐ) 48 h Staphylococcus aureus ATCO 6 538,
Penicillin sensitive 24 hours 1 Staphylococcus aureus UC 1 128,
Penicillin Resistant 1 1 Staphylococcus aureus Exp. Fr. 54 146 1 1 Streptococcus pyogenes A 561 1 0.05 Streptococcus faecalis 5 432 0.05 5 Bacillus subtilis ATCC 6 633 5 2 Escherichia CoIi ATCC 9 637,
! Tetracycline sensitive 2 1 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 0.5 0.05 Escherichia CoIi Exp. TO ₂₆ Bg 0.05 0.2 Escherichia CoIi R ^ 123 D,
Gentamycin resistant
T obramyc in-r esi st ent 0.2 0.2 Klebsiella pneuraoniae Exp. 52 145 0.2 0.05 Klebsiella pneumoniae 2 536,
Gentamycin resistant 0.05 0.5 Proteus mirabilis (indole -) A 235 0.5 0.05 Salmonella typhimurium 420 0.05 0.2 Enterobacter cloacae 681 0.2 20th Providencia Du 48 15th 5 Serratia 2532, gentamycin resistant 5 2 2

9 0 9 8 U 0/0 8 8 p

-995-

Compound of Example 46

tribe DMI (μ g / ml) 48 h Staphylococcus aureus ATCC 6 538,
Penicillin sensitive 24 hours vji Staphylococcus aureus UC 1 128,
Penicillin Resistant 5 10 Staphylococcus aureus Exp. No. 54 146 5 Streptococcus pyogenea A 561 3 0.05 Bacillus subtilis ATCC 6 633 0.05 2 Escherichia CoIi ATCC 9 637,
Tetracycline sensitive 1 3 Escherichia CoIi ATCC 11 303,
Tetracycline resistant 3 0.5 Escherichia CoIi Exp. T0 _oc B, - 0.2 2 Escherichia CoIi E 55 123 D,
Gentamycin resistant
Tobramycin resistant 1 3 Klebsiella pneumoniae Exp. 52 145 2 1 Klebsieila pneumoniae 2 536,
Gentamycin resistant 0 _T 5 10 Proteus mirabilis (indole -) A 235 10 1 Salmonella typhimurium 420 1 2 Providencia Du 48 1 40 Serratia 2532, gentamycin resistant 40 2 2

Claims (1)

BEETZ-LAMPRECHT-BEETZ Steinsdorfstr. 10 D-8000 Munich 22 Telephone (089) 227201 - 22 72 44 - 295910 Telex 522048 - Telegram Allpalent Munich PATENT LAWYERS Dip] .- Ing. R. BEETZ sen. Dipi.-Ing. K. LAMPRECHT Dr.-Ing. R. BEETZ jr. Lawyer Dipl.-Phys. Dr. jur. U. HEIDRICH Or.-Intj. W. TIMPE Dipl.-Ing. J. SIEGFRIED Priv.-Doz RiPL-ChSmJk. rer. nat. W. SCHMITT-FUMIAN March 3, 1979 Expectations 1. O-substituted oxime derivatives of 7-aminot; hiazolyl acetamido-cephalosporanic acid, syn isomers, the general formula I ' 50i- (1843 F / D) -SF / nu 909840/0886 in the "mean: B: a) a substituent Ή, which in turn means: - a group -CR ¹ with X = S or 0 and R ¹ = G ₁ - to C ^ -alkyl or G ₁ - to -alkoxy, phenyl, / ^R 2 - (CH ₂ ) _n -N with O ^ n '* ^ (integer) and Ro and R, = simultaneously or independently H, C ₁ - to C ^ -alkyl or together with the N atom piperidino, morpholino or Phthalimido, R " - a group -C-COpA ¹ R ₄ with A ¹ = H, an equivalent of an alkali metal, alkaline earth metal, magnesium, ammonium or an organic amine base or 4 0 / 088S an easily cleavable ester group, R ₄ = phenyl, hydroxyethyl or nitrile and R "» H or C ₁ - to C ₄ -alkyl, a Y -lactone group of the formula __ / 0 or a group - _n with 1 ^ n '^ - 4 (integer)
and
R = O ₁ - to C ₄ -AlkOXy, AIk-S- with C ₁ - to C ₄ -alkyl part and 0 ^ nst ^ 2 (integer), with R ₆ and Rr, = H, C ₁ - to C ₄ - -alkyl or together with the N atom phthalimido or 1-pyridinyl, Fitril if n ^1/1, -C-UH ₂ with X ¹ m S or X '= 0, if n ^1/1, 4-methyl, 4-amino-1,3-thiazol-2-yl, 909840/0888 Asido
or
C ₂ - t> is b) a substituent R; ,
which in turn means: - a group -( with 1- ^ n '^ 4- (integer)
and
Rca = halogen or a group -S-R__ with B _ = phenyl or an aro- sr matic heterocyclic group with 5 to 6 ring members and 1 to 4 selected from S, Ή and O heteroatoms », where the groups Ε _{& τ} , if necessary s also with one or more amino, Mitro, Cj to σ ^ -alkyl or Mitrilgruppen can be substituted, or e) a substituent a H ^, who in turn 2912823 _ 5 - - a group - (CH ₂ ) _n . -Rcb with 1s £ = n * £ 4 (all ζ aiii ig) and where Hgb and H ^ b with the N atom, to which they are bound, an imidazolyl, morpholinyl or li-alkylpiperazinyl group with C ^ - to C 1-4 alkyl part represents Cl, methoxy, C ^ - to Cc-alkyl, C ₁ - to Cc-cycloalkyl, Cc-alkylthio, "" CHp ~ S ^ E ^ ο - until with E / J2 = a nitrogen-containing heterocyclic group,
Cp to C ^ acyl, 2-Oxo (3H) -tb.iazolin-4-yl-carbonyl or 3-methyl-1,2-oxazol-5-yl-carbonyl, Acetoxymethyl, carbamoyloxymethyl or -NH-C-AIk ₀ with Alk = O ₁ - to Ο, -alkyl H a ai * r A .: H or an equivalent of an alkali metal, S09840 / 088S Alkaline earth metal, magnesium, ammonium or an x ¹ organic amine base or an easily cleavable ester group as well as their salts with inorganic and organic acids. 2. Oxime derivatives of 7-aminothiazolyl-acetamido-cephalosporanic acid according to claim 1, syn isomers, of formula I. (D with H, E /] and A as in claim 3. Oxime derivatives of y-aminothiazolyl-acetamido-cephalo sporanic acid, syn isomers, according to claim Λ of the formula I. 109840/0888 291282! with Ε _& , ILj and A as in claim 1. M-, Qxime derivatives of 7-aminothiazolyl-acetamido-cephalosporanic acid, syn isomers, according to claim 1 of the formula I ^ NHr CONH with Ry, ü | and A as in claim 1 5. Oxime derivatives of γ -aminothiasolyl-acetaaido-cephalosporansämre of the formula I ¹ according to claim 1 $ 09840/0 with E ₁₂ = 1.2.3-, 1.2.5-, 1.2.4- or 1.3.4-thiadiazolyl, 1-H-tetrazolyl, 1.3-thiazolyl, 1.2.3-, 1.2.4- or 1.3-4-triazolyl or 1.2.3-, 1.2.4-, 1.2.5- or 1.3.4-0xadiazolyl, where the above substituents, if necessary, one or more times with methyl, ethyl, propyl, isopropyl, Methosy, ethoxy, propyloxy, isopropyloxy, Amino, hydroxycarbonylmethyl, dimethyl aminoäthy1 and / or diethylaminoäthyl can be substituted, or Acetyl, propionyl or butyryl. 6. Oxime derivatives of 7-aminothiazolyl ~ acetamido-cephalosporanic acid of formula I 'according to claim 1 with H ₁₂ = acetyl, i-methyl-tetraziolyl, 2-methyl- 1.3.4-thiadiazolyl, 3-methyl-1.2.4-thi adiazol ~ 5-yl, 3-methoxy-1.2.4-thiadiazolyl, 1.3 «4-Thiadiazol-5-yls 2-Amino-1» 3 »4-thia- diazol-5-yIs J-Bydro ^ igrcarborjyliHetliyl-i «2.4- 3-yl / 4-methyl-5-liyäro3sycar'bonyla © tliyl-1. 3 thiazol-2-yl or 1-dimethylaiainoethyl-1 · 2.J.4-t © trazol-5-yl. 7 «Oxine derivatives of 7-aiaiaothiazolyl- = aeetaiaido-esplialosporic acid Forüael 1 according to claim 2, in which: 9098 ^ 0/088 2912329 R: - a group -CR ¹ Z
with X = O and
R ¹ = C ₁ to Phenyl or . \ with η - 0 or 1 and 3 R ₂ and R ₇ w: claim 1, and R ₇ as in R " - a group -C-CO ₀ A ¹ with A ¹ and R "= H and Ri, = phenyl or hydroxyethyl, - a V-lactone group from iOrinel or group - (CH ₂ ) _n , -R ₅ like i one n ¹ = 1 or 2 with E ₅ = TUlCi τ *
-N with Rg and Rn or -C-KH ₀ ,
S. 1 ^^. ^ - Tetrazol - ^ - yl
Acetyl, 909840/0886 -ίο- 2312829 C ₁ - Ws Cc-y,
—CHp — SR ₁ ρ with R ₁₂ ⁼ 2-methyl-1.3.4-thiadiazolyl or
1-methyltetrazolyl, or
Acetoxymethyl and A_: H or an equivalent of an alkali metal, alkaline earth metal, Magnesium, ammonium or an organic amine base. 8. Oxime derivatives of 7-aminothiazolyl-acetamido-cephalosporanic acid of formula I according to claim 2, in which: R acetyl, benzoyl, phthalimidoacetyl, N.N-dimethylcarbamoyl, QL-Carboxyphenylmethyl-S-oxo - ^ - tetrahydropyranyl / 1,4-dihydroxy-1-oxo-2-butyl, phthal imidomethyl, aminoethyl, tetrazol-5-yl-methyl, 2-amino-2-thioxoethyl or 2-oxopropyl, R ₁ methyl, acetoxymethyl, 2-methyl-1,3.4-thiadiazol-5-yl-thiomethyl or 1-methyl-tetrazolylthiomethyl and
AH or sodium. 9. Oxime derivatives of 7-aminothiazolyl-acetamido-cephalosporanic acid of formula I according to claim 2, 909840/0886 291282S in the "mean: R acetyl, benzoyl, phthalimidoacetyl, 5-tetrazolyl, Aminoethyl or oL-Cai * boxypheny! Methyl, and FL ₁ acetoxymethyl, 2-methyl-1.3. ^z l-thiadiazol-5-ylthiomethyl or i-methyl-tetrazol-5-yl-thiomethyl, 10-oxime derivatives of 7-aminothiazolyl-acetamido-cephalosporanic acids of the formula I according to claim 3? in which R ₁ -S means: Bi * or J or phenylthio, 2-pyridinylthio, 2-amino-1.3 · ^ - thiadiazol-5-yl-thio, 1-methyl-1H-tetrazol-5-yl-thio, 2-aminophenylthio, 5-nitro-2-pyridinyl-thio or 3-cyano-6-methyl-2-pyridinylthio » 11. 3-Acetoxytethyl-7- [C2-C (2-bromoetho ^) - imino] -2- (2-aiHinothiazol-4- yl) -acetylJ -amino] -ceph ~ 3-em-4 ~ carboxylic acid (syn-isomer) as / ie their salts with alkali metals, Alkaline earth metals, magnesium, ammonium and organic amine bases as well as their easily cleavable esters « 12 "5-Acst03ijmethyl" 7 - [[2 - [(2-iodoethoxy) -imino] -2- (2-aiainothiazol-t-yl) -acetylJ -aminoj ~ ceph-3-em-4-carboxylic acid (sjn isomer) and their salts with alkali metals, Alkaline earth metals, magnesium, ammonium and organic amine bases as well as their easily cleavable esters «. 809840/0886 13. 3-Acetoxymethyl-7-Q [2-C2-aminothiazol-4-yl) -2- (2-aminoä bhoxyimino) -ac ety Ij -aminoj-c eph-3-em-4 ~ carboxylic acid (syn isomer) and their salts with alkali metals, alkaline earth metals, magnesium, ammonium and organic Amine bases and their easily cleavable esters. 14 ·. Compounds of Formula A NH R CO ₂ A " in which: E ^ the same as in claim 1,
an amino protection group,
H or an easily cleavable group and 9G9840 / 0888 "2312.82! -C-CO ₂ A "', - ^(GH 2> n '· - ^ R ^f . * Ό $ 09840/0898 2912529 or where mean: R ', C ₁ - to C ^ -alkyl, C ₁ - to C ^ -alkoxy, phenyl or pn / 2
with 0 * £ n ^ 4- (integer) E " ₂ and K" ₅ = H or C ₁ - to C ^ - alkyl, where at least one of the substituents R " ₂ and R" is alkyl when η = 0, or together with the N atom phthalimido, Piperidino or morpholino, X 0 or S, R "H or C ₁ - to C ^ -alkyl, 109840/0888 R ¹ 4 phenyl or uritrile, A " ^{1 is} an easily split off protective group, η ^{1 is} an integer from 1 to 4-, E'c C ₂ - to C ^ -acyl, O ₁ - to C ^ -AUcoxy, C ₁ - to C ^ -alkylthio, where the S atom may be present in oxidized form as sulfoxide or sulfone, n _{2 is} an integer from 2 to 4 _t n "is an integer from 1 to 4 when X = S and n" / 1 when X = O, R'r; Methyl or amino, a group which can be easily split off by acid hydrolysis or hydrogenolysis, or C ^ to C ^ alkyl and H or C ₁ - to C ^ -alkyl, or together with R ₁ g of phthalimido, where R _{16 is} not a chloroacetyl group when R, -C-CH, and R ^ -CHo-OC-CH, are. XO Compounds of the formula B (syn isomers) S09840 / 0 88S 2312829 NH R 16 CO ₂ H S. in which: R ^ ₆ mean the same as in claim ttnd R ". -CR ¹ ti Il with R '. _z equals R ^! _x except methyl, R " -G-GO ₂ A "'R' ₄ 2312829 - (CH ₉ ), i ' or B, with E ' ₃ , X, E ", R \, A"', n ¹ , and E ^ q as in claim 1 16. Compounds of the formula XII ;, Πρ, Ε'π, E, 7 '18 909840/0818 -18- 291282: in which: E ^ g an Aminoechutzgruppe, A "H or an easily cleavable ester group, -n 'an integer from 1 to 4- and
Ey, and E_ the same as in claim 17. Compounds of the formula in which: R ¹ ^ c is an amino protective group selected from trityl and chloroacetyl, n ^ 1 or 2, HaI ₁ Br or J, A "H or an easily cleavable ester group and 909340 / 088S 19- "■ 29T28 S ^ H, Aeetoxy, Oarbamoyloixy, 1-MethyItetraeol-5-yl or 2-Met? Hyl-1.3 _e 4-tliladiaaol-5-yl. 18 » Compounds of the formula Uli (Uli) with η 'and H _& as in claim. 16, where ILjg is a line protecting group ". 19 · Refinements of the formula _x CO ₂ H \ with E '^ g ₅ n.' ^ and HaI ^ as in claim 17 " 909840/0886 291282S 20. Compounds of the formula HI'L \ Rb in which: E ^ g is an amino protective group, A "is an easily cleavable ester group and
Ej ₅ and R _{1 the} same as in claim 1 «. 21. Compounds of the formula YI * L CO H (UI ¹ L), with B, and B ^ g as in claim 1, S09340 / 088S - 20a -ZA- 22. A process for the preparation of the compounds of the formula I ¹ according to claim I ₃ marked by (Al) Implementation of a compound of the formula II - 20b - 9098 4 0/0886 (H) CO ₀ / .. ¹¹ with E ^ g = an amino push group, A "= H or an easily cleavable ester group
and R ₁ as in claim 1 (a) with a functional derivative of the group -C-R ', X
with X = 0 or S. and R'x = C ₁ - to C ^ -alkyl, C ₁ - to C ^ -alkoxy, phenyl, with O ^ niS.4 (integer) and R " ₂ and E" ₅ = H or up to C ₄ - 20c 909840/0888 291282. where at least one of the substituents R "^ wad E" ^ is alkyl when η = 0,
or together with the N atom Phthalimide »Piperidino or Morpholine» to a compound of the formula III, (I1I _A ) or (b) with a combination of the formula
with X = O or S. 909840/0886 - 20d - a compound of the formula III ¹ (ΐη _Α ) or (c) with a compound of the formula E " XC-OO ₂ A ¹ "with H" «H or C ₁ - to C ^ -alkyl R% T = halogen, sulfate or SuIf onat, R ^! ₄ = phenyl or nitrile and A ^"! = A readily removable Bchnt ζgruppe to a compound of the formula Ul ₃ - 20a - 903840/0886 291282! FH R (His) or (d) with a compound Y ₁ O with = as above Y to a compound of the formula III ο << '- * (HI ₀ ), if necessary by treatment with an alkali base - 2Of - 909840/0886 a compound of the formula III ' Till ii (in _σ ) is implemented in the A'y | an easily cleavable ester group or one equivalent of an alkali metal and
A _{1 is} an equivalent of an alkali metal mean, or (e) with a compound of the formula ) i-B'c with 1 — η'ώ.4 (integer), Yp = as above Y
and R * = G ₂ to C ^ acy}. C ₁ - to C ^ -alkoxy, C ₁ - to C ^ -alkylthio, the S atom of - 20g - A 0/0886 291282S Alkylthio group if necessary auoi sulfoxld or The sulfon is oxidized, a compound of the formula MH R ₁₆ oöer (f) with a compound of the formula with T _x = as above Ϊ and «snssi4 (integer) a compound of the formula - 20h - 909840 / 08BS -ÄS- NHH ₁₆ HH. CM (CH ₂ ) _n 2 -CH CO ₂ A " or (g) with a Vei-binduag of the formula Hai- ( CH ₂ ) _n , -Hai to a negotiation of Formula V NHR either by treatment with pyridine to give a compound of the formula 909840/0888 2Oi - -39- 29128 NH R NU. CT or with an azide to a compound of the formula III HH R NH. R. is implemented, if necessary with a reducing agent into a compound of the formula HIV - 20y - 9098A0 / 088B 291282 ' KIIR CO ₂ A " (CH ₂ ) _n , -NH ₂ (ΐΐτ. _κ ) is transformed, or (A2) Implementation of a compound of the formula IV (IV) with R / j and A "as above and '* = 4 (integer) 909840/0886 - 20h - 2S1282 & (a) with hydrogen sulfide or, if n ^! / - is 1, by hydrolysis in the presence of a base to a compound of the formula III ™ PR ₁₆ μ Ii ο WL. _ (Hip) CO ₂ A " with X = S or 0 and 1 ^ η "ί ^ 4 · (integer), if X respectively. n "^ 1, if X = O, if necessary, if χ = s, with a compound of the formula Shark 909840/0888 " ²⁰¹ " 291282: with R'π = methyl or amino and Hal = halogen to a compound of the formula is implemented, or (b) with an azide to give a compound of the formula Illrr 309840/08 - 20m - - 2ÖflT - 2932829 NHR (11%) or (A3) Implementation of a compound of the formula V (a) with an amine derivative of the formula ■ ^ß 18 Ί9 with R ^ q = a group which can be easily _{split off by acid hydrolysis or hydrogenolysis or C 1} - to C ^ -alkyl and R _1g »H or C ₁ - to C 1-4 alkyl or together with R ^, _Q phthalimido to a compound of the formula - '! On - 9098A Π / 0886 -gön- W Il (IU ₁₁ ) ('CH ₂ ) _{n <} or (B) with imidazole, morpholine or an N-Alkylpipera zin to a compound of the formula IH'τ NIIR _1n \ ¹⁶ V jl / II. CONlI "Rb with Ri. As in claim 1 or (c) with a compound of the formula R _n -SH Θ.Χ with R ^ as in claim 1 9098A0 / 0886 - 2Oo - - 20ο - 291282 to a compound of the formula III. NHR CONH ar (HI _M ) and (B) Umsetsung the compounds of formulas, III · _Α, III _{B, 0} IH, III _{'C, D} III, IH _{E, g} , iii _h , v, HI _M with one or more agents for hydrolysis, for hydrogenolysis or with thiourea ouch - Compounds of formula 1. - 20p - 909840/0886 with X, It | and R ', as above, - connections of the IOrmel I ¹ » rait X and E ^ as above, - Compounds of the formula 909840/0886 - 2Oq - R ₁ , E "and R ¹ ^ as above, - Compounds of formula I. NILE (I _n ) CO ₂ H with R ^ as above, -, ¹ Or- - ■ '' O 9 B A fi / fi B 8 8 which, if necessary, are converted ^{into compounds of the formula T 1} ^ ₁ with a base and then with an acid: NII., if (t. "" ti -.._.> - '\ UO ₀ Ii pH Oilp - CH ₂ OH - Compounds of the formula I ¹ ^ as above, - Compounds of the formula NH ₂ Ai with n ¹ , IL] and R'r as above, (I 'n - 20s - BAD OBlG * N ^Al - - Compounds of the formula with ILj tmd n2 as above, - Compounds of formula I. with X, n "and R ₁ as above, - Compounds of the formula I « - 20t - 909840/0886 2912 & 29 with ^. Retina E ¹ ^ with R ₁ and ii as above, 909840/0886 - aea - 2312829 - Compounds of the formula NH, CONH Ci ' with ILj, n 'and Hai as above, the compounds of the formula I correspond, el in the fi _& = - <0Ή ₂ ) _η ι-Ης » and ßca = halogen, Compounds of the formula Ij NH. - 2Ov - 909840/0886 -η- 291282Β with Rj and η ¹ as above, - Compounds 3-way formula with It | and n 'as above, - Compounds of the formula with R * as above, - compounds of the formula It 909840/0886 - 20w - t 282! with% ^ R ₁ -I tend nt, as ofrerl Hjoder C _n - bis ^ Connections of
. NII C ¹ V with R ₁ and% S & e above, y ^r correspond to the compounds 4er ^ rmei 'I., i which is A = H, respectively. - Compounds of the formula L - 2Ox - 909840/0886 with R ₁ , R _ar and n ^f above, the compounds of formula I ' _a correspond, in the -SE _ar is and if necessary (0) Preparation of salts or esterification of the compounds of the formulas I _A , I ^f _A , I ₃₁ I ₀ , I ' _c , 1 _D , I _E , I ₁ • »/ τ- · Χτγ % J« ττ · J "ίγ ·" ^ T? "· J · tr * § JLf β gji." T * UmW «* -? Yr vT XX XX ν Xv JV * jj υ £ ί in a manner known per se " - 21 - 909840/0886 2912S23 23 · Process for the preparation of the compounds of the formula I ¹ according to claim 1, marked by (A1) Implementation of a compound of the formula VI (VI), in which S ^ g means a group which can be easily split off by acid hydrolysis or hydrogenolysis, (a) with a functional derivative of the group -CH ¹ ^ X with Z »O or S and - 21a - 909840/0886 291282 Alkoxy, phenyl or with O ^ n ^ 4 (whole numbers) R " ₂ and R" ₃ = H or C ₁ - to C ^ -Alkyi, where at least one of the substituents R "^ and R" _{3 is} alkyl when η =, or together with the N atom piperidino, morpholino or Phthalimido, to a compound of the formula VI. (VI _A ) - 21b - 909840/0888 or (b) with a compound of the formula X = KT = KH with X = O or S. su a compound of the formula VI '" ir or (c) with a compound of the formula R "TO-CO ₂ A"'with R " = H or C ₁ - to C ^R 4- X = halogen, sulfate or SuIfonat, B. \ ■ = phenyl or hitrile and A "'* one by acid hydrolysis or hydrogenolysis easily removable protective group - 21c - S0984O / Q686 to a compound of the formula VI 0-C-CO ₂ A "» or
(d) with a compound of the formula? _r rait X, j as above T to a compound of the formula VI ^ NH R _T6 \ = YY ₂ (VI _n ) §09840 / 088 - 21d - or (e) with a compound Y ₂ - (CH ₂ ) _n , -R ' _Γ with 1 ^ n '^ 4 (integer), Y ₂ ^β w ³ - ⁰ οΐ> βη Y
and β · = C ₂ - "to C ^ -acyl, Ο, - to C ^ -alkoxy or C / j- to O ^ -alkylthio, where the S atom of the alkylthio group, if necessary to the corresponding sulfoxide or sulfone oxidized to a compound of the formula or
(f) with a compound of the formula with 2 S-Sn ₂ -S ^ - (integer) and - 21e - 2912-2 T, β as above Y to a compound of the formula (VI _E ) or (A2) Implementation of a compound of the formula VII NH R ₁₆ V = / v ^CO 2 ^H "V N> - (OH (a) either with hydrogen sulfide or, when n " £ Λ , with a base for hydrolysis - 21 f - 909840/0886 2912820 to a connection of the lormel HHH ₁₆ with 1 -r ~ n. "i ^ 4- (whole-number lines), if X = S and n "/ 1, if X = O» and X = S or 0, JE al ls X = S ,, the possibly,% it of a compound of the formula with E'n = methyl or amino and
Hai = halogen - 21g - 909840/088 $ is converted to a compound of the formula YIq , NH R (vi _G ) _r or (b) with an azide to give a compound of the formula VI Ψ ¹ hey (vi _H ) - 21h - 909840/0888 231282 (A3) Implementation of a compound of the formula VIII Ίβ (VIII) - (CH ₂ ) _n , -Hal either with pyridine to form a compound of the formula VI _T NH R 16 or with an azide to give a compound of the formula VI 909840/0888 2312323 ) _n , -N ₃ with an amine derivative of the formula HN with R ^ jo = a through, acidic hydrolysis or Hydrogenolysis easily removable group or C ₁ - to C ^ -alkyl and = H or C ₁ to C 1-4 alkyl or together with R ₁ Q phthalimido to a compound of the formula VI-r NHR ₁₆ - (CH ₂ J _n , - 909840/0886 2912823 with imidazole, korpholine or an N-alkylpiperazine to form a compound of the formula VI ¹ ^ NHR with R ^ as above or with a compound of the formula with R ^ as above to a compound of the formula VX MHR \ J / CO ₂ H N. (Vi ₁₁ ) 0 9 fi ι, Ο / 08 $ β - 21k - 29 Ί 282 (B) Implementation of the compounds of the formulas VI., VI ^1. , vi _B , vr _c , Vi ₁ J, vi _E , vi _p , vi _G , vi _H , viii, vij, vi _e , VIt, VI't and VI ^ or their derivatives with a combination of! formula IX (IX) with A ″ = H or a group which can be easily split off by acid hydrolysis or hydrogenolysis and
R ^ - as above to compounds of the formulas IIL, III '^ ₅ IHg ₅ JIX _r , ₉ UI ₁₃₈ IH ₃₃₅ IHj ₁₉ HIg ₅ III _H , V ₅ HIj ₉ III _es H III'j unö IH _M as above ₅ whereas the compounds of formula III «if necessary with an alkali base in compounds of Formula III'ρ can be converted, whereupon the compounds of the formulas IH ^ ₉ Hl ΙΙΊ _Β , IH ₀₉ III ' _OS IU ₂ J, III _E , III _p , III IIIj, IHg-, IHj ₁ , ^τττ \ ^bsw ° ¹ - 21 1 - & 09840 / 08Ü . 57, 2S1282 as in claim 22 are converted into the corresponding compounds of the formula I ¹ . 24. Pharmaceutical compositions, characterized by at least one compound according to one of claims 1
until 13. - 22 - S09840 / 088S