DE2311005A1 - BETA-LACTAM DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL PRODUCTS CONTAINING THEM - Google Patents

Description

Dr. rians-Heinrich Willrath

Dr. Dieter Weber Dipl.-Phys. Klaus Seiffert

PATENT LAWYERS

D-62 WIESBADEN, March 2, 1973 Po'tiadi 1327 ύύ / α \ 3u $ t v-Freytag-StTiS «25 S (06121) 372720 Telegram *!« «·. WILLPATENT

LA - 339-1

Astra Läkemedel Aktiebolag

Kvarnbergagatan 16 S-151 85 Södertälje, Sweden

β-lactam derivatives, processes for their preparation and containing them Dharmaceutical Means

Priority: from March 13, 1972 in Great Britain,

Registration number 11 686/72

The present invention relates to new β-lactams with antibiotic Properties and methods of their manufacture. The invention also relates to pharmaceutical agents containing these antibiotics contain.

In particular, the invention relates to new esters of β-lactam antibiotics the general formula

CO-N-R- COOR "

Poststf.eA: Frankfurt / Main 4765

R-CO-NH-C-CH -S

309844/1 1 17

Bank: Dresdner Bank AG. Wiesbaden. Account no. 276 807

and pharmaceutically acceptable salts thereof, where ^ κι · the ^ Formally I

H denotes an organic radical, such as, for example, the radical

R ¹¹ - (X ¹ ) -

CH, in which

ι.

m ι

R is an alkyl group having 1 to 8 carbon atoms, a Cycloalkyl group with 3 to 10 carbon atoms, an aryl radical such as the phenyl radical or naphthyl radical, a heterocyclic group, such as the thienyl, furyl, pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, thiazolyl, Isothiazolyl, thiadiazolyl, sydnonyl or tetrazolyl group, the alkyl, cycloalkyl, Unsubstituted aryl or heterocyclic groups or with one or more alkyl groups having 1 to 3 carbon atoms, such as methyl, ethyl, propyl or Isopropyl groups, halogen atoms, such as chlorine-> bromine, Iodine or fluorine atoms, hydroxyl groups, nitro groups, nitri! Groups, azido groups, alkoxy groups with 1 to Carbon atoms such as methoxy, ethoxy, propoxy or isopropoxy groups, carboxy groups, carboxymethyl groups or carboxamidomethyl groups may be substituted can,

X means 0 or S

Y is a hydrogen atom, a hydroxyl group, an alkyloxycarbonyl group, such as the methoxycarbonyl group, a halogen atom, such as a bromine, chlorine, fluorine or iodine atom, an azido group, an amino group, a sub-30984Λ / 1117

ORIGINAL INSPECTED

substituted amino group, such as the methylamines) -, diethylaraino or acetamido, benzylsulfonylamino, methoxy (hydroxy) phosphinylamino group, a carboxy group

3 3

or the group -COOR, in which R is as defined below, or denotes a nitrile group,

η is O or 1 and

m is O or 1,

R ² a the groups S.
^CH 3 l / ^H 3 ■ CH - ( , in which a V means barrel R ⁵

or CH

- CH "- R ⁵

a hydrogen atom, an alkanoyloxy group such as Acetoxy or propionyloxy group, a carbonyloxy group, such as the methylaminocarbonyloxy group, or the 1-pyridinium radical, where the alkanoyloxy, Carbonyloxy group and the 1-pyridinium radical, if appropriate with one or more alkyl groups with 1 to 3 carbon atoms, such as methyl, ethyl, propyl or isopropyl group, halogen atoms, such as chlorine, Bromine, iodine or fluorine atom, hydroxyl groups, nitrile groups, hydroxymethyl groups, alkoxycarbony groups or aminocarbonyl groups can be substituted, or R is the group S-R, in which R is a methyl group, a Ethyl group, a benzyl group or a heterocyclic group such as an imidazolyl, benzoimidazolyl, benzo

309844/1117

is thiazolyl / benzoxazolyl or thiadiazolyl group, a xanthate group, a dithiocarbamate group, such as a Dimethyl, piperidyl, 4-alkylpiperazido or 4-dialkylpiperazonium dithiocarbamate group, a thiouronium group, an azido group or an alkoxy group with 1 to 4 carbon atoms, such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert

Butoxy group, means

3 8

R denotes the radical R O in which

I II- ₇

-CH -X-C-O-R

R is an alkyl group, such as methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, pentyl or 2-ethylhexyl group, a cycloalkyl group, such as the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, an aryl radical, such as the phenyl or naphthyl radical, an aralkyl group, such as the benzyl or naphthylmethyl radical, or a heterocyclic group, where the alkyl, cycloalkyl, aryl, aralkyl or heterocyclic groups unsubstituted or with one or more amino groups, substituted amino groups, such as methylamino, diethylamino or acetamido groups, Halogen atoms, such as fluorine, chlorine or bromine atoms, nitro groups, trifluoromethyl groups or alkoxy groups, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy or isobutoxy groups can be substituted,

R is -H, -CH ₃ or -C ₂ H ₅ , preferably "CH ₃ , and

30984A / 1117

X is NH or O, preferably 0 and

R is an alkoxy, alkylthio, aralkyloxy group or a halogen atom, preferably an alkoxy group.

Illustrative examples of radicals in the above definitions and within the definitions for the entire invention are as follows:

Alkyl: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, Hexyl, heptyl, octyl, 2-ethylhexyl.

Cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

Alkoxy: methoxy, ethoxy, propyloxy, isopropyloxy, butoxy, isobutoxy.

Halogen: F, Cl, Br.

Aryl: phenyl, naphthyl, naphthylmethyl, indanyl.

Aralkyl: benzyl, naphthylmethyl.

Keterocyclic Groups:

ο-

The above examples illustrate all of the residues where applicable

l 8
R to R and other radicals that appear in the description below, namely for the scope of the specified for each radical

30984W 1117

the definition and within the limits regarding the carbon atomic number that can be prescribed for the respective remainder.

According to a further aspect, the invention relates to chemical intermediates / which are new and useful in the preparation of the compounds of the formula I.

The compounds of the invention are of value in treatment of infectious diseases in humans and animals caused by bacteria. The connections can be isolated and can be used as such, but depending on the presence of basic or acidic groups in the molecule, they can also isolated and used in the form of salts with pharmaceutically acceptable organic or inorganic acids or bases will. Examples of suitable bases are sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, ammonium hydroxide, non-toxic amines, such as trialkylamines including triethylamine, procaine, dibenzylamine, N-benzyl-ß-phenetylamine, 1-ephenamine, N, N -dibenzylethylenediamine, dehydroabiet-t-ylamine, N, N bis-dahydroabiet-yl-ethylenediamine, N-lower alky! Piperidine (such as for example N-ethylpiperidine), and other bases that are used to produce of salts with cephalosporins or penicillins have already been used.

The side chain (R) of the compounds of formula I can be asymmetrical center included. Depending on the configuration around this center, the connection comes in different

309844/1117

-Jf-

diastereoisomeric forms, all of which are biologically active. In the same way, the ester group can contain asymmetric atoms, for example when R is the group CH, OC _O H _C O

I ³ β ₇ I ^{2 5} Il ₇

-CH -X-C-O-R or -CH -X-C-O- r '

means that different diastereoisomeric forms occur, all of which are also biologically active. Thus, the invention includes the pure diastereoisomers as well as mixtures thereof.

Compounds of the general formula

R ⁴
R ¹ - CO - NH - C - CH - S II

I \ I ₂

CO - N - R - COOH

12 4
wherein R, R and R are as defined above, possess valuable antibacterial properties and are therefore useful in the treatment of infectious diseases in humans and animals which are caused by bacteria. A large number of compounds of this type are described in Belgian patent 768 528 and Belgian patent 768 529. The compounds of the formula II can be synthesized from penicillanic acid or cephalosporanic acid or partly from 7- (D-5'-amino-5'-carboxyvaleramido) -3-acetoxymethyl-7-methoxy-3-cephem-4-carboxylic acid or the corresponding 3 - Carbamoyl oxy methyl derivative, which is obtainable by fermentation, can be produced.

In fighting infectious diseases it is desirable to use antibacterial To have agents that are well absorbed orally

3 0984A / 1 1 17

and thus an easy, convenient and safe treatment of the infection allow. It is an object of the present invention to obtain esters of the compounds of general formula II, which are well absorbed orally and then hydrolyzed in the body to provide blood and organ levels of the compounds of Formula II sufficient for the treatment of infectious diseases caused by bacteria that oppose the compounds of formula II are sensitive. To achieve the full antibacterial activity of the latter, it is necessary to select those ester groups that rapidly release the compounds of general formula II in vivo be hydrolyzed. It is an essential feature of the present invention to take those ester groups that are present in the body rapidly hydrolyzed after oral absorption.

The compounds of formula I are well tolerated, result in a low frequency of side effects and can easily be used in pharmaceuticals Preparations can be used, either as such or in the form of their salts, and they can be mixed with solid Carriers or auxiliaries or both »are mixed. In such Preparations, the ratio between the therapeutic substance and the carriers and excipients can be between 1% and 95% vary. The preparations can either be processed into tablets, pills or dragees, for example, or in medical containers, such as capsules, enclosed or bottled as mixtures. In the manufacture of the preparations you can pharmaceutically acceptable organic or inorganic, solid or liquid carriers can be used, expediently

30984A / 1117

-y-

for oral or enteral administration or for topical application. Gelatine, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, vegetable gum and polyalkylene glycol as well as other known carriers for pharmaceuticals are all for the manufacture of preparations of these compounds suitable. In addition, the preparation can also contain other pharmaceutically active compounds, which are useful together with the Compounds according to the invention can be administered for the treatment of infectious diseases, such as, for example, other suitable ones antibiotic substances such as gentamicin and polymyxin.

In treating bacterial infections in humans, for example, the compounds of the invention are used in appropriate amounts 5 to 200 mg per kg per day, preferably in the range from 10 to 100 mg per kg per day in individual doses, such as twice, three times, or four times a day. They are administered in dosage units, dLe for example 175, 350, 500 or 1000 mg of the compounds contain.

Examples of preferred compounds according to the invention are listed in the table below.

309844/1117

cc

■ * «

1005

to ι ο — ο

tO

ο =:

CvJ K O

ir »

VO O

in

CJ

ο ο

O = O

O I,

ο — ο

to

cn

CJ te ο

OJ K O

O O O

O to!

ο — ο

to

cm O

O I

rHO

P.

CM

VO

O Pn P.

CJ

to

309844/1117

O -O

O ITV CM 2311 CV I. - O ι ί VO • I. »3η O B. O CM O < O ^aa ^ 3 I. O 1 \ / O CM I. <ί \ / Κ "\ I SC O SC δ-B O I. VO I. O = O O ο CvJ I. ι I. J5 O to ι CM ι ο — ο
* * SC CC ο I. ο . ο P. O
I. I. ΙΛ O I. K I
CM K
O O ITV SC ΚΛ O ο — a: O ι I. ιη I. SC CM VD SC υ O I. <f SC VD O I. O κ SC I. (η

309844/1117

* γ * Ι

"\ y

kn te

KN

ο ο

Ni.

CC - OI

ο ο

cc

I 1

O O

cc '-''ι - * t
t
O
O
O
OJ
O
I.
O = O
I.
ITN O
^ oj tr;
ο — ο te td
ο ο
O
O
-. ^ = O
O
&
O 23T
I '
O
O = O
O
I.
OJ
O
I. KN
O
O
I. K
O
O
I. KN
O
O
1 I CC
ί
[■ I.
I.
SC
O
I.
O
ε o— ^:
I.
trf ■
VO
O
Eu I.
K KN
o-s
VO
O
I. U
is CO ί
ON i
____ "_ -I

3098A4 / 1 1 17

R ¹ - CONH - C

ic:

I I

N-

CH - COOR-

No. 10

12th

PFC ₆ H ₄ -CH-

NH

NH

P-HO-C ₆ H ₄ -CH-NH

In-HO-C ₆ H ₄ -CH-NHo

-OH,

-OH,

-OH,

-OH,

-CH ₂ -O-COO '

-CH-O-COO-CH ₂ -CH ₂ -NH-C-Ch ₃

CH ₃
CH

-j

Me

CH ₂ -O-COO-CH ₂ -CH-Me

Me

NJ

- ^ Tue

ta too

ta κ ο ο ο λ / I ¹

-ο

O {25

ΚΛ

CvJ U

O I O = O

-O

ta ο

CNJ

Cs! O I

CsJ

K O

O O O

O I

-O

οι

ντ \ K VD

O ; ι CM • O JlJ -ϋ I υ— ι VO ν—

309844/1 1 1

23-1005

3Ö9844 / 1117

OC

tO ΚΛΟ Vi υ —— ο .7.

-u-

O -O

t ι § Ü O j I. i I <J- f VO i υ t O i I. i P- \

Osa = O O CM

if

vo O

CvJ

O O

.1

ΚΛ

O I

CM

te

O I

U5 U

CM

309844/1 1 17

t U ■ in to . I. I. , -I to in to to f
ι to to ■ I. : - / 311005 ■ vo I. K cc ; CM O CC CC O
I. O CM • CC CM OJ O cc CVJ O VO O υ I. O cc LO O υ O O U
I. O O I. O I. O O CM O I. I. I. O = U
I. I. CM I. I. I. - I. O O I. to CC CM O • I I. CM O (it: 1 υ -d " CM I. O I.
O VD cc CM to ι υ O CM [ CC. CC I. I. O ι to t
I. O-O r-I CM I. υ to ! I. υ CC O U-O ι cc X I. O O I. O P. I. ι to U O O "—— \ I. O cc cc I.
. in ο I. υ co CM CM O O U CC I cc * I. E.
O \
i CM U O CVJ CC VD O
I. I. I. O CM O
I. I. I. cc CM Cr ₄ O CC I. I. O B. I. <r ο CC CM O Ü - ^ uv O co CM Κ O O > I.

30984 A / 1 1 17

to

O O \ / O I

i, _ I. * r V ^ * ί ^C M r J i ί i 1 # ■ j 1 } (

O I

CJ

CVJ

K O

O O

F OJ

te

U I

O O

O I. CJ

CJ O

CJ Ά

U O '

LTN O O O

O I

CJ

Ü t

(M

^ ZZ / 2311035

in

CJ

O = O

O -I

O O

! i K t CJ j O ■! O - O O ) O I. ! \ \

^ I

CM

CO CJ cn

CJ

ΝΛ

309844/1117

CM

/ Λ

r *

O-

I>

O O

Γ O

O I.

CM

CJ

CM

O O

O I.

Ö I.

-f

tf \

O I

U I

CM O

CM O

O O O

to

.CM

CM

+ S

rf *

CM

CM

2311001

CM

O I

κ \

30S8A4 / 1 1 17

ιη

co u

O - O

υ
ι

LP \

ι rs

309844/1117

co / V τ— in • I.
1 cn Γ ■ * «; IO in to I. O ■ o - pu = o 2311005 - • - * ■ - W. O- tO! O CvJ
O • OCH < I. 1
■ I. O- I.
CJ g!
O j I. O
I. I. ■ A, A, O -O j O = O I.
O i o — s r ~> r ! I. sT * rc ! ro to I.
in 1 I. 4th O O O Y pH
VO • i
i ] I. VJ
O O I. j I.
r> -O 1
*
1
j
I. ? ONI \ j (P O O- ) O I. / J
1 "" he:! vo I I. -S J O )
I.
j •
I. 5
? *
j O 4th
] VO < O I. ΓΟ '
< - T. to I. OCH I. , j ¹ r S5 j I. \ ! -

309844/1 117

Ci

O O

■ * «

-22-

υ ι

O I

CM O

-O

O I.

K O O

c \ j

cn

309844/1117

CM

in CS

υ ι

KN

CtS O O Ο — CJ

ΙΓΛ

O O

to

ν /

CJ S

-οι

π:

he:

O I *

ΚΛ Ι

K K

O O

irv

CM O

CJ

CJ

O I

<M

K O.

b = /

CM

3098AA / 1117

309844/1117 ORIGINAL INSPECTED

in

CO

CM

O.

χ,

"Ί

cc ο ο ο — ο

CC - OI

O O

ο -ο

\ U -25- X I. ω η CM E. CM E.
O S. ; ι CO E. O Ί ί Φ E Φ I. -0-C ι I. # S-O S CM \ CM »Γ O ί T- VD I. O O CM • E. O O O ι σ I. I. ο CM O ο E. pi I. ι -0-C CM in O LTv E -J E. O CM E VD I. O O O I. CC

309844/1117

-O

in

- CvJ O CJ I

CO t

r O

cn — o — o

26- pi rc ί KN OJ LfN CNi j KN KN KN ITN 2311005 I. ϊ I. I. JU O • O O
I. O K j KN J I.
I. CM f O I. VO I. I. VD { tn ■ I t G I. O f I. ο I ο! J ₃ -J O ί I. O CTi O I. T— O IXN O I. I. 1 I.
t υ O CM Co ι O K i O u I O Ü O ■ CM I. I. I. LCN OJ O (M j O KN I I f I. O O O CM j I. I. O: KN O I 1 KN KN K KN O LfN CC O K O O O CJ I. "" vo O I. O IfN O O ο — ο J £ - & ' ρ f I. In I. I. CM Ö O O O I. O KN I O U I.

30984A / 1117

a
ι

CVJ

O I.

CM

ο υ

ta ο-

■ Ν

(Λ

O O O

a:

υ ι

"α:

in

CM O

O O

υ ο

CM

cn

U Λ

30984W 1117

The compounds of the invention are prepared by different methods ^v chen.

Method a

R ⁴ R ¹ '-C0-NH-i- _fH - _{f + R} 3 _Y:

CO - N - R ^ - COOM III

• y

CO - NH - C - CH -

CO -N - * - R ² '-. COOR ⁵ IV

R ²

R ¹ - CO - NH - C - CH - S

ι ι ίο,

CO-N —R- COOR-

According to this method, a compound of formula III is preferred in the form of their salt, such as sodium, potassium, calcium, trialkylammonium or tetraalkyl

1 '2' 4 ammonium salt, where the groups R, R and R represent the groups

12 4
R, R or R in the above meaning are or derivatives of these groups protected on the amino or carboxy groups

3 3 th, with a compound R Y, in which R has the above meaning and Y is a halogen atom, preferably a chlorine atom, bromine atom or iodine atom, or a group functionally equivalent thereto, such as an organic sulfonic acid group, reacted to give compounds of Formula IV.

309844/1117

The reaction is preferably carried out in an organic solvent, such as acetone / tetrahydrofuran, chloroform, methylene chloride, dimethylformamide, dimethyl sulfoxide or hexamethyl phosphoramide, or in a mixture of water and an organic solvent, such as, for example, in aqueous dioxane or acetone , carried out.

The above-described use of tetraalkylammonium salts a penicillin or cephalosporin has not yet been described, so that this use is a new method of production of penicillin and cephalosporin esters. The preferred tetraalkylammonium salt in this method is Tetrabutylammonium salt, and the preferred solvents are Chloroform, methylene chloride and acetone.

1 · 2 '1 2

If R and R are the groups R and R, respectively, the compounds of the formula IV belong to the compounds according to the invention according to the general formula I. If they contain amino or carboxyl groups provided with protective groups, the protective groups can are removed in at least one additional stage and give compounds of the general formula I. As Protecting groups can be used which can be removed without destroying the β-lactam ring system. Such protecting groups are known in the art and are, for example, benzyloxycarbonyl groups, the o-nitrophenylsulphenyl radical, the 2-p-Tolylsulphonyläthoxycarbonylrest, the ß-Trichloräthoxycarbonylrest and the 1-methoxycarbony! propen-2-yl radical as a protective group

309844/1 117

pen for amino groups and, for example, the benzyl radical, the ß-trichloroethyl radical or the 2, G- ^ dichlorobenzyl radical for the Protection of carboxy groups. In order to obtain amino-substituted compounds of the general formula I, the corresponding Azido or nitro compounds, which also belong to the compounds of general formula I, are reduced, such as, for example by catalytic hydrogenation.

Method B.

R ¹ - CO - Z + H _n N -C-CH-

: h - s

III ₂ - 3

CO-N - R ^ - COOR ^

• VI

ΐ ■

R ¹ - CO - NH - C - CH - S

II ■ I ₂ - 3

CO-N - R- COOR ^

IV ^ ^v

R ¹ - CO - NPI - C - CH - S

CO - N - R ^ - COOR ^ I.

According to this method, an activated carboxylic acid derivative V, in which R is as defined in method A and -CO-Z is a means reactive group which can react with an amino group to form an amide residue, such as, for example, a Acid chloride or its functional equivalent, with a

2 · 3 4 reacted compound of formula VI, wherein R, R "and R as

30984W 1117

are defined above. This gives the ester IV. As stated above in connection with method A, this is Ester either a compound according to the invention of the general formula I or can be converted into such a compound by removal the protecting groups are converted.

The reaction between compounds V and VI is an acylation and can be described in that for the acylation of esters of 6-aminopenicillanic acid or 7-aminocephalosporanic acid Way to be carried out. The acylating group -CO-Z in the Formula V can contain an acid bromide group, an acid azide group, an acid anhydride group, one with an inorganic acid or an organic acid such as an alkyl carboxylic acid, for example Isobutyl carboxylic acid, a carboxylic acid, a sulfonic acid and especially an alkoxyformic acid, mixed anhydride group formed or a radical that can be obtained by reaction the <> - substituted phenylacetic acid and a carbodiimide or N, N -carbonyldiimidazole or another in the like Way responsive connection receives.

The reaction can be carried out in organic solvents such as in diethyl ether, tetrahydrofuran, acetone, ethyl acetate, chloroform, methylene chloride, dimethylformamide, Whore thy lsulf oxide or hexamethylphosphoramide, you can but also in water or in aqueous organic solvents in the presence of organic or inorganic bases, such as Triethylamine, quinoline, pyridine, N-methylmorpholine, sodium hydroxide, sodium bicarbonate or potassium carbonate.

^the '309844/1117

The esters of the general formula VI can by treatment
of salts of the corresponding acids of the formula

v.-ff: f ₂ .

CO - N - R - COOH VII

with RY, where R and Y have the above meaning. The reaction is preferably carried out in organic solvents, such as in dimethylformamide, dimethyl sulfoxide
or hexamethylphosphoramide.

1 ·

Other compounds of the formula IV in which R - COr is an acyl

group means that without destroying the ß-lactam ring system
can be removed, are in compounds of formula VI
convicted. A preferred acyl group is the phenylacetyl group, which is removed by treatment with phosphorus pentachloride in the presence of a tertiary organic base to form an iminochloride, which in turn is hydrolyzed by adding water, according to the method described in Dutch patent 6,401 4 or South African patent application 67/2927 or alcoholysed by the addition of alcohol to give the ester VI. Instead, the phenylacetyl side chain can be produced by enzymatic hydrolysis using
E. coli ^A cyclase in analogy to the procedure described in French Patent 1,576,027 method be removed.

30984W 1117

Another method uses N-protected derivatives the acids of the general formula VIII

R ⁹ - HN - C - CH - S.

CH

II ₂ ' CO-N - R - COOH

VIII

2 '4 9

wherein R and R are as defined above and R is a protective group which can be removed without destroying the ß-lactam ring system, reacted with RY by method A to form corresponding esters, from which the protective groups are removed to form the compounds of formula VI will.

Examples of protecting groups that can be used are the benzyloxycarbonyl group formed by catalytic hydrogenation is removed the o-nitrophenylsulphenyl group, which by treatment can be removed with nucleophilic agents at acidic pH (Japanese Patent 505 176), as well as the Trity! group, which can be removed by mild acidic hydrolysis. Other methods of making the compounds of Formula VI are the conversions of the corresponding 6-aminopenicillanic acid and of compounds of the formula

H ₂ M - CH - CH CH ₂

- CH ₂ - R ₅

COOH 309844/1117

via the qiazo derivatives of the formula

- CH - S

R ² - COOR ¹⁰

IX

wherein R has the above meaning and R means R or a protective group for the carboxyl group, which without destruction of the β-lactam ring system can be removed, such as, for example, a methyl, benzyl, trimethylsilyl or trialkyltin group. Such methods are known per se. If R is in the Formula IX R denotes, where R is as defined above, the compounds of the formula IX are new.

In one embodiment of method B, the connection of the Formula IX with a halogen azide, such as a bromine, chlorine or iodine azide, in the presence of a tertiary amino azide Formation of a compound of the formula

Hal

- CH - S

- R - CCOR ¹

XI

implemented, wherein Hai is a chlorine, bromine or iodine atom and

2 10

R denotes the group R in the above definition, according to which the compound of the formula XI by reaction with a suitable nucleophilic agent, such as, for example, an alcohol, is converted into a

3 0 9 8 L k! 1 1 1 ⁿ

Compound of the general formula XII

R ⁴ - C - CH - S

CO Λ -R ² -COOR ¹⁰

XII

is converted, in which R, R and R have the above meaning, after which the compound of formula XII to a compound of the formula VI or by carrying out the reduction in the presence of a suitable acylating agent into a compound of formula I is converted.

As a suitable starting material, the following can be found by Fer-r Compounds available mentation (French patent application 2 104 768) can be used:

OCH,

³ S

HOOC - CH ν (CH ₉ ), - CO - NH -C-CH CH ₀ I II I

I.
CH-

- CH ₂ R ¹²

COOH

12th

where R is an acetoxy group, carbamoyloxy group or the group -) OH '. means.

icii, ^ '

309844/1117

According to methods known per se, the 4 -adipoyl side chain can be removed or replaced by groups R -CO-, whereby one Compounds obtained which can be converted into compounds of the formula I according to the invention by the methods described above.

The starting material of the formula X can also be in a form can be used in which the ring carboxyl group is esterified with a group R in the above definition.

Method c

According to this method, a natural penicillin or cephalosporin of the general formula is made

R ⁴
R-CO-NH-C-CH-S ^N Ϊ

ι ■ ι L - ■ ■

CO-N- R - COOM j

■ f f

XIII '

2 '4

where R and R have the above meaning and RCO- is the acyl group in the side chain of the natural penicillin or cephalosporin and M is a hydrogen atom or for example an alkali metal atom, v / ie sodium or potassium, or an alkaline earth metal atom, v / ie calcium, by reaction with a compound of the general formula R-Y, in which R and Y have the above Have meaning, implemented, before the ester of formal XIV formed in this way

309844/1117

R-CO-NH-C - CH - S

CO - N - ΪΓ - COOR ^

XIV

is reacted with a phosphorus halide in an inert solvent and expediently in the presence of a tertiary amine to form an iminohalide compound, which in turn is reacted with a low molecular weight alcohol to form an imino ether derivative, which is then reacted with a compound of the general formula V

R ¹ - CO - Z

wherein R and 2 have the above meaning, is reacted and the resulting reaction product with water or an Alko hol to form a compound of the formula IV

R ¹ - CO - NH - CC

H-

R ² - COOR ⁵

IV

is treated. This connection is then in a connection of the formula I according to the oban described under method A

309844/1117

surrounded converted method.

With this method there? Intermediate product, the imino ether compound, acylates directly without isolating any intermediate products. The group RCO- in the compound of the formula XI-II is an organic acyl group which is contained in known natural penicillins and cephalosporins. Thus, the group R can be an alkyl group, cycloalkyl group, aryl group, aralkyl group

group or a heterocyclic group or a derivative thereof Be groups. Examples of suitable phosphorus halides are phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, Phosphorus trichloride, etc. Phosphorus pentachloride is preferred. Examples of suitable alcohols with which the iminohalide are lower alkyl alcohols such as methanol, ethanol and n-propanol.

As described above, the starting material can be in the form a salt such as a sodium, potassium, calcium or trialkylammonium salt can be used in various ways to prepare the compounds of the invention.

In addition, tetraalkylammonium salts and other analogous salts can be used, wherein the cation has the formula

A ¹ A ² A ³ A ⁴ NS

has, wherein A ^{1 is} a straight-chain or branched-chain alkyl group with 3 to 6 carbon atoms, a substituted or unsubstituted aryl radical or a substituted or unsubstituted

2 3 4 denotes aralkyl group and A, A and A are identical or

30984W 1117

can be different and straight chain or branched chain

Alkyl groups with 1 to! «6 mean carbon atoms, where A ² ,

4th
A and A are alkyl groups with 3 to 6 carbon atoms »if

A is an alkyl group.

12th

Illustrative examples of suitable combinations of A , A , A and A in the quaternary ammonium ion AAAAN are compiled as follows:

are after

Table I. Examples of checked tombi «etions of the remainders A JsIs A in the

Ion A ¹ A ² A ³ A ⁴ N

n-propyl n-propyl i-propyl i-propyl n-butyl n-butyl i-butyl i-butyl n-pentyl n-pentyl n-kexyl n-hexyl Phenyl methyl Phenyl ethyl p-tolyl ethyl p-chlorophenyl ethyl

n-propyl

i-propyl

n-butyl

i-butyl

Λ-pentyl

n-hexyl

methyl

ethyl

ethyl

ethyl

n-propyl i-propyl n-butyl i-butyl n-pentyl n-flexyl Methyl ethyl ethyl ethyl

1 4

If the radicals A through A are all different, the resulting contains Ion has an asymmetric center and can be divided into two

309844/1 117

tiomsren forms exist. Epimeric forms can occur, though

12 3 4

A, A _r A and / or A contain one or more asymmetric carbon ato ::: e.

Examples of quaternary ammonium ions that have an asymmetric center are listed in Table II below:

Table II

Examples of quaternary ammonium ions AAAAN ^, which are an asymmetric Center included

Benzyl n-propyl i-propyl n-butyl Benzyl n-propyl i-propyl sec-butyl Benzyl n-propyl n-butyl sec-butyl n-propyl n-propyl n-butyl se c-butyl n-propyl n-propyl n-propyl sec-butyl n-propyl n-propyl n-propyl sec-pentyl n-propyl n-propyl n-propyl sec-hexyl n-propyl n-propyl n-butyl sec-hexyl

The above-described use of a quaternary salt des Starting material for the preparation of the compounds according to the invention was previously in the literature, which this technical Area concerns, not described. In this method, the preferred cation is the tetraalkylammonium ion, especially the tetra-

309844/1 1 1 7

butylamirionium ion. The preferred solvents are chloroform, Methylene chloride and acetone.

The quaternary ammonium salt of the starting material described above can by reacting the starting material in question with a quaternary ammonium salt of the formula

A ¹ A ² A ³ A ⁴ N ⁺ BG

12 3 4 where A, A, A and A 'are as defined above and B is a suitable anion, such as HSO. , Cl ^ or CH ₃ COO ^ which is capable of forming a quaternary salt of the starting material.

The salts of the above formula containing B as the anion can be prepared in a manner known per se, analogous to the information in Belgian patent specification 751 791. The anion B ^ in the preferred embodiment is HSO. ^

The following examples serve to further illustrate the invention.

example 1

Production of ß-Phenylacetamido-eo ^ -methoxypenicillanäure- 3- (1 -äthoxycarbonyloxyäthyl) -ester

3t / -chlorodiethyl carbonate (304 mg, 2 mmol) in dry dimethylformamide (0.5 ml) was added dropwise to a stirred and cooled Suspension of 6 ß-phenylacetamido-6 o ^ -methoxypenicillanic acid sodium salt (773 mg, 2 mmol) and potassium iodide (50 mg) in

309844/1 1 17

added dry dimethylformamide (1.5 ml). Stirring was continued for 48 hours at +4 ⁰ C.

Ethyl acetate (25 ml) was added and the mixture was sequentially washed with saturated sodium bicarbonate solution and sodium chloride solution. After drying, the organic Phase evaporated and the residue (455 mg) on a silica gel column (15 g) with a mixture of isopropyl ether and acetone (9: 1) chromatographed. The fractions were examined for TLC using the same solvent system. The desired one Compound became a white foam (177 mg, 18.4%) from a the middle fractions of the eluate isolated.

This substance was uniform by TLC. _The infrared spectrum (KBr tablet) had an absorption maximum (cm) at 1,780 to 1,755 (ß-lactam and ester) and at 1,670 (amide) τ The nuclear magnetic resonance spectrum (NMR) in deuterochloroform showed absorptions (ppm (<> ^r ) of tetramethylsilane ) at 7.35 (s, CgH, -); 6.80 (q, OCH (CH4) O); 5.58 (s, 5-H); 4.35 (s, 3-H); 4.22 (q, OCH-CH ₃ J; 3.63 (s, CgH ₅ CH ₂ O); 3.38 (s, OCH ₃ J; 1.58 (s, according to CH ₃ ); 1.45 (d, OCH (CH ₃ ) O); 1.25 (t, OCH ₂ CH ₃ ).

Analysis: Calculated for C ₂₂ H ₂₈ N ₃ O ₈ S (480.55): C, 54.99; H 5.87; N 5.83; 0 26.64; S 6.67%
Found: C, 55.12; H 5.96; N 5.73; 0 26.42; S 6.52%.

The degree of hydrolysis of all penicillin and cephalosporin esters described here was measured in Sörensen buffer solution (B), in

309844/1117

50% human serum (H) and in 5% rat serum (R) determined in the presence of 10% dimethyl sulfoxide, the pH each mixture was adjusted to 6.8. The mixtures were incubated at 37 C, with at different time intervals Samples were taken. The concentration of the released free penicillin or cephalosporin was after the microbiological cup and plate method measured, and the fourth in% after 3 hours (B3 and H3) and 1 hour (Rl) are listed. The degree of hydrolysis of that described in this example Substance was: B3 = 6.8%; H3 = 39.5%; Rl = 102%.

The following esters were also prepared in the same way: 6β-phenylacetamido-6 o ^ -methoxypenicillanic acid-3- (1'-cyclopentyloxycarbonyloxyethyl ester) and -3- (ethoxycarbonylaminomethyl) esters and also 7β-phenylacetamido-72 ^ -methoxydesacetoxycephalosporanic acid - (1'-Ethoxycarbonyloxyethyl) ester.

Example 2

Production of eß-phenylacetamido-e'y ^ -'-methoxypenicillanic acid 3- (2-azido-ethoxycarbonyloxymathyl) ester

Chloromethyl-2-azidoethyl carbonate (540 mg, 3 mflol) in dry Dimethyl sulfoxide (0.5 ml) was added dropwise to a stirred and cooled suspension of ß-phenylacetamido-e. ^ - methoxypenicillanic acid potassium salt (1.2 g, 3 mmol) in dry dimethyl sulfoxide (1 ml) was added. The stirring was at room temperature Continued for 5 hours.

309844/1117

Ethyl acetate (30 ml) was added and the mixture was dissolved in Worked up in a similar manner as in Example 1 and chromatographed on silica gel (25 g). The desired ester was found to be a Foam (750 mg, 49.5%) isolated from one of the middle fractions of the eluate.

This substance was uniform by TLC. IR spectrum: 2150 <azido); 1775-1745 (β-lactams and esters); 1675 (amide); NMRs 7.35 (s, C ₆ H ₅ ); 5.82 (s, OCH ₂ O); 5.52 (s, 5-H); 4.40-4.32 (a, 3-H, OCH ₂ CH ₂ N ₃ ); 3.64 (s, C ₆ H ₅ CH ₂ CO); 3.50 (t, OCH 3.40 (s, OCH ₃ ); 1.55 (s, according to CH ₃ ).

Analysis: Calculated for ^C ₂ 1 ^H 25 ^N 5 ° 8 ^S ^ ⁵⁰⁷ * ⁵⁴ ) ^{1 c} 49.70; H 4.96; N 13.8O; O 25.22; S 6.32.
Found: C, 49.86; H 5.15; N 13.62; 0 25.18; S 6.15.

Degree of hydrolysis: B3 = 13.5%; H3 = 48.3%; Rl = 99.2%.

In the same way, β-phenylacetamido-eo ^ -methoxypenicillanic acid-3-t: is-2-methyl-1, S-dioxanyl-S-oxycarbonyloxymethyl) ester and 7ß-phenylacetamido-7 ^; 9 ^ - methoxydesacetoxycephalosporanic acid 3- (ethoxycarbonyloxymethyl) ester.

Example 3

Preparation of 7β- (D-oO-aminoxyphenylacet-amido) -7O ^ -methoxydesacetoxycephalosporanic acid 3- (1'-ethoxycarbonyloxyethyl) ester hydrochloride

(a) To a stirred and ice-cold suspension of 7ß- (D-cO-

309844/1117

Azidophenylacetainido) -7OC -methoxydesacetoxycephalosporanic acid sodium salt (951 mg, 2 rtiMol) and sodium hydrogen carbonate (0.5 g, 6 ml) in 50% dioxane (4 ml) became fcC-chlorodiethyl carbonate (912 mg, 6 mmol) added in one portion. The stirring was continued at room temperature for 64 hours.

The precipitate was filtered off with carbon tetrachloride (2 times 5 ml) washed, separated off, and the organic phase was successively washed with saturated sodium hydrogen carbonate solution and washed water. After drying and evaporation, the residue (385 mg) was deposited on a silica gel column (15 g) with a mixed solvent Chromatographed (4: 6) of carbon tetrachloride and dry chloroform. The desired ester was found to be a heavy oil (210 mg, 20.2%) isolated from one of the middle fractions of the eluate.

The substance was uniform by TLC. IR: 2070 (azido), 1780 to 1755 (β-lactam and esters); 1665 (amide).

(b) The azido ester (200 mg) was dissolved in ethyl acetate (12 ml) and hydrogenated over palladium-on-carbon (200 mg, palladium content 10%) at room temperature and normal pressure. After 2.5 hours the catalyst was filtered off, water (5 ml) was added to the filtrate at +3 ⁰ C, the pH was adjusted to 2.0 with 1 η hydrochloric acid, the two layers were separated, the water phase with Isopropyl ether extracted and the isopropyl ether-free water phase freeze-dried.

The dried product (134 mg, 6 3.5%) was according to TLC under Ver

309844/1117

conversion of a solvent system of butanone, pyridine, water and acetic acid (70: 15: 15: 2) uniformly. IR: 1770 to 1760 (β-lactam and esters); 1690 (amide). NMR: 7.35 (s, CgH ₅ ); .6.75 (q, OCH (CH ₃ ) O); 5.10 to 5.05 (m, C ₆ H ₅ CHCO, 6-H); 4.15 (q, OCH ₂ CH ₃ ); 3.45 (s, OCH ₃ ); 3.25 (d, SCH ₂ O; 2.10 (s, CCH ₃ ); 1.45 (d, OCH (CH ₃ ) O); 1.20 (t, OCH ₂ CH ₃ ). Analysis: calculated for C ₂₂ H ₂₈ N ₃ OgSCL (530.01): C 49.86;

H 5.32; N 7.93; 0 24; 15; S 6.05; Cl 6.69.

Found: C, 49.98; H 5.44; ίί 7.86; 0 24.30; S 6.02;

Cl 6.8-8.

Degree of hydrolysis: B3 = 9.8%; H3 = 42.5%; Rl = 112%.

6ß- (D-oL -aminophenylacetamido) -6 ^ O methoxy-penicillanic acid S- (1 '-isopropoxycarbonyloxyethyl) ester hydrochloride and 7ß- (Dc ^ -amino-phenylacetamido) -7o ^ -methoxydesacetoxycephalosporanic acid-3- (1 '-cyclopentyloxycarbonyloxyethyl) ester hydrochloride produced.

Example 4

6β- (2-Thienylacetamido) -Gc ^ -methoxypenicillanic acid-S- (1'-ethoxy carbonyloxyethyl) ester

(a) To a mixture of methylene chloride (200 ml), crushed Ice (200 g) and matriuronitrite (1.72 g, 25 mmol) was inside of 5 minutes with vigorous stirring 6-aminopenicillanic acid-3-

(1'-Ethoxycarbonyloxyethyl) ester-p-toluenesulfonic acid salt (2.52 g, 5 mol) was added. To the reaction mixture was added p-toluenesulfonic acid monohydrate (0.95 g, 5 ml-lol) in portions v / over over 10 minutes. Stirring was continued at +5 ⁰ C for 30 minutes.

3098iU / 1117

set. The two phases were separated, the organic phase was dried (MgSO ₄ ) and evaporated to a smaller volume (15 ml).

(b) To this solution were added nitromethane (15 mils and triethylammonium azide (about 4.30 g, 30 mmol) in methylene chloride (23.8 ml). The reaction mixture was ^{cooled to 0} ° C. and bromine azide (about 1.22 g, 10 mmol) in methylene chloride (17.2 ml) was added dropwise over 1 minute. After 5 minutes, 0.2 η sodium thiosulfate solution (about 20 ml) and after a further 3 hours excess sodium bicarbonate were added to the vigorously stirred mixture the two phases were separated, the water phase was extracted with methylene chloride (2 times 15 ml), the combined organic phases were washed with cold 1.0 η potassium bicarbonate solution (2 times 10 ml), dried (MgSO *), and the unevaporated solution was absorbed A KieeeIgelsäule (12Ο g) applied and chromatographed with a solvent mixture of carbon tetrachloride and isopropyl ether (9: 1) The desired azido compound was isolated as an oil (0.282 g) from one of the middle fractions of the eluate.

IR: 215Ο (azido); 179Ο - 1760 (ß-lactam and esters).

(c) The isolated 6β-azido-6 Cl · -brompenicillanic acid ester (0.265 g, 0.61 mmol) was dissolved in methanol (22 ml) and, after addition of silver tetrafluoroborate (150 mg, 0.77 mmol), stirring was stopped while Continued for 2 hours at room temperature. Then the suspension was evaporated in vacuo, the residue with methylene

309844/1117

Chloride (3 times 20 ml) extracted through Hyflo filter aid filtered and successively with saturated sodium bicarbonate solution and sodium chloride solution. After drying (MgSO-) the solution was evaporated and again on a Chromatographed silica gel column (40 g) with the same solvent system as before.

The pure ß-azido-eoo-methoxypenicillanic acid ester was isolated from one of the middle fractions of the Eluafrs (268 mg) and identified on the basis of its spectra. IR: 2145 (azido); 1795 1760 (ß-lactam and ester). NMR: 6.75 (q, OCH (CH ₃ ) O); 5.40 (s, 5-H); 4.53 (s, 3-H); 4.15 (q, OCH ₂ CH ₃ ); 3.65 (s, OCH ₃ ); L50 - 1.45 (m, according to CH ,, OCH (CH,) 0) .; 1.30 (t, OCH ₀ CH.,).

(d) 6β-AzidOT6 & * -methoxypenicillanäure-S- (1'-ethoxycarbonyloxyethyl) ester (0.77 g, 2 mmol) was dissolved in ethyl acetate (50 ml) over palladium-on-charcoal (0.8 g, palladium content 10%) Hydrogenated at room temperature and normal pressure. After 3 hours the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue (0.72 g) was dissolved in cold, dry methylene chloride (60 ml) containing pyridine (1.2 ml) and, with efficient stirring, 2-thienylacetyl chloride (0.8 g, 5 mmol ) in dry methylene chloride (5 ml) was added. After stirring for one hour, cold 0.5 μm sodium bicarbonate solution (16 ml) was added, the two phases were separated, and the water phase was extracted with methylene chloride. The combined organic phases were washed with cold water, dried and evaporated. The residue was on a

309844/1117

Silica gel column (40 g) irritates a mixture of benzene and isopropyl ether and acetone (5: 4: 1).

One of the middle fractions became the desired product
(0.52 g, 53%) and this was uniform by TLC using a mixed solvent of isopropyl ether and acetone (7: 3).

IR: 1785-1750 (β-lactam and esters) ;, 1690 (amide). ·
NMR: 7.20 (s, thienyl); 6.75 (q, OCH (CH ₃ ) O); 5.55 (s, 5-H);
4.32 (s, 3-H); 4.15 (q, OCH ₂ CH ₃ ); 3.90 (5, (C ₄ H ₃ S) CH ₂ O); 3.42
(s, OCH ₃ ); 1.60 (s, according to CH ₃ ); 1.45 (d, OCH (CH ₃ ) O); 1.30 (t,
OCH ₂ CH ₃ ).

Analysis: Calculated for C ₂₀ H ₂₆ N ₂ O ₉ S ₂ (486.58): C, 49.37;

H 5.33; N 5.76; 0 26.31; S 13.18.

Found: C, 49.46; H 5.64; N 5.38; 0 26.28; S 13.02.

Degree of hydrolysis: B3 = 2.8%; H 3 = 29.6%; Rl = 87.4%.

In the same way, 6β- (2-thienylacetamido) -6 / ^ - methoxypenicillanic acid 3- (1'-phenoxycarbonyloxyethyl) ester was obtained and 7ß- (2-thienylacetamido) -6 cc- -methoxy-acetoxycephalosp-oranoic acid 3- (1'-ethoxycarbonyloxyethyl) ester manufactured.

6ß- (D- rf * -aminophenylacetamido) -e / ^ - methoxypenicillanic acid-S- (1'-phenoxycarbonyloxyethyl) ester hydrochloride

(a) 6ß-Azido-6 Cl · · -methoxypenicillanic acid 3- (1'-phenoxycarbonyloxyethyl) ester (1.2 g, 3 mmoles; prepared in a manner similar to

309844/1117

in Example 4) was hydrogenated in ethyl acetate (85 ml) over palladium carbon (1.0 g, palladium content 10%) at room temperature and normal pressure. After 3.5 hours, the catalyst was filtered off and (continuous addition and evaporation of methylene chloride under vacuum at +20 ⁰ C) changed without the solvent evaporation on methylene chloride and adjusted to the required volume (100 ml).

(b) The solution was cooled and pyridine (1.8 ml) and, with vigorous stirring, D - ^ - azidophenylacetyl chloride (1 _# 6 g, 8 mmol) in dry methylene chloride (8 ml) were added over 5 minutes. After stirring for one hour, cold 0.5 μm sodium bicarbonate solution (24 ml) was added, the two phases were separated, and the water phase was extracted with methylene chloride. The combined organic phases were washed in cold water, dried and evaporated. The residue (1.55 g) was chromatographed on a silica gel column with a mixture of isopropyl ether and acetone (8: 2). A uniform neutral substance (1.18 g, 69.1%) was isolated in one of the middle fractions of the eluate. IR: 2150 (azido); 1785-1760 (β-lactams and esters); 1685 (amide).

(c) This substance was dissolved in stylacetate (55 ml) over palladium carbon (0.7 g, palladium content 10%) hydrogenated without stirring. After two hours of hydrogenation, the catalyst was filtered off,

to the filtrate was added water (30 mL) at ⁰ +3 C, the pH was adjusted with hydrochloric acid to 2.7 η 1, the two

309844/1117

Layers were separated, the water phase was washed with isopropyl ether extracted, and the isopropyl ether-free Viasser phase was freeze dried.

The dry product (680 mg, 58.5%) was uniform by TLC analysis.

IR; 1790-1765 (β-lactams and esters); 1700 (amide). NMR: 7.32 (s, 2 CgK ₅ ); 6.84 (q, OCH (GH ₃ ) O); ' 5.15 to 5.10 (m, C ₆ H ₅ C H CO, 5-H); 4.35 (s, 3-H); 3.40 (s, OCH ₃ ); 1.50-1.45 (m, according to CH ₃ , OCH (CH ₃ ) O).

Analysis: Calculated for C ₂₆ H ₃₀ N ₃ O ₃ SCl (580.10): C 53.83; H 5.21; N 7.25; O 22.06; S 5.53; Cl 6.11.

Found: C, 53.72; H 5.42; N 7.18; 0 22.14; S 5.42; Cl 6.20.
Degree of hydrolysis: B3 - 9.6%; H3 = 39.8%; Rl = 91.1%.

Similarly, 6β- {D-c ^ -amino-phenylacetamido) -6c7C-methoxypenicillanic acid 3- (1'-ethoxycarbonyloxyethyl) ester hydrochloride and 7β- (D-o ^ -amino-phenylacetamido) ^ oC'-inethoxydesacetoxycephalosporanic acid 3- (1'-ethoxycarbonyloxyethyl) ester hydrochloride manufactured.

Example 6

6ß- (D-.TC-acetylureido-phenylacetaraido) -6 <* - -methoxypenicillanic acid 3- (1'-phenoxycarbonyloxyethyl) ester

To a shaken and ice-cold suspension of 6ß aminophenylacetamido) -6 c ^ -mnethoxypenicillanäure-3- (1 '-phenoxy-

30984 4./1117 "

carbonyloxyethyl) ester hydrochloride (435 mg, 0.75 mmol) and dry Triethylamine (75 mg, 0.75 mmol) in dry methylene chloride (5 ml) was acetyl isocyanate (65 mg, 0.75 mcol) in dry Methylene chloride (1 ml) added. After 30 minutes, water (5 ml) was added, the two layers separated and the organic layer was washed with cold water (2.5 ml). After drying, the solution was evaporated and the residue (290 mg) on a short silica gel column (9g) with a Mixture of isopropyl ether and acetone (8: '2) .chromatographed. The desired product was found as a heavy oil (185 mg, 39.4%) isolated.

The substance showed only one spot on TLC analysis. IR: 1780-1760 (β-lactam and esters); 1700-1680 (amide). NMR: 7.32 (s, 2CgH ₅ ); 6.84 (q, OCH (CH ₃ ) OJ; 5.9O (d, C ₆ H ₅ CHO); 5.05 (s, 5-H); 4 _f 33 (s, 3-H); 3, 45 (s, OCH ₃ ); 2> 10 (s, NHCOCH ₃ ); X, 55 (s, according to CH ₃ ); 1.45 (d, OCH (CH ₃ ) O). Analysis: calculated for ^C ₂ 9 ^H 32 ^N 4 ° 10 ^S ^ ^{628 '68} ) ^{: c} 55.40; H 5.13; N 8.91; 0 25.45; S 5.10.

Found: C, 55.56; H 5.18; N 8.80; 0 25.58; S 5.12.

Degree of hydrolysis: B3 = 6.5%; H3 = 36.5%; Rl = 90.4%.

In the same way were 6ß- (D- ^ C-2'-furylureido-phenylacetamido) - 6 oo-rttethoxypenicillanäure-3- (1'-äfchoxycarbonyloxyäthyl) -ester and 70- (D-ciC-Acetylureido-phenylacetamido) -7CS ' -methoxydesacetoxycephalosporanic acid 3- (1'-athoxycarbonyloxyethyl) ester.

3098AA / 1117

Example 7

73 - (^ - Carboxyphenylacetamido) - ^^ o-methoxydesacetoxycephalosporanic acid-.T ^ -ethoxycarbonyloxymethyl-S- (1 '-äthoxycarbonyloxyäthyl) diester

(a) To a stirred and ice-cold suspension of potassium phenyl acetate (43.5 g, 0.25 mmol) in dry dimethyl sulfoxide (80 ml) was added dropwise chloromethyl ethyl carbonate (27.7 g, 0.20 mmol). Stirring was at room temperature for 18 hours continued. The mixture was in an ice-cold 0.5 η Poured sodium bicarbonate solution (500 ml), and after 20 minutes it is poured While stirring, the mixture was extracted with ethyl acetate (3 times 150 ml). The combined organic phases were washed with cold water washed, dried and evaporated. The crude oil (44.9 g, 94%) was used in the next stage.

(b) To a stirred solution of N-isopropyl-cyclohexylamine (13.0 g, 60 mmol) in dry tetrahydrofuran (60 ml) was a 1.5 η solution of n-butyllithium in hexane (40 ml, 60 mmol) added under a nitrogen atmosphere and at -78 ° C. To A solution of the ethoxycarbonyloxyrcathylphenyl acetate obtained above became 15 minutes (13.0 g, 54.5 mmol) in dry tetrahydrofuran (40 ml) was added dropwise over 1 hour, and then an excess of powdered dry corn was added and stirring continued for 13 minutes. The reaction mixture was added dropwise to ice-cold 2N hydrochloric acid (100 ml), and after stirring for 15 minutes, this mixture was washed with chloroform (3 times 75 ml) extracted. The combined organic phases were

309844/1 1 17

the washed with cold water, water (100 ml) was added and the pH was adjusted to 7.5 with 1 N sodium bicarbonate solution. The organic phase was washed with water. After washing with chloroform, the combined water phases were added to diethyl ether and the pH was adjusted to 2.0 with 2N hydrochloric acid. The water phase was washed with ether, the combined organic phases were washed with cold water and dried. Evaporation gave a crystalline residue (9.7 g, 63%) which was identified as -Pheny! Malonic acid methoxycarbonyloxymethyl monoester. IR: 3700-2150 (carboxyl); 1755 (ester); 1690 (carbonyl). NMR: 9.50 (s, COOH); 4.19 (q, OCH ₂ CH ₃ ); 1.23 (t, OCH ₂ CH ₃ ).

(c) The phenylmalonic acid ethoxycarbonyloxymethyl monoester (1.13 g, 4 mmol) was stirred with thionyl chloride (1.67 g, 14 mmol) at 65 C for 1 hour and then together with dry benzene (4 times 25 ml) distilled. The crude acid chloride (1.20 g, 4 mmol) was dissolved in dry methylene chloride (5 ml) and added dropwise to a stirred and ice-cooled mixture of 7ß-amino-7; rC methoxydesacetoxycephalosporanic acid S- (1'-ethoxycarbonyloxyethyl) ester, made from öß-azido-ec ^ -methoxydesacetoxycephalosporanic acid (1.3 g, 3 mmol) in a manner similar to that described in Examples 4 and 5, and dry triethylamine (0.50 g, 5 mmol) in dry methylene chloride (35 ml) was added. Stirring was continued for 90 minutes, then cold water (40 ml) was added and the pH was adjusted with 2N hydrochloric acid set to 2.0. The organic phase was separated and washed successively with saturated sodium bicarbonate solution and sodium

3098AA / 1117

chloride solution washed. After drying and evaporation, vmrde the residue (1.4 g) on a silica gel column (40 g) prepared in dry benzene, chromatographed. The residue, dissolved in the smallest amount of benzene, was applied and eluted by the step method, with the second solvent Isopropyl ether / acetone (8: 2) was used. The collected Fractions were analyzed using TLC on silica gel investigated the same solvent mixture.

The substance was isolated as a white powder (855 mg, 47.5%) from one of the middle fractions of the eluate. It only gave one spot in TLC analysis.

IR: 1785-1735 (β-lactam and esters); 1685 (amide).

NMR: 7.25 (s, C ₆ H ₅ ); 6.70 (q, OCH (CH ₃ ) O); 5.78 (s, OCH ₃ O);

4.95 (s, 6-H); 4.65 (d, C ₆ H ₅ C H CO); 4.20-4.10 (m, OCH ₂ CH ₃ ); 3.35 (s, OCH ₃ ); 3.10 (d, SCH ₂ O; 2.05 (s, CCH ₃ ); 1.40 (d,

OCH (CH ₃ ) O); 1.30-1.20 (m, 2 OCH ₂ CH ₃ ).

Analysis: Calculated for C ₃₆ H ₃₂ N ₂ O ₁₃ S (612.64): C 59.97; H 5.27;

: i 4.57; 0 33.95; S 5.23.

Found: C, 60.08; H 5.42; N 4.52; 0 33.8O; S 5.22.

Degree of hydrolysis: B3 = 1.3%; H3 - 24.8%; Rl = 87.5%.

In the same way 6ß- (oC-carboxyphenylacetamido) methoxypenicillanic acid- <70- (ethoxycarbonyloxymethyl) -3- (1'-ethoxycarbonyloxyethyl) -diester and -3- (1'-phenoxycarbonyloxyethyl) -diester manufactured.

30984W 1117

Example 8 Pharmaceutical preparations

The following recipes were used to produce tablets applied:

a) eß-Phenylacetamido-eö ^ -methoxypenicillanic acid-

3- (1'-ethoxycarbonyloxyethyl) radical 4OO mg

Strength _m 100 mg

Magnesium stearate 10 mg

b) 7ß- (ö ^ -CarboxyphenylacetamidoJ-T. ^ - methoxydesacetoxycephalosporic acid - ^ - ethoxycarbonyloxymethyl-3- (1'-ethoxycarbonyloxyethyl) -

diester 350 mg

Calcium carbonate 100 mg

Magnesium stearate 10 mg

c) Tβ-Phenylacetamido-T-ioC-methoxydesacetoxycejphalosporaic acid 3- (1'-ethoxycarbonyloxyethyl) ester 4OO mg

Lactose 100 mg

Magnesium stearate 10 mg

309844/1117

Claims (14)

Claims R is a hydrogen atom, an alkanoyloxy group such as the Acetoxy group or propionyloxy group, a carbonyloxy group, such as the methylaminocarbonyloxy group, or the 1-pyridinium radical, where the alkanoyloxy groups, Carbonyloxy groups and the 1-pyridinium radical with one or more alkyl groups with 1 to 3 carbon atoms, Halogen atoms, hydroxyl groups, nitrile groups, Hydroxymethyl groups, alkoxycarbonyl groups or aminocarbonyl groups may be substituted, or R is the group S-R, in which R is a methyl group, ethyl group, Benzyl group or heterocyclic group such as an imidazolyl group, benzoimidazolyl group, benzothiazolyl group, Is benzoxazolyl group or thiadiazolyl group, 309844/1117 a xanthate group, a dithiocarbamate group such as a Dimethyl, piperidyl, 4-alkylpiperazido or 4-dialkylpiperazonium dithiocarbamate group, a thiouronium group, an azido group or an alkoxy group with 1 to 4 carbon atoms means ■ j Q R- the group R O -CH -XCOR ⁷ means in which R is an alkyl group, such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or 2-ethylhexyl group, a cycloalkyl group such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, an aryl group such as the phenyl or naphthyl group, an aralkyl group such as the eenzyl or naphthylmethyl group, or a heterocyclic group, the alkyl, cycloalkyl, aryl, aralkyl and heterocyclic Groups unsubstituted or substituted with one or more amino groups, such as Methylamino, diethylamino or acetamido groups, halogen atoms, Nitro groups, trifluoromethyl groups or alkoxy groups, such as methoxy, ethoxy, propoxy, isopropoxy, Butoxy or isobutoxy group, can be substituted, R ^{8 is} -H, -CH ₃ or -C ₃ H ₅ , X is NH or 0 and R is an alkoxy, alkylthio or aralkyloxy group or a halogen atom means. 309844/1117 2. ß-lactain according to claim 1, characterized in that X is -O- . 3. ß-lactam according to claim 1 and 2, characterized in that R is an ethyl group. 4. ß-lactam according to claim 1 to 3, characterized in that R represents a methyl group. 5. ß-lactam according to claim 1 to 4, characterized in that 4th
R represents a methoxy group. 6. öß-Phenylacetamido-ö / jO-methoxypenicillanic acid-S- (1 '-äthoxycarbonyloxyäthyl) -ester.und their pharmaceutically acceptable salts. 7. ß-Phenylacetamido-iJc ^ -methoxypenicillanic acid S- (2-azidoethoxycarbonyloxymethyl) ester and their pharmaceutically acceptable salts. 8. 7β- (D- M- -aminoxyphenylacetamido) -7c * - -methoxydesacetoxycephalosporanic acid-3- (l'-ethoxycarbonyloxyethyl) -ester and their pharmaceutically acceptable salts. 9. 6ß- (2-Thienylacetamido) -6cC * -methoxypenicillanäure-3- (l · - ethoxycarbonyloxyethyl) -eater and their pharmaceutically acceptable salts. 10. 6ß- (D-O ^ -aminophenylacetamido) -eo ^ - 30984A / 1117 (1'-phenoxycarbonyloxyethyl) esters and their pharmaceuticals compatible salts. 11. 6β- (D-O'-acetylureido-phenylacetamido) -e ^ C-methoxypenicillanic acid 3- (1'-phenoxycarbonyloxyethyl) ester and their pharmaceutically acceptable salts. 12. 7ß- (<? * - Carboxyphenylacetamido) -To ^ -methoxydesacetoxycephalosporanic acid-o ^ -äthoxycarbonyloxyntethyl-3- (1 '-äthoxycarbonyloxyäthyl) -diester.und their pharmaceutically acceptable salts. 13. Process for the production of β-lactams according to claim 1 to 12, characterized in that one A) a compound of the general formula R ⁴ R ^x - CO - NH - C - CH - S _T __ CO- N - R ² - COOH 1 '2' 4 12 or a salt thereof, wherein R, R and R R, R or 4th
R in the above definition is or are optionally amino- or carboxy-protected derivatives of these groups, 3 3 with a compound of the general formula RY, wherein R has the above meaning and Y is a halogen atom or an organic sulfonic acid radical, converts or B) one compound of the general formula 309844/1117 2311 R ¹ - CO - ZV ι « where R has the above meaning and - CO-Z is a reactive one Means group that can react with an amino group to form an amide residue, such as, for example Acid chloride group or its functional equivalent, with a compound of the general formula R ⁴ K ₀ N - C - CH - S., _ * ι I I VI 1 '"2" 3 CO -N - R - COOR 2 '3 4
wherein R, R and R have the above meaning, or C) a compound of the general formula R ⁴ I.
R-CO-NH-C-CH-S XIII II l ₂ i CO -N - R - COOM 2 »4
wherein R and R have the above meaning and the group RCO- is the acyl group in the side chain of a natural penicillin or cephalosporin and M is a hydrogen atom or an alkali metal atom, with a compound of the general formula R -Y, in which R and Y are as defined above are implemented, the ester thus obtained is reacted with a phosphorus halide to form an iminohalide, this with a low molecular weight alcohol to form an imino 1 »noether converts this with a compound of the formula R - I ·
CO-Z, wherein R and Z have the above meaning, converts, the 309844/1117 the resulting reaction product is treated with water or an alcohol and then the compound thus obtained, if appropriate converted into a compound of the formula I and optionally into a pharmaceutically acceptable salt converts. 14. Pharmaceutical agent, characterized in that it contains at least one of the compounds according to Claims 1 to 12 in conjunction with a pharmaceutically acceptable carrier material known per se. 309844/1117