DE1770620A1 - New penicillins - Google Patents

Description

The invention relates to Gram-co 3.1. ti ve and grief negatives Bacteria-effective new penicillins and their salts and a process for their production. The invention New penicillins have a wider spectrum of activity than the well-known D (-) o-aminobenzylpenicillin compared to the Gram-negative organisms.

Ever since the main body of penicillins, 6-aminopenicillanic acid, became easily accessible in 1959, it has been one large numbers of penicillins have been produced semisynthetically, some of which have considerable advantages over penicillin-G in various fields. By doing Article * 'Biological Properties of Semisynthetic Penicillins » Structure-Activity Relationships' by K. E. Price, A. Gourevitch and L. C. Cheney in Antimicrobial Agents and Chemotherapy, 1966, there is a diagram on page 693, from which one can see that up to around 1966 some new penicillins were introduced into therapy have been introduced that have the disadvantages of those previously used

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Penicillins (acid and penicillin sensitivity) not own. Furthermore, it can be seen from this diagram that the successes in terms of improving the effectiveness against gram-negative bacteria are still relatively modest. Only one penicillin has been introduced into therapy so far, which is the vachatum of some Gram-negative bacterial species able to inhibit. Ea this is the a-aminobenzylpenicillin (Ampicillin), which is very effective against the most important strains of Eecherichia coli and Salmonella. . To fight infections- caused by gram-negative Bacteria such as Klebsieila, Proteus and Pseudoaon ·· species, However, ampicillin is not suitable · In this area, initial successes have recently been achieved with a-carboxybenaylpenicillin (carbenicillin), which is used against some of the Gram-negative bacteria have a wider range of effects than Possesses ampicillin.

It has now been found that penicillins of the general formula I

(ι) (a) R ₁ NH- CO — NH- C

** ^R 5 I L___LjCOOH

and their non-toxic salts, in which R _{1 is} the radical of a carboxylic acid or sulfonic acid (acyl radical) with up to 26 carbon atoms, Rf is a hydrogen atom, an optionally substituted one

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or alkyl radical interrupted by heteroatoms or an optionally substituted cycloaliphatic, aromatic, araliphatic or heterocyclic radical, R _{3 has the} same meaning as R ₂ - without R ₃ and R ₃ having to be identical in individual cases - and in which R ₂ and R ₃ also below Formation of a cycloaliphatic or heterocyclic ring with three to seven ring members can be linked, and, in which the carbon atom provided with an asterisk can be asymmetrical, are effective against Gram-positive and Gram-negative bacteria. When compared with a-aminobenzylpenicillin (ampicillin), they have a strongly expanded spectrum of activity compared to the Gram-negative germs; ie with approximately the same effectiveness against the Atnpic illin-sensitive Escherichia coli strains, the penicillins according to the invention have a significantly greater effectiveness against Klebsieila, Proteus and Pseudomonaebacteria than α-aminobenzylpenicillin. This fact is to be regarded as extremely surprising) because in the field of penicillins with free amino groups in the side chain (penicillin-N, p-aminobenzylpenicillin, α-aminobenzylpenicillin), the doctrine prevails that acylation of this free amino group is effective against Gram-negative Bacteria decreases (cf. article by Price, Gourevitch and Cheney cited above on p. 673 "left column, p. 682, right column and p. 683, above). Since the penicillins according to the invention are penicillins containing amino groups with acylated amino groups, should

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177062G

they are expected to be less effective against Gram-negative bacteria. However, the opposite is true, as will be shown below.

The novel penicilines of the general formula I according to the invention are produced by tying the bonds (l) or (2) (see general formula i)

a) Penicillins of the general formulas II or III, or their salts, or IV, V, VI or VII

CH ₃

H ₂ - C - CO - NRH

CH ₃

COOH

CH ₃

H ₂ N — CO — NH — C— CO — NH- ίζ R ₃

XOOH

H ₂ NC-CO-NH-R ₂ K ₃

0 '

-N-

Si - NH - C - CO - NH - R ₂ R ₃

CH ₃

CH ₃

-COOSi- CH ₃

COOSi ^ -

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BATH

177062G

H ₂ N - CO - NH - C - CO - NH - 4

CH ₃

--COOSi ^ -

R ₃ -Si-NH-CO-NH- or

H ₂ NC = N-

0
R ₃ -Si

or

HN = C-NH-0

R, —Si

JC

-C— ΐζ R ₃

NH-

CH,

0OSi ^ -R ₃

in which R ₂ and R _{3 have} the meaning given above and in which R ^, R ₃ and R $ are identical or different alkyl, aralkyl, cycloalkyl, interrupted by heteroatoms, alkyl with up to 10 carbon atoms or aryl radicals, with acyl isocyanates of the general formula VIII or with N-acylcarbamic acid derivatives of the general formula IX or X

VIII IX

R ₁ -N = C = O

R ₁ NH-C

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-0

R ₁ -NH-C '

AR ₇

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BATH ORIGINAL

where R _{t has} the meaning given above, X is a radical as it occurs in Isocyanatabspa Item (see Houben-Weyl: 8 p. 13O-L35), A stands for -O- or -S- and R _{7 is} an optionally substituted one or alkyl radical interrupted by heteroatoms or an optionally substituted cycloaliphatic, aromatic, araliphatic or heterocyclic radical, or the group -AR ₇ also, for example

CO
same; _Q / 1 can be implemented, or

by tying the bond (l) (s * general formula Χ)

b) Penicillins of the general formulas III, VI or VII ( _{see above), in which R 2} »Rj» R *> R5 and R $ have the meaning given above, with acylic agents or mixtures, such as carboxylic acids of the general formula XI

XI R ₈ - COOH

where R ₈ -CO is R ₁ , in the presence of dehydrating agents such as carbodiimides, carbonyldiimidazole, carbonylditriazole or with acylating functional derivatives of the acids of the general formula XI, e.g. an acid halogenic, anhydride, mixed anhydride, azide, imidazolide, pyrasolide, p-nitrophenyl ester, pseudosaccharin ester / "see British Pat. No. 1 OZk 8O9_7 or other functional derivatives of carboxylic acids, as they are known in peptide chemistry / see NF Albertsont Organic Reactions 12 157-352_7,

109846/1879

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or with isocyanates of the general formula XXX

N = C - O

wherein R _{9 is} the radical of a primary amine, brings it to reaction, or by making the bond (3) (see general formula i)

c) 6-aminopenicillanic acid, its salts or derivatives of the general Formulas XIII or XIV

H ₂ N

COOSi ^

CH ₃

Si-NH

N-

in which R4, R ₃ and R4 have the meaning given above , with acids of the general formula XV

R ₁ NH-C-NH-C-COOH

^ H / \ 0 R ₂ R ₃

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wherein R ₁ , R ₂ , R ₃ and C have the meaning given above, in the presence of a carbodiimide, carbonyldiimidazole or carbonylditriazole or with functional derivatives of the acids of the general formula XV _1, for example an acid halide, anhydride, mixed anhydride, azide, imidazolide, pyrazolide , p-nitrophenyl ester, pseudosaccharin ester / _ see British Pat. No. 1 024 8O9_ / or other functional derivatives as they are known in peptide chemistry / see NF Albertson: so_7 or, in the case of the non-silylated 6-aminopenicillanic acid, on * fermentative route / _ see K. Bauer, W. Kaufmann, HA Offet Natw. kj_ _t 469- ^ 70 (1960) and "Antimicrobial Agents Annual - 1960, Plenum Press NY ¹ , p. 1-5_J with the glycine, glycolic acid or thioglycolic acid derivatives of the acids of the general formula XVl

XVI R | - NH-CO-NH-C-CO-B-CH ₂ COOH

R ₂ R ₃

χ
wherein R ₁ , R ₂ , R ₃ , C have the meaning given above and

B stands for -NH-, -0- and -S-.

_{For the acyl radical R t of} a carboxylic acid listed in the general formula I of the penicillins according to the invention, some examples may be mentioned as an illustration.

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R ₁ can be t

N5C- ⁰ J ^ C- C ₂ H ₃ -O-CO- HC ₃ H ₁₁ -O-CO- Cl- ^ Jh-CH ₂ -O-CO- -0-C0- CH ₃ -CO- F-CH ₂ -CO- F ₂ CH-CO- F ₃ C-CO-

Cl ₂ CH-CO- Cl ₃ C-CO- (CHj) ₂ CH-CO- (CHj) ₃ C-CO- NC-CH ₂ -CO-CH ₃ -CH ₂ -CO- (C ₂ H ₃ J ₂ CH-CO- (CHj) ₂ CH-CH ₂ -CH ₂ -CO-

CH ₃ - (CHa) ₃ -CH-CO- CH ₃ - (CH ₂ ) S-CO- £ ² ^ pCH-O-CH ₂ -CO-

C ₂ H ₃

HV-O-CH ₂ -CO-

CH ₃ - (CH ₂ ) ^ - CO- C ₂ H ₃ -O-CH ₂ -CO-

Hj

H ₂ N-CO-CH ₂ -CO- H ₂ N-CO-CH ₂ -CH ₂ -CO- (CHjO) ₂ CH-CO- (C ₂ H ₃ O) ₃ C-CO- (C ₂ H ₃ O-CH ₂ ) ₂ CH-O-CH ₂ -CO- C ₂ H ₅ OOC-CH ₂ -CH ₂ -CO- CH ₂ -CH-CO-

CH ₂ BC-CO- CH ₃ -CHeCH-CO- CH ₂ >> CH-CHj -rCO- CH ₃ -CH-CH-CHaCH-CO-CH ₃

CH ₂ -CH- (CH ₂ ) J-CO- CH ₃ - (CHa) ₇ -CH = CH- (CH ₂ ) ₇ -CO- CH ₃ -CH-C-CO-

Br

-CO-NH-CH ₂ -CO-

-CO-

CH ₃
^ N-CH-CO-

(CHj) ₂ N-CO- CH ₃

(' Vn- co-

N-CO-

-Qi-CO- (^ Λϊ-CO-

CO-

O ^co -

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CN
I.
CH-CO-

CN

-CO- AA-CH ₂ -CO CH ₃ ^^

CH-, CO-

Ac-O

^ CH-CH ₂ -CH ₂ -CO-

CH ₉

I CO

-COOL

CH ₃
O

Q-

Si (CH ₃ ) _a - ^ ca-co-

Cl

CH-CO- CH ₃ -OV. / HO-CH ₂ -CO-CO-

Cl I -CO-H ₃ CC

Cl CO-CO- C ₂

CO -CO-

CH,

CH ₃

Cl

-CH-CO-CH,

Cl

Cl - (^ - O-CH ₂ -CO- Cl -0-CH-CO-

I.
C ₂ H ₃

-O-CH-CO- CH ₃ - (

CH. OCH,

-CO- i , VO-CH-CO-COOC ₂ H ₉

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BATH ORIGINAL

177062G.

-0-C-CO-CH

JH-CO-C ₂ H,

y 0-CH ₂ -CH ₂ -CO-

0-

O-

H ₃ CO-C Λ-CH-CO- CH ₃ -OC — CO-

IC ₄ H ₅ CH ₃ —C — CH, —CH ₂ —CO • C ₄ H ₃

CH ₃

-CH ₂ -CH ₂ -CO- Cl - ^ - CH ₂ -CO- CH ₃ O - ^ - CH ₂ -CH ₂ -CO-Cl - ^ - CH ₂ -CH ₂ -CO-

C ₂ H ₅

O-CH ₂ -CO-C ₂ H ₅

JS-CH ₂ -CO Cl CH ₃

S-CH ₂ -CO

SS-CH ₁ -CO-

CO

-CO- I Wi-O-CH ₂ -CO-

2H-C-CO-CH ₃

CH-CH-CO-

ι C

CH ₃

, / - C = CH-CO- Cl -L .V-CH-CH-CO- C ₂ H,

Cl .- (^ - CH-CH-CO-Cl

Cl-C / V-CH-CH-CO-

^ CH-CH-CO-CO- Cl-4 Λ-CH-CH-CO-CO-

ci Ci

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1098A6 / 18-79

CH ₃ -O - ^^ - CHsCH-CO-CO- CH ₃ - (CH ₈ ) ₃ -O ~ Q> -CH-CH-CO-CO-

Cl - ^) - S-CH = CH-CO-

4 ^) - O-CHaCH-CO- CH ₃ -0-ΛΛ

CH ₂ -CO-

S-CHeCH-CO-

Cl

^C1 \ J- \ J- ^CO - Cl Cl -CO- . ^ ^co ~
Cl ci-Q-co-
Cl

^ CO- ^ Cl

Cl

Cl

Cl

-CO- V-CO-

Cl- ( _x / -CO- CH ₃ O -C /) - CO-

Cl

Cl

O-

F ₃ C

F ₃ C

CO- C ₂ H ₅ -S- ^ A-CO- 0Η ₃ -0-ζ ~ \ ~

CO-

Cl

H ₃ CO

CO- 4> C0-

H ₃ CO

OCH ₃ H ₃ C-

CO-

H ₃ C A. J-CO- CH ₃ Le 11 483

OCH ₃

H ₃ C- ^ ~ V-CO CH ₃

H, C- (

CH ₃

- 12 -

109846/1879 ORIGINAL BATHROOM

177062G

CO-

C (CH ₃ ),

co-

C (CH ₃ ),

C ₂ H ₅

H ₃ CO

Cl

H ₃ CO - / \ - CO-Cl

-CH ₂ -

CH ₃ -CH ₂ -CH ₂ -CH-CH ₃

CH ₃ -CH-CH-CH ₂ -O-

C ^

CH ₃ - (CH ₂ ) ₉ -0- <λ) —CO- CHj- (CH ₂ J _n -O - (^ - CO- CH ₂ SCH-CH ₂ -O-O7CO-

CH ₂ -C-CH ₂ -0- <Γ ~ \ - CO-CH ₃

HC = C-CH ₂

-0 - ^) - CO-

^ // "CH ₂ -

C1-4 J.

-0-ς _{/ Γ} -00- H ₃ CK _n y-CHa-0

-CO-

ri- ^ H ₇ -0- ^ J) -CO- (CH ₃ ) ₂ CH-O- ^ '/ r-CO- nC ^ H, -OA ^ y-CO-

nC ₃ H ₁ , -0 - <\ - C0- CH ₃ -0-CH ₂ -CH ₂ -0- ^ ^ * - CO- O ₂ N- ( _v /) - CO-

O-C0- W-CO-

M ζ- ⁷

^F 3 ^C ^ / - ^C0 "

NO ₂ CH ₃

F ₃ C

CH ₃ -C0-0- ( _N V-CO- HO

* ο- (ν> - co- Ci- ^ y-CO-

Cl OH

Cl

O ₂ N

CO-0-COCH ₃

S-CH ₃ CO-

-CO-

OH

H ₃ CO

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CH ₃ -CO-NH-Ty-CO-

N-CH ₃ NH ₉

H ₃ C-GO

H S.

_CO- H ₂ N-SO ₂ -V-CO- CO-

-CO-

VcO-CH ₃ H ₃ C 0-CO-C (CH ₃ ),

H ₃ C

H ₃ C 0

CO-CH ₃

(CHj) ₃ C

, - CO-0-CO-CH ₃ -CO-

CH ₃ -CO-

O-CO-C ₆ H ₃ Q-CO-CH ₃

H ₃ CO ₁

H ₃ CO

C ₂ H ₉ -O

CH ₃ -CO-O - ^ - CO- C ₂ H ₃ -0- ^ y-CO- _{v / y} > - CO-

O-CO-CH ₃ S-CH ₂ -CHa-O-CO-CH ₃ C ₂ H ₉ -O

H ₃ CO CO-

H ₃ C-

(CH ₃ ) ₂ N-SO ₂ -λ « ₇ -CO-CH ₃ -NH-SO ₂ -λ _ν . -CO-

(CH ₃ ) ₂ N-SO ₂ -ζ ~ j -CO-Cl

H ₃ C-

Cl

" _% , —CO- -CO-

Cl

Le A 11 483

SO ₂

/ η

C ₄ H ₃

- 14 - ^ Q-co - (^ - co-

CO

Cl

109846/1879

BATH ORIGINAL

177062C

coco

CH ₃

OCH ₃

H ₃ CO

OCH ₃

H ₂ NQ) -CO-

CO-

OCH ₃

(CH ₃ ), N ^ Q

F ₃ C

CO-

CO-

CO- CH ₃ -C,

co-

CF ₃

CH ₃ HM >> -CO-

Cl

CH ₃ CH ₃

C ₂ H ₅

CH ₃ -CO-NH-Q-CO-

CH,

CH ₃ -CO-NQ) -CO-CH ₃

CH ₃ - (CH ₂ ), - CO-N

CH ₃ -CO-NQ-CO- CH ₃ -CH ₂ -CO-NH-Qh-CO-C ₄ H, (η)

^C ° -

CO-

H ₂ N-CO

CO-

NH

CH ₃ -O ^ y-CO-

NH

CO-CH ₃

OCH ₅

SO ₂ N (CH ₃ ) ₂

CO

CK,

CO-

OCH ₃

OCH,

0-

co-

N-CO-CH ₃

CH ₃

CO-

CO-

CO-

Cl

OCH,

-CO-

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BATH ORIGINAL

177062G

CO-

-CO-

Q-CO-NH-Q-CO -

CO- Cl

Cl-y. '-> - S.

Cl

Cl-QS-CH ₂ J _x J Cl

4 Λ-S -CO-

CH,

Cl
Cl- ^ VO-CH ₂

Cl

Cl-V ^ yO-CH ₂

Gl C ₂ H ₅ -0-CH ₂ -LJ-CO-

₂ Hj-S-CH ₂ -I ₀ JlCO- Cl -ζ, / - SO ₂ -CH ₂ -Ü ^ -CO- CH ₃ -

Cl - (^ V-CH ₂ -0-CH ₂ -C ₀ XcO "ClH ^ -CO-NH-CH ₂

C ₂ H ₅ -CO-NH-CH ₂ J ^ j-CO-

CH ₃

CH ₃ CO-

H ₃ C CO-

CH,

N N

N-N

Cl - ^ - O-CH ₂

N-N

Cl- ^

yS-CH ₁ Cl Cl- ^ yS-CH ₂

N—,

C 1- ( _ ClQv-S-CH ₂

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CO-

SO ₂ NH ₂

Cl

CO-

0-

CO-

C ₂ H ₅

0-

CO-

co-

CH

I "
CSN

CO-

CO-

NH
I.
SO ₂ C1- ( _N > _ S-CH ₂

CO-NH-d y- CO-

H ₃ C-CO-NH CO-

" ^N -

O-

-SO, - H,

Cl- ^ J-SO ₂ -

H ₃

Cl Br

/> - S0 ₂ -.-SO ₂ -Cl

/ ^ SO, -

Cl -SO ₂ -

ci

O ₉ N

H ₃ C

so, -

SO ₂ - CH ₃ -0-TV SO ₂ - CH ₃ - (CH ₂ ) ₃ -0-T

/ r ° Q * -

H ₃ CO- ^> -SO _a

C ₂ H ₅ O

O ₉ -

Λ-so,

Cl

CO-Br

Cl
SO ₂ - ( _N ^ -CO-

0-C ₄ H ₉

CO-

0OCH ₉

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177062G

Let the radical Ry contained in the general formula X be

the following examples are given as an illustration of this remainder.

K ₇ can be t H ₉ C- C ₂ H, - CH, -0-CH ₁ -CH ₂ - Cl-CH, -CH ₂ - (CH, J ₁ M-CH ₂ -CH ₁ - F ₉ C-CH, - Cl ₉ C-CHi- CH ₁ -CH-CHj- C ₂ H ₉ O-CO-CH ₁ - MSC-CH ₁ - (/ CI ^ - Cl-C ^ V-CH ₁ -

Cl-

The following examples are given as an illustration of the _{bed R 9 of} a primary amine listed in the general formula XXI.

R ₉ can be t

Cl Cl

1 cl

Cl-

Cl

^C1 "\ i / ~ ^ '/ Cl Cl Cl Cl

Cl

CH, -O Cl Cl

Cl

Cl

CHj-O-

CH ₂ -CH-CH ₁ -O

CH, - (CH ₁ ) _%

CH,

CH,

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109846/1879

CH, (CH ₁ ),

F ₉ C Γ, C

F ₉ d

177062G

, HH />

Cl

CH ₃ -SO ₂ -T

Cl-

CH ₃

CH ₃

SO ₂

H ₃ C- / CH ₃

CH ₃ - C ₂ H ₃ - C ₃ H ₇ - (n- and ieo-)

Cl

- (CH ₂ U- CH ₃ - (CH ₂ ) ^ ₁₁ - CH ₂ -CH-CH ₂ - C ₂ H ₃ O-CO-CH ₂ -

H- CO-CO-CH- i H,

CH ₃

Furthermore, to the part of the general F ο inn · 1 I of the invented penicillins, which contains R ₂ , R ₃ and C *, the

the following examples are given:

can be t

G ^

CO-

λ CH ₃ -NC

CO-

CH ₃ " C ₂ Η, '"

Le A 11

CO-

HO '

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ORIGINAL INSPECTED

CH ₃ . CH, -

CH ,, C ₂ H ₃ -

C ₂ H ₃ , C ₂ H ₃ -

Ο ":

-NH-CO-

-NH- -CO-

, NH-CO-

, NH-

'CO-

KH-

'CO-

H.

Cl

H ₃ C

CO-

V-V

, NH-CO-

Cl

-NH- -CO-

-NH-CO-

OCH ₃

CO-

CH ₃

H ₃ C ^ _ ^ - KH-

^c «C

^ CO-

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ORIGINAL INSPECTEO

CO-

.NH-

CO-

.NH-

CO-

H ₃ C

Cl

CH ₃

NH-CO-

The new penicillins according to the invention are contained in the Side chain optionally one or more asymmetric carbon atoms ·. They can then be used in several stereoiaomers Forms exist. The invention applies to each of these forms as well as to all mixtures thereof.

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ORIGINAL INSPECTED

j 177062C

For the production of the new penicillins according to the invention we perform the following

If you use penicillins of the general formula II or IXX as the starting material and etch them with acyliaocyanates of the general formula VXXX or with N-acylcarbemic acid derivatives of the general formula XX or X, or you use penicillins of the general formula III as the starting material and set them with acylating agents functional derivatives of the acids of the general formula XI, for example an acid halide, anhydride, mixed anhydride, aaid, xmidazolide, pyrazolide, triazolide, p-nitrophenyl ester, pseudosaccharin ester (or amide) or other acylating functional derivatives of carboxylic acids XI, for example such as they are customary in peptide chemistry / see NF Albertson t so_7, or penicillins of the general formula III are converted in the presence of waaser-splitting agents such as carbodiimides, carbonyldiimidazole or carbonyldltriazole with acids of the general formula XI or with isocyanates of the general formula XII , or used m on as starting material 6-aminopenicillanic acid bsw. Salme represents 6-aminopenicillanic acid and etches it either in the presence of, for example, carbodiimides, carbonyldiimidaseole or carbonylditriazole with acids of the general formula XT ₁ or directly with acylating derivatives of the seeds XV, e.g. an acid halide, anhydride, mixed anhydride, azide, xmidazolide, pyrazolide, p-mitrophenyl ester,

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ORIGINAL INSPECTED

Peeudoeaccharxnester or -amid or other functional, Acylating derivatives of acids XV, for example such as are used in peptide chemistry to so nan these reactions can for example in solvents, such as water, acetone, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethyl acetamide, pyridine or dimethyl sulfoxide, or in mixtures thereof, for example in carry out aqueous acetone, aqueous tetrahydrofuran or aucb in aqueous alcohols.

It is advantageous to bring the starting penicillin or the free 6-aminopenicillanic acid in the solvent or solvent mixture with the aid of a base, for example a trialkylamine such as triethylamine, N-ethylpiperidine or, if this has not already been added as a solvent, with pyridine or with a Alkali, alkaline earth hydroxide, oxide, carbonate or bicarbonate in solution and then gives one of the acylating agents or mixtures listed above as such, or dissolved in an inert solvent, at temperatures between about -15 ° G and 4-50 ⁰ C, preferably at ⁰ ° C. to room temperature. However, Main can also proceed in reverse and present the acylating agents and then add the penicillins or 6-aminopenicillanic acid. If you work in water or water-based solvents, it can be of advantage to achieve a better yield if the pH is adjusted during the reaction, possibly by adding appropriate

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109846/1879 _{0RlriKS & l}

ORiGiNAL INSPECTED

Amounts of base, holds in the range 6.5 to 8.0. The reaction but can also be carried out in a different pH range, for example between 5 »0 and 9» 0. As the initial penicillins of the general formulas II and III and 6-aminopenicillanic acid are also bases, they are known with the help of acids Bring into solution as salts and then acylate. The yields are then, however, especially when using the N-acylcarbamic acid derivatives of the general formula X and of mixtures of the acids of the general formula XI and dehydrating agents, such as carbodiimides, mostly worse.

To keep the reaction mixture in a certain pH range you can also use buffer solutions. Suitable Buffer mixtures are e.g. mixtures of organic and inorganic, water-soluble acids and bases or salts, such as Na acetate / acetic acid, calcium acetate / acetic acid, pyridine / Acetic acid, formic acid / ammonia, etc .. You may have to work in an aqueous solution or the diluent add so much water that the salts of the buffer mixture remain in solution.

Furthermore, it is often possible to use water-immiscible solvents, preferably chloroform or methylene chloride, with the addition of preferably triethylamine or N-ethylpiperidine to work. Some penicillins of the general formula II or III and 6-aminopenicillanic acid are found in these devices easily soluble. Even if it is less functional

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the starting penicillins can also be in suspension bring to implementation in the presence of bases. The number of bases that can be used is hardly limited, provided that they are free from easily acylable groups. The reactants are preferably used in equimolecular amounts with one another brought to reaction. In individual cases, however, it may be useful to use one of the two reactants in the To use excess in order to facilitate the cleaning or purification of the desired penicillin or to increase the yield. The amount of bases used is, e.g. due to the desired maintenance of a certain pH set. Where pH measurement and adjustment are not carried out or is not possible or useful due to the lack of sufficient amounts of water in the diluent preferably one mole equivalent per mole of starting penicillin, where acidic cleavage products are formed during the reaction, 2 molar equivalents of base used. However, these quantities do not have to be strictly adhered to.

The reaction can be accelerated by adding equivalent amounts of, for example, pyrazole, 4-bromo- or 4-nitropyrazole or 1,2,4-triazole / see HC Beyermann, W. Maassen, von den Brink: Proceed, formerly Soc. 1963t p. 266_ /.

If the starting material used for the preparation of the penicillins according to the invention is the penicillin derivatives of general formulas XV, V, VX or VXX and adds them

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.Acyl isocyanates of the general formula IiIII or with N-acylcarbaic acid derivatives of the general formula IX or X to, or penicillin derivatives of the general formulas VI or VII are used as the starting material and these are added Acylating functional derivatives of acids of the general formula Xl, e.g. an acid halide, anhydride, mixed anhydride, azide, imidazolide, pyrazolide, triazolide, p-nitrophenyl ester, pseudosaccharin ester (or amide) or other acylating functional derivatives of Carboxylic acids XI (see below), or, in the presence of carbodiimides ^ Carbonyldiimidazole or carbonylditriazole with acids of the general formula XI or with isocyanates of the general Formula XII to, or is used as the starting material the o-Aminopenlcillansäurederivate XIIl or XIV and sets these either in the presence of, for example, carbodiimides, carbonyldiimidazole or carbonylditriazole with acids of the general formula XV or directly with acylating derivatives of acids XV, e.g. an acid halide, anhydride, mixed anhydride, azide, imidazolide, pyrazolide, p-nitrophenyl ester, pseudosaccharin ester (or amide) or others functional, acylating derivatives of acids XV, such as those used in peptide chemistry (see above), so this reaction can be carried out as well perform how the acylation of penicillins of the general formula II or III and the free 6-aminopenicillanic acid, only that one does not use hydrolysing solvents or solvent mixtures, such as ether,

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Tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, acetonitrile, Dimethylformamide, benzene, chloroform, methylene chloride, ethylene chloride or ethyl acetate, must work. In the cases in which acidic groups or acidic cleavage products are formed in the course of the reaction, it is expedient to use one of these equivalent amount of an acid-binding agent, for example an amine such as triethylamine, pyridine, lutidine, quinoline, diethylaniline or diisopropylamine.

The reaction may in principle in a wide temperature range, for example between -25 ° C and +80 ⁰ C are performed. However, it is preferred to work at from 0 ^° C. to room temperature. In general, nan presents the penicillin derivatives and then adds the acylating agents. But you can also proceed in reverse.

The penicillin derivatives of the general formulas IV, V, VX and VXl used as starting material are obtained from the penicillins of the general formulas XX and XXX in the same way as the corresponding silylation products are obtained from 6-aminopenicillanic acid / see, for example, K. ¥. Glombitza * Ann. 673 . 166; L. Birkhofer, Belgian Pat. 615 ¹ K) I, and B. 0. H. Sjober, BA Bkström, Belgian Pat. 628 23iJ7.

It is useful if the penicillins to be silylated are used as free of water as possible. Xm FaXIe of α-aminobenzylpenicillin, which usually contains 10-14 % water,

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you should precede a drying process or use the so-called 'ampicillin B ¹ / _ see US Pat. 3 -1 ^ 4 ^ 5_ / go out. But you can also proceed in such a way that one dissolves the penicillin to be silylated, for example in methylene chloride as the triethylamine salt, and this solution is first dried before the silylation reaction is started.

If 6-aminopenicillic acid or its silyl derivatives of the general formula XIIl or XIV and acids of the general formula XV are used as starting materials for the preparation of the penicillins according to the invention, then one can for the most part use the many methods for carrying out this reaction as are used in corresponding reactions in peptide chemistry and are generally known £ Cf. a. E. Schröder, K. Lübke, The Peptides, Method of Peptide Synthesis, Vol. 1, pp. 76-128_ /. For example, the acid chlorides of the acids of the general formula XV can be prepared in solution, if appropriate under mild conditions using the methods of G. P ₁ Vlasov, Mitin and Koton / Dokl. Akad. SSSR. 168 , 1069-7 using N-methylacetimide chloride as a reagent or according to the method of IB Lee l_I Amer. Chem. Soc. tijB, 3440 (1966) _ / using carbon tetrachloride - triphenylphosphine as a reagent, or according to the method of L. Heslinga, IF Arens / Rec. Trav. Chim. 76, 982 (1957) _7 with the help of ο, a-dichlorodialkyl ethers, or the method \ on M. Zaoral and Z. Arnold / Tetrahedron

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IS

Letters, p. 9 (196O) _7, or by conventional means, if necessary under catalysis with dimethylformamide and possibly also without prior isolation with 6-aminopenicillanic acid or convert their silyl compounds.

However, the acids XV can also be converted into functional derivatives which are equivalent to the acid chlorides and which can be used for the acylation of 6-aminopenicillanic acid, its salts or silyl derivatives. The functional derivatives listed below are known. They include, for example, the acid bromides, anhydrides and mixed anhydrides, for example with the aliphatic Memoes tern of carbonic acid, with alkyl and aryl sulfonic acids or with acids containing a sterically hindered carboxyl group, such as diphenylacetic acid or trimethyl acetic acid. Furthermore, as functional derivatives of the acids of the general. Formula XV use the azides and the active esters and thioesters, particularly with p-nitrophenol, 2,4-dinitrophenol and thiophenol. The 6-aminopenicillanic acid can also be acylated with the free acids of the general formula XV by adding a suitable enzyme or the acylation reaction by adding dehydrating agents such as N, N'-carbonyldiimidazole, Ν, Ν'-carbonylditriazole, a carbodiimide, in particular N, N'-dicyclohexylcarbodiimide, N, N ¹ -diisopropylcarbodiimide or N- (3-dimethylaminopropyl) -N ¹ -tert.-butylcarbodiimide / "cf. DBP 1 070 6J9_J ', an alkylamine" / "cf. R. Buijle, Viehe: Angew. Chem., Int. Ed., 2, 582 (1964) _7,

* ²⁹ - ORIGINAL BATHROOM

109846/1879

. of a ketenimine / cf. Stevens, Monk t I. Aatr. Chen. Soc. 80 . kO65 (1956) _7 or of an Isoxazoliuaaalzea / cf. Woodward, Olofsson, Mayer, I. Aner. Chem. Soc. B ^, 1010 (l96l) _ / carried out.

Further functional derivatives of the acids of the general formula XT suitable for the acylation of 6-aminopenicillanic acid are the azolides, ie amides in which the amide nitrogen is part of a quasi-aromatic five-membered ring and which contains at least two nitrogen atoms as ring members, e.g. imidazoles, pyrazoles, triazoles , Benzimidazoles, benzotriazoles and their substitution derivatives. To prepare the azolides, for example, an acid of the general formula IX can be reacted with a molar equivalent of an N ₁ N * carbonyldiimidazole, for example in tetrahydrofuran, chloroform, dimethylformamide or an analogous inert solvent at room temperature or with cooling, the azolide being able to react , for example the imidazolide, forms with the release of carbon dioxide and imidazole. The imidazolide can then, without having to be isolated, be reacted with 6-aminopenicillanic acid to form penicillin of general formula I.

It is entirely possible that the conversion of the acids of the general formula XV into activated on the carboxyl group Derivatives, including intermediate anhydrides of the general formula XTII

Le A 11 483 - 30 -

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R ₂ -C CO

ί o ^XVI1

NH

A,

are formed, which then, however, also with 6-aminopenicillanic acid or their silyl compounds react further to form the penicillins according to the invention.

One uses penicillins for the synthesis of the emälien according to the invention 6-aminopenicillanic acid or its salts and the acids of the general formula XV. in the form of their glycine, glycolic acid or thioglycolic acid derivatives of the general formula XVI as starting materials, this reaction can be carried out in acidic as well as weakly alkaline aqueous medium, in the presence of washed cells of Escherichia coli bacteria that have enzymes in their cell walls that able to catalyze the desired reaction, i.e. the amide-like linkage of the 6-amino group of 6-aminopenicillanic acid with the carboxyl group of the acids of the general formula XV, where glycine, glycolic acid or thioglycolic acid is set free.

The work-up of the reaction batches for the preparation of the penicillins according to the invention takes place throughout in the case of the penicillins, commonly known way. For example one can get the penicillins, which are initially in general

Le A -3-1 483 - 21 -

are obtained in the form of their dissolved salts, optionally after removal of the organic solvents and dilution with water, precipitate by acidification to about pH 2 and isolate as the free acid. You can also take this up in an organic solvent and then, for example, precipitate the sodium or potassium salt with an ethereal sodium or potassium 2-ethylhexanoate solution. One can also, the acid form of the iiputn penicillins easily thereby converted into a salt, that brings them together in water or a water-containing organic solvent with a suitable base, here treatment erf an i ndungsgemäßen penicillin with aqueous ammonia yields the ammonium salt. Xn similarly can. vr aiidtr «salts such as calcium, magnesium, aluminum, Kai Lina, sodium salts are obtained. In addition one can amine salts such as zH dna procaine, dibenzylamine, N, N'-Dibenzyläthylendiaiain-, Dehydroabietylamin-, 1-Ephenarain-, N-benzyl-.beta.-phen> läthylamin- and dicyclohexylamine salt, prepared in that a solution raajri of the penicillin in question in an aqueous or non-aqueous solvent with the desired amine z; i «-a; nrr ^ nbringt · In addition, the amine salts of the penicillins can be obtained by adding a metal salt thereof, for example the sodium salt, in aqueous solution with an acid salt corresponding amine, for example the Arainhydrochlorid or acetat, brings together. If necessary, salts of the penicillins can be isolated by freezing their solutions and subjecting them to freeze-drying.

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The novel penicillins of the formula I according to the invention draw As mentioned, they have advantageous properties certain gram-negative bacterial species, as from the following selected results of the microbiological Examination emerges.

Table 1
Selection of tested compounds of general formula 1

penicillin

No. ^R * R ₂ R ₃

1 benzoyl phenyl water

material

2 4-methoxybenzoyl ""

3 4-chlorobenzoyl "'·

4 2-chlorobenzoyl ^f ''

5 2-bromobenzoyl * '"

6 2,5-dichlorobenzoyl "··

7 3,4-dichlornenzoyl ""

8 2,4-dichlorobenzoyl »« "

9 2,4-dichlorocinnamoyl ^fl "

2,4-dichlorophenoxyacetyl " ^fl

11 4-methylphenylsulfonyl

12 3,4-dichlorophenylsulfonyl

13 4-chlorophenylsulfonyl

/ (^) - NH-CO- ^f '"

15 2-chloro-4-ethylthiobanzoyl

109846/1879

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Il Il

Il ti

Il Il

Il Il

177062G

co ^

16 ,, JnAp ,, Phenyl hydrogen ^Η > ° ^ΠΗ 'hydrogen

17 ij ^ L-co- »·" J.8 α-naphthoyl- "ι»

J ^ O "3 ^w It il I» »·

20th

ti it

H ₂ N-CO 21st 3-chlorobenzoy 1 22nd 2-chloro-4-ethylthiobenzoyl 23 U-methoxybenzoyi 2k 2-chloro-5-methoxybenzoyl 25th 2-iodobenzene / 1 26th 3-iodobenzoyL 27 4-iodobenzoyl

- (CH ₈ )% -

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109846/1879 * ^{AD 0R1GlNAL}

The chemotherapeutic effectiveness of the new penicillins was tested in-ritro and in vivo.

Tables 2 and 3 "own there · in the tube serial dilution tea in" in ·· liquid culture medium determined · effect · epectrue of the new subitamen (5.9518 · 10 ^e E · 1 mol.).

Da · effect · epektrue includes both gram-positive and Gram negative bacteria. The particular advantage of penicillin is that it is gram-negative, ampicillin-resistant Bacteria e.g. from the Klebsiella and Proteus groups Inhibit in concentrations of 1.56-12-50 U / ml. Also di Usually the ampicillin-resistant Paeudomona aeruginoaa strain requires minimal inhibitory concentration of only 3-12-50 S / ml.

Like the experiments with O (- (3,4-dichlorobenzoyl-ureido) -benzylpenicillin (Tab 1; penicillin no. 7) on the white mouse (Tab. 4) show that therapeutically effective blood or tissue concentrations are achieved with penicillins in infections of the Mouse with Gram-positive (e.g. Staphylococcus aureus) and Gram-negative (e.g. Bact. Coil, Klebsiella) pathogens. Either a single dose was given 1/4 hour before or two times 1/2 and 1 1/2 hours after infection.

If you give Kaninchan 50,000 U / kg penicillin No. 7 (Tab. 1) i. m., • o one obtains maximum seruteactivities of 18.5-38 U / ml correspond. The serum levels drop rapidly, after 6 hours

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activities are no longer measurable. After the same dose, determined with the aupiuillin-resistant Proteus morganii 1272, with hourly amounts of 6.5 to 43 ml in the urine in the first 5 hours after administration, concentrations corresponding to 64-240-465 U / ml are achieved.

A 11 483 - <6 J0S846 / 1879

it I. i BATH ORIGINAL Tabel 2 { to water 7705 In Vitro experiments with the tube serial dilution test 56 Minimal inhibitory concentration in 1
of listed in Table 1] Llin
3 No. t
4th E. 12th j 5 S / ml culture media after 24 hours
Penicillins. 25th 7th 56 8th 12th 11 Incubation < 3400 . ATCC Penici]
2 3, 12 y I.
6.25 3. »2 ^i% ί 1, 3, 3.12 1 tribe Psdm.Lodenenkämper
Padm. Bonn Ampici There 1.56 200 200 50 6, 50 100 > 4oo 6.25 E. coli 14th Scaph. 0, 76 100 > 400 > 400 400 , 5 100 > 400 4oo > 400 200 E. coli A 201 Bnterok
9790 > 4oo , 5 > 4C0 > 400 > 4oo > 4oo , 5 > 4oo > 400 25th 400 5 > 4oo > 400 177062G CD
co! E. coil T 7 > 4oo >; oo Λ.2 5 25th 12th > 4oo , 25 6, 56 12, 12th 200 > 4oo σ » E. coli T 20 II > 400 i.i.3 6th 25th 6.25 6th 25th 1 25th 3, 5 1.56 25th OO
co Klebsiella 100-200 1.56 25th 50 25th 6th 6th , 5 12th > 400 6.25 Proteus 1 • J.25 NJ Ut
Ui O 50
25th 25th
12th 25th , 5 25th
12th 25th
25th , 5 100
50 50 Proteus > 4oo NJ Ut
Ut C 25th 25th 12th NJ Ut
Ut C 25th , 5 12th , 5 25th NJ NJ
Ut Ut 4oc
200 50 12th , 5 12.5 25th 12th • 12th 12th 50 50 50 25th 25th 12.5 12th

Table 3

In vitro experiments with the tube serial dilution uriga test,

MH K. in U / ml after incubating penicillins listed in Table 1 for 24 hours.

penicillin No. I 2
1 t ' Ampicillin tribe <0.78 < 7th £ 0.78 Sfcaph. SG 511 4 ° ^'78 < 0.78 S 0.78 Staph. P 209 200 0.78 400 Staph. 1219 200 100 400 Staph. 7705 3.12 200 I.56 Strept.faec. 8564 <0.78 <
ss 3.12 3.12 Strept.faec. 8 $ 8O 6.25; 0.78 6.25 Strept.faec. 8709 12.5: 3.12 3.12 Strept, faec. ATCC
9790 1.56 12.5 1.56 E. coli 14 3.12 1.56! 6.25 E. coli C I65 3.12 6.25 6.25 E. coli 055 B 5 3.12; 6.25 E. coli 26/6 3.12 > 4oo E. coli A 26I 3.12 j 400; > 400 E. coli T 7 200 4oo > 4oo E. coli T 20 II > 400> 400 L56 Klebs. 8085 > 4oo > 0.78 200 Glue. K 10 £ 1.56 25; 100 Klebs. 63 50 12.5 50 Klebs. 69 L2.5 12.5 200 Klebs. 70 12.5 13.5 y 50 Klebs. 75, .. 12.5 25th f.e / \] 1 48 5 12.5 46/1879 11
...; ti - 098

BATH ORIGINAL

(Cont. Tab. 3)

Glue. 1498
Glue. 1774
Psdm. Walter
Pedal. mouse
Psdm. 3 ^ 00
Psdm. Lodenkämper Psdm. 1

Psdm. Freiburg
Psdm. McCune
Psdm. V 7602
Psdm. V 7608
Prot.mir.Gießen
Prot.vulg. 3400
Prot.vulg. IOI7
Prot.vulg. 766
P ot.rettg. IO5O
Γrot.morg. 12? 2
Prot.morg. 932
Prot.morg. 1102
Prot.mir. 605
Prot.mir. 1235
S.typhi. ATCC 6539 S. paratyphi. B oll Shig Flexneri III

400

UDO

25 6.25

6.25 12.5 12.5

3, -12

12, *.

3.1 * 6.25> 4ü0 12.5

25th

400 100

3.12 1.56

1.56

6.25 100

4oo

12 _t ^K. 12.5

• -, 25 12.5

6.25

3.12

6.25

12.5 6.25 1 50 6.25 3.12 J 400 j..1.2
3.I

12, ϊ 100
I 56 0.78 ■, 56

200 400 50 400 200 400 400

1.56

;. «IOO Ü0

♦ υο

-00

4oo> 4oo

0/8

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Table k :

Animal experiments with dar white mouse

O to oo

Preparation of
!Table 1
(Penicillin No. Dosage E / mouse
subcutaneous X
X 3000
1500 E / M.
E / M. Infectious germ 133 ¹ P survivors
Therapy animals 24 Hours after infection
Control animals t
i
i L.
i X
X 3000
1500 E / M.
£ / M, Klebsielia 8Ο85 100
90 0-20 / 1
2 X
X 1500
750 E / M.
E / M. Bakt, coli C I65 100
90 IC
10 7th 1
1 Staphylococcus aureus 100
100 10-20

177062G Hi

Since the penicillins have a high acid resistance to Tej. 1, the possibility of an oral application is given.

The penicillins according to the method can be used alone or in Combination with a pharmaceutically safe carrier substance according to the usual pharmaceutical processes formulated and administered. For oral administration they can be in the form of tablets, for example in addition Starch, milk sugar, certain types; of clay etc. contain can, or in the form of capsules, drops or granules, alone or together with the same or equivalent Additions are given. They can also be taken orally in the form of juices or suspensions made for such purposes Contain the usual flavor corrections or colorings can be given.

Furthermore, the penicillins according to the method can by parenteral Application, e.g. intramuscular, subcutaneous or intravenous, may be administered as a continuous drip infusion. «In the case of parenteral administration, this is done on best as a sterile solution, which may also contain other components of the solution, such as sodium chloride or glucose To make solution isotonic. In order to prepare such solutions, one can expediently use penicillins in the form of dry ampoules use. For oral and parenteral administration iet a dosage of 25,000 to 1 million U / kg body weight / Day expedient. Man. it can be given as a single gift or distributed

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give on several doses. For a local treatment, the penicillins according to the procedure can be used as ointments or powders
prepare and use.

The induiigsgemäüen new i'enicillins and their non-toxic salts are said to be used as anti-bacterial agents in human and
Veterinary medicine, as animal feed additives , as agents for the treatment of bovine mastitis and as therapeutic agents for the treatment of gram-positive and gram-negative
Serve bacteria causing infections in poultry, other animals and the human body.

The following examples illustrate the invention without limiting it.

In the examples where o-aminobenzylpenicillin (* ampicillin A) was used, the so-called 'ampicillin B' / ~ cf. US Pat. 3 Insert ikk 445_7.

All melting points were determined on the Kofierheizbank. You are corrected.

The numbers (U / ml) given for the effectiveness against certain bacteria are minimal inhibitory concentrations in the
Tube serial dilution test after 24 hours of incubation.

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The ß-lactam content was determined iodometrically. All penicillins show an IR spectrum (i.KBr) corresponding to their constitution.

The acyl isocyanates, isocyanates and acyl isothiocyanates used as starting materials were prepared by known methods, for example the acyl isocyanates from the corresponding amides with oxalyl chloride, the isocyanates from the corresponding amines with phosgene and the acyl isothiocyanates from the corresponding acid chlorides with lead thiocyanate or with trimethylsilyl thiocyanate. The acyl isocyanates were prepared from the corresponding acid chlorides with trimethylsilyl part.

The IR spectra of these intermediates showed the bands consistent with the desired constitution.

The penicillins obtained as crude products can, if desired, be purified by chromatography, for example on silica gel, in accordance with a procedure known for penicillins .

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example 1

Di -) a- (Beiizoy x-ureido) -benzylpenicillin-potassium:

D (-) oc-aminobenzylperii, illin (ampicillin) (21 parts by weight) was suspended in 60 tigern n-ätr - '^ en Ta trahydroturan (200 vol, Ti.), Then as much triethylamine (approx 7.5 vol. TIe.) Was added dropwise at 20 ° C. so that the u-aminobenzylpenicillin was just dissolved and the pH of the mixture was between 7.5 and 0.1 (glass electrode). Dan> i Wurd "under stirring at about 20 ⁰ C the solution of Benzoyli.socyanat (ö, 9 wt. TIe.) In Tetrahydi'ofuran (35 Vol. TIe.) Was added dropwise over the course of about 30 minutes while keeping the pH by corresponding addition of triethylamine kept at 7 »5. The mixture was then stirred (about 45 minutes) until no more triethylamine had to be added in order to maintain the pH 7-5. It was then diluted with 200 ml of water, the pH was adjusted to 6.5 with a little dilute sulfuric acid, most of the tetrahydrofuran was removed in a rotary evaporator, and the remaining aqueous solution was shaken out with ether. Then the aqueous phase is covered with a 1/1 cup of ether and Esstgester (600 vol. TIe.) and the pH is adjusted to 2.0 with dilute sulfuric acid with slow stirring. The organic phase is then separated off, three times with .00 vol. TIn each time. Water washed, ^ 5 minutes ^{dried over magnesium sulfate at about 0 0} C and after filtration from the desiccant with an about 1 molar solution of potassium 2-ethylhexanoate in ether, to which a small amount of methanol was added, the potassium salt of the solution Penicillins like. The mixture was left overnight at about

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te

Left to stand at 0 ° C, then poured off from the precipitation, the latter then rubbed with ether, sucked off and placed in a desiccator

dried over PaO _3.

Yield (crude product) j 6.4 parts by weight.,

Melting point: decomposition at approximately 200 ⁰ C (Kofler heating bench)

ß-lactam content (determined iodometrically): 95 ^ U / mg, Efficacy against Bakterxum Proteus 34OO: 50 U / ml.

Example 2

Di -) a- (4-Methoxybenzoyl-ure'ido) -benzylpenicillin-Kaliumi This penicillin was in the manner described in Example 1 from 18 wt. TIn. D (-) a-Amiriobenzylpenicillin (ampicillin) and 11.9 wt. TIn. 4-methoxybenzoyl _{isocyanate (bp 13} = 14O-42 °)

prepared in 60% aqueous tetrahydrofuran.

Yield (crude product): 4.4 wt TIe, melting point:.. Decomposition at about 170 ⁰ C, ß-Lactamgehalti 64l U / mg,

Specific rotation: Z ~ a_7_g + 96.2 ° (l, 0; 50% aq. Methanol),

Efficacy against the bacterium Proteus 3 ^ 00: 6.25 U / ml.

Example 3

D (-) a- (4-chlorobenzoyl-ure'ido) -benzylpenicillin sodium i This penicillin was in the manner described in Example 1 from 20 wt. TIn. Di-) o-aminobenzylpenicillin (ampicillin) (1580 U / mg) and 10.4 wt. TIn. 4-chlorobenzoyl isocyanate (about t " 76-85 °) in 75% aqueous tetrahydrofuran

, 1-U, λ.

- ^ _109846/1879

BAD ORiGINAL

Precipitation made with sodium 2 ethylhexanoate.

Yield (crude t .i S, L wt TIE, melting point;.. Decomposition at about 215 ° C, J3-lactam B 957 / mg,!

Specific rotation? / _ O_y ' _g + 151.2 ° (l, OO6; 50 <jb aq. Methanol),

C ₂₄ Ha ₂ ClN ^ NaO ₆ S (553). C 52.1 H 4.0 Cl 6.4 N 10.1 S 5.8

found C 52.30 H 4.73 Cl 7.0 N 8.30 S 5.38, activity against Bikterium Pseudomonas Bonn: 25 U / ml.

Example 4

Di -) a- (2-chlorobenzoyl-ure'ido) -benesylpenicillin sodium i This penicillin was in the orphan described in Examples 1 and J from 20 wt. TIn. D (-) α-aminobenzylpenicillin (ampicillin) " and 10.4 parts by weight of 2-chlorobenzoyl isocyanate (boiling point H7-19 ⁰ ) in 75 aqueous tetrahydrofuran.

Yield (crude product; s 7.2 parts by weight., Melting point: decomposition at approx. 155 ° C, ß-lactam content: 813

Specific rotation: Ζ ~ ^α ._7, - ₈ ο ^{+ 12} ^ »5 ° (l» 0? 50 ^ b wss. Methanol), effectiveness against ßacterium Pseudomonas Bonn: 25 U / ml.

Example 5

Di -) a- (2-bromobenzoyl-ure'idü) -benzylpenicillin-potassium! This penicillin was in the manner described in de * Example 1 from 20 wt. TIn. Di-) a-aminobenzyipanicillin and

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BATH ORIGINAL

13.0 wt. Tin. 2-Brombenzoylisocyanat (Kp = ⁰ I63) in 75 / tigern prepared aqueous tetrahydrofuran. Yield (crude product); 6.5 wt. Tie., Melting point: decomposition at approx. 208 ° C, ß-lactam content t 7ho E / mg,

Specific rotation: / <* J7 kqq ⁺ H ² *, 9 ° (1.006} 50> vss. Methanol), effectiveness against the bacterium Klebsiella K 10: 12.5 U / ml ..

Example 6

D (-) e- (2,5-dichlorobenzoyl-ure'ido) -benzylpenicillin sodium: This penicillin was prepared in the manner described in Example 1 or 3 from 17.5 wt ill in and 10.8 wt. tin. 2,5-dichlorobeiizayl _{isocyanate (bp n K} = 12 ^ -126 °) in 75% tetrahydrofuran.
Yield (crude product): k, 9 parts by weight.,
Melting point: decomposes at approx. 2O6 ° G,
ß-lactam content: 811 U / mg,

Specific rotation: '/ _ a_7_g + 123t5 ° (O, 998 | 50 % aq. Methanol), effectiveness against the bacterium Pseudomonas Bonn: 25 U / ml.

Example 7

D (-) a- (3 »4-dichlorobenzoyl-ure'ido) -benzylpenicillin sodium: D (-) a-aminobenzylpenicillin (30.3 each. Tie.) Was in abs.
Suspended tetrahydrofuran (300 parts by volume), triethylaniine
(ll, 2 Vol. TIe.) are added, then at room temperature the solution of 3, ^ - dichlorobenzoyl isocyanate (17, ^ wt. Tie.)

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SADORfGiNAL

in tetrahydrofuran (30 vol. Tie.) was added dropwise, then stirred for 20 minutes. The clear reaction solution was then diluted mat water (pH of the mixture was then 7 »8) and then in de (200 vol TIe..): Example 1 or worked ,, 3 beschrieber cn manner.

Yield (crude product): 8.8 parts by weight,
Melting point: decomposition at approx. 210 ° C, ß-lactam content t 9O7 U / mg,

Specific rotation: / ~ a_7c _ög ⁺ 126.3 ° (l »0; 50% aq. Methanol), C ₂ I ¹ ^ i Cl ₂ K ₄ NaO ₆ S (587) ber, C 49.1 H 3.6 Cl 12.1 N 9.5 S 5.5

found C 48.4l H 4.37 Cl 11.73 N 8.98 S 5.34 Effectiveness against the bacterium Pseudomonas Bonn: 12.5 U / ml.

Example 8

D (-) a- (2, 4-dichlorobenzoyl-ure'ido) -benzylpenici Hin sodium: This penicillin was made from D (-) a-aminobenzylpeniciHin (25 parts by weight) and 2,4-dichlorobenzoyl isocyanate (bp = 87-91 °)

U, 1

prepared in the manner described in the example '].

Yield (crude product): 6.9 parts by weight.,

Melting point: decomposes at approx. 210 ° C,

fl-lactam content: 857 U / mg,

Specific rotation! / a__7 _ßg + 135.9 ° (10; 50 ⁰ Jo watery methanol), effectiveness against the bacterium Proteus 3 ^ -00: 12.5 U / ml.

Example 9

D (-) α- (2, 4-dichloro innaiiioyl-ure'ido) -benzylpenicillin sodium x This penicillin was made from D (-) α-aminobenzylpenicillin

109846/1879

a 11 4e; .; 48 -

BATHROOM OBlGINAL

(26.5 wt. Tie.) And 2,4-dichlorocinnamoyl isocyanate (bp =

U ₁ Y ...

125-3O ⁰ C) prepared in the manner described in Example 7. Yield (crude product): 15.5 wt TIE, melting point:.. Decomposition at about -220 ⁰ C,

ß-lactam content: 789 U / mg,
Specific rotation: / <x__7egg ⁺ 1 ^ 3 ° (l, 002; 50 # aq. Methanol).

Example 10

D (-) <x- (2, ^ -Dichlorophenoxyacetyl-ure'ido) "benzylpenicillin sodium: 19.5 parts by weight. Di-) α-ure'idobenzylpenicillin (degree of purity 82.4 " jo% 125O U / mg ) were in 200 Vol. TIe. a mixture of acetone and water (i »l) with the addition of 7» 5 wt. TIn. Dissolved sodium hydrogen carbonate. With stirring, 12 wt. TIe at 0 ⁰ C. 2, ^ - dichlorophenoxyacetyl chloride (bp β 157-Ι58 ⁰ )

in 50 vol. Acetone was added dropwise. It was stirred for 1 hour at ⁰ ° C. and then for a further 2 hours at room temperature. The acetone was then distilled off on a rotary evaporator, the solution with 100 vol. TIn. The water is further diluted and covered with a mixture of ether and ethyl acetate (1: 1). While stirring and cooling with ice, the pH was adjusted to 2 with 1N sulfuric acid and the organic phase was separated off. This was twice with 100 vol. TIn. Washed with water, then dried over sodium sulfate for 2 hours and, after filtration, treated dropwise with an approx. 1 molar solution of sodium - <- 2-ethylhexanoate in isobutyl methyl ketone in order to precipitate the sodium salt of penicillin.

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177062G

Yield (crude product) ί 3 »9 wt. Tie., Melting point: Zersetaiunjs from approx. 180 ° C, ß-lactam content: 74O U / mg, Efficacy against Proteus Gießen «<0.7 & U / ml, effectiveness against Pseudomonas Bonn: 50 U / ml.

Beisf ) i el 11

Df -) a- (4-Meth.ylphenylsulfonyl-ureido) -benzylpenicillin sodium: This penicillin was prepared in the manner described in Example 10 from 19 × 5 wt. TIn, D (-) ot-ureldobenzylpenicillin and 9.5 Weight TIn. Obtained p-toluenesulfonyl chloride. Instead of an ether-ethyl acetate mixture, isobutyl-methyl ketone was added. After the organic phase had been dried, the sodium salt was precipitated therefrom with sodium 2-ethylhexanoate. Yield (crude product): t, 5 g,
Melting point: decomposition at approximately 200 ⁰ C, .beta.-lactam: 1169 U / mg,
Effectiveness g gen bacterium Pseudomonas in Bonn: 5 ° E / ml.

Example 12

D (-) 0 £ - (3, 4-Dichlorpheriylsulfonyl-ure'ido) -benzylpenicillin-sodium t This penicillin was prepared in the manner described in Example 10 from 19.5 wt. TIn. D (-) a-ureidobenzylpenicillin and 12.5 wt. Tin. 3,4-dichlorobenzenesulfonic acid chloride obtained, In contrast to this, it was again covered with isobutyl methyl ketone and the sodium salt precipitated therefrom.

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BATH ORIGINAL

Yield (crude product) t 2.5 parts by weight, melting point ι decomposition around 2OO ° C, ß-Laetam content IO38 U / mg,

Efficacy against Proteus Gieöent <0.78 U / ml, Efficacy against Paeudomonas Bonn: 50 U / ml.

Example 13

D (-) a- (4-chlorophenylsulfonyl-ure'ido) -benzylpenicillin sodium:

This penicillin was used in the method described in Example 10 Way from 19.5 wt. TIn. Di-) a-ureidobenzylpenicillin and

10.5 wt. Tin. Obtained Λ-chlorobenzenesulfonic acid chloride.

It was again covered with isobutyl methyl ketone and from this the sodium salt with approx. 1 molar solution of sodium

2-ethylhexanoate precipitated in isobutyl methyl ketone.

Yield (crude product) t 3.5 wt TIE, melting point:.. Decomposition at about 220 ⁰ C, ß-Lactamgehaltt 1153 U / mg,

Efficacy against Proteus Gießen * <0.7ö U / ml, Efficacy against Pseudomonas Bonn: 5 ° U / ml.

Example 14

D. (-) a- (Phenylcarbamoyl-ure'ido) -benzylpenicillin-Potassium 19.5 parts by weight. D (-) o-ure'idobenzylpenicillin (degree of purity 82, i * ^ v, 1250 U / mg) were in 300 vol. suspended from tetrahydrofuran and water ItI. It was ^{cooled to 0 c} C. and slowly added 7.0 vol. TIe. Triethylamine

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10 9846/1879

SAD

added, the pH being adjusted to 7 ♦ 5-7 »8. Then 6.0 wt. Tie. Phenyl isocyanate in 50 parts by volume. Tetrahydrofuran was added dropwise, stirring was continued for L hour at 0 ^° C. and then for a further 5 hours at room temperature. The tetrahydrofuran was then drawn off in vacuo on a rotary evaporator, and the aqueous solution was overlaid with a mixture of ether and ethyl acetate. Under ice cooling, the mixture was acidified to pH 2 with 1N sulfuric acid and the organic phase was separated off. The aqueous phase was twice with 100 vol. TIe. of the same mixture shaken out. The combined extracts were washed with a little water and then dried with sodium sulfate for 2 hours. The penicillin salt was precipitated using a solution of potassium 2-ethylhexanoate in ether. Yield (crude product): 3.5 wt TIe, Sclimelzpunkt.:. Decomposition at about 170 ⁰ C ß-Lactamgehaltϊ, 860 U / mg,

Efficacy against Proteus Gießent <0.78 U / ml, effectiveness against Pseudomonas Bonn: 50 U / ml.

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Example 15

D (-) α- (2-Chi or-4-ethylthio-benzoy "l ~ ur * e'ida) -benzylpenicillin Kaliumt This penicillin was described in Example 7 xii Way from 21 wt. TIn. D (-) cc-aminobenzylpenicillin and 14.5

Weight TIn. 2-chloro-4-ethylthio-benzoyl isocyanate (bp ^ ₁ _ ■ »

168-172 °) »The work-up was carried out as in

Example 1 given. It was precipitated with potassium 2-ethylhexanoate.

Yield (crude product) s 3.2 parts by weight.,. A.

Melting point: 'Decomposition at approx. 200 ⁰ C, ß-Lac tauige halt (iodom. Best.): 822 U / mg, effectiveness against Proteus 3400: 6.25 U / ml, effectiveness against Pseudoinoiias Boxua: 12.5 U / ml.

Example l6

D (-) a- (2,5-Dimethyl-furan-3-carbonyl-ure'ido) -benzylpenicillin potassium

This penicillin was described in the JK described in Example 7

Way from 21 wt. TIn. D (-) a-aminobenzylpenicillin and 10 wt. TIn. 2,5-dimethyl furancarbonyl isocyanate (crude product) was obtained. Work-up was carried out as indicated in Example 1. It was precipitated with potassium 2-ethylhexanoate. Yield (crude): 9i2 TIe weight, melting point:.. Decomposition at about 190 ⁰ C, .beta.-lactam: / mg 956 E,

Efficacy against Proteus 3400: 12.5 U / ml,

Efficacy against Pseudomonas Lodenkämper: 25 U / ml.

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Le All 483 ■ - b'5 -

BATH ORIGINAL

177062Ü

example x _ / m * L

Di-) ot- (Furaii "2-cai boiiyl --urei.io) benzylpenicilliu potassium:

This penicillin was described in Example 7 Way from 21 wt. TIn. D (~) a-aminobenzylpenicil1 in and 8.1 Weight TIn. Furan-2-carbonyl isocyanate (crude product) obtained.

Work-up was carried out as indicated in Example 1.

It was precipitated with potassium 2-ethylhexanoate.

Yield (crude product) t 6.9 parts by weight, Melting point: decomposition from 180 ° C, ß-Lactamgehalfc i 972 E / mfe-.

Efficacy g & gtm Proteus 3 ^^ 0: 50 U / ml,

Efficacy against Pseudomonas Lodenkämperi 12.5 U / ml.

Example IB

Di -) a- (Naphthoyl-ura'ido) -benzylpenicillin-Kaliuin:

This penicillin was described in Example 7 Way from 21 wt. TIn. D (-) o-aminobenzylpenicillin and 12

Weight TIn. Naphthoyl isocyanate (bp "» 118 °) shown.

Work-up was carried out as indicated in Example 1.

It was precipitated with potassium 2-ethylhexanoate.

Yield (crude product): k, 2 parts by weight, melting point: decomposition from 200 ° C, ß-lactam content 685 .L / mg, effectiveness against Pseudomonas Bonn 50 U / ml.

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^ BATH ORIGINAL

Example 19

55

DC-) α- (3, S-dimethylisoxazole-if-carbonyl-ureido) -benzylpeni-

ciliin potassium:

This penicillin was prepared in the manner described in Example 7 from 21 wt. TIn. D (-) a-aminobenzylpenicillin and 9 »9 Weight TIn. 3 »5-dimethylisoxazole-4-carbonyl isocyanate obtained.

The work-up was carried out as indicated in Example 1 '.

It was precipitated with potassium 2-ether ylhexanoate.

Yield (crude product) t 3.9 wt TIE, melting point:.. Decomposed from about 180 ⁰ C, .beta.-lactam: 790 E / mg

Efficacy against Klebsieila K 10: 50 U / ml, Efficacy against Pseudomonas Bonn: 100 U / ml.

Example 20

Di -) a- (U-chloro-3-carbamoyl) -ure'ido-benzylpenicillin potassium: This penicillin was prepared in the manner described in Example 7 from 21 wt. TIn. Di *) a-aminobenzylpenicillin and 13.5 wt. TIn. ^ -Chlor - ^ - carbamoylbenzoyl isocyanate (crude product) produced. Work-up was carried out as indicated in Example 1. It was precipitated with an approx. 1 molar solution of potassium 2-ethylhexanoate in ether. Yield (crude product): 9.2 wt TIE, melting point:.. Decomposed from 17O ⁰ C,
ß-lactam content: 800 U / mg,

Efficacy against Proteus 3400: 25 U / ml,

Efficacy against Pseudomonas Lodöiikämper: 25 U / mi, Effectiveness against Pseudomonas Bonn; 25 U / ml.

1 0 9 846/1879

Le A 11 483 - _: = -

ÖAD ORIGINAL

177062G

Example 21

D (-) α- (3-chlorobenzoyl-urexdo) -benzylpenicillin potassium: This penicillin was prepared in the manner described in Example 7 from 21 wt. TIn. D (-) a-aminobenzylpenicillin and 10.8 wt. TIn. 3-chlorobenzoy] isocyanate (crude product). The work-up was carried out again as indicated in Example 1. It was precipitated with potassium 2-ethylhexanoate. Yield (crude product): 3 »ö parts by weight, melting point: decomposition at approx. 220 ° C, ß-lactam content: 978 U / mg,

Example 22

2-chloro-4-ethylthiobenzoyl-uΓexdo-l-cyclopentylpenicillin-

Sodium:. -

This penicillin was prepared in the manner described in Example 7 from 16.5 wt. TIn. 1-Ainocyclopentylpenicilin

(Degree of purity 86.0 #) and 12.0 wt. TIn. 2-chloro-4-ethylthio-

benzoyl isocyanate (bp: = 160-170 °) obtained. The work-up took place as indicated in Example 1. Was liked with one

approx. 1 molar solution of sodium 2-ethylhexanoate in isobutyl

methyl ketone.

Yield (crude product): 3i5 parts by weight., Melting point: decomposition at approx. 160 ° C, ß-lactam content: 702 U / mg.

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SAD ORiGfNAL

Example 23 C * f

^ -Methoxybenzoyl-ure'ido-l-cyclopentylpenicillin potassium: This penicillin was in the manner described in Example 7 from 16.5 wt. TIn. l-aminocyclopentylpenicillin ( degree of purity 86.0 io) and 9 »O wt. TIn. 4-Methoxybenzoyl isocyanate (boiling point β 130 °) was obtained. Work-up was carried out as indicated in Example 1. It was precipitated with a solution of potassium 2-ethylhexanoate in ether.
Yield (crude product): 3.0 parts by weight, melting point: decomposition from 170 ° C., α1-lactam content: 795 U / ml. .

Example 2k

D (-) a- (5-Methoxy-2-chlorobenzoyl-ure'ido) -benzylpenicillin Potassium:

This penicillin was prepared in the manner described in Example 7 from 21 wt. TIn. D (-) a-aminobenzylpenicillin and 13 wt. TIn. 3-methoxy-2-chlorobenzoyl isocyanate (crude product) shown. Work-up was carried out as indicated in Example 1. It was precipitated with potassium 2-ethylhexanoate. Yield (crude product): 3.1 parts by weight., Melting point: decomposition from 170 ° C, ß-lactam content: 872 U / mg.

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8ADORIGINAL

■ Example 25

Di -) a- (2-Jodbenzoyl -ureido) -benzy Lpenicillin-Potassium:

This penicillin was prepared in the manner described in Example 7 from 21 wt. TIn. D (-) ce-aminobenzylpenic illin and

16, 2 wt. TIn. 2-iodobenzoyl isocyanate (crude product) is shown.

Work-up was carried out as indicated in Example 1.

Yield (crude product): 3.5 parts by weight, melting point: decomposition from 180 ° C., ß-lactam content: 839 U / mg.

Example game 26

D (-) a- (3-iodobenzoyl-ure "ido) -benzylpenicillin-potassium:

The presentation and processing was carried out in the same way as for

2-iodine derivative indicated.

Yield (crude product): 2.5 parts by weight, melting point: decomposition from 180 ° C., β-lactam content: 69k U / mg.

Example 27

D (-) <x- (4-iodobenzoyl-ure'ido) -benzylpenicillin-potassiumx

The representation was carried out in the same way as for the 2-iodine derivative

specified.

Le A 11 483 - 58 10984671879

BATH ORIGINAL

53

It was precipitated with potassium 2-ethylhexanoate. Yield (crude product) ϊ 6.5 wt. Tie "Schmelzpunktt decomposition from 17O ⁰ C beta-lactam, t / mg E 806.

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1.098A6 / 18-79

Claims (1)

Claims 177062D 1) Penicillins of the general formula I - NH - CO - KH - C - CO --NH R, COOH and their non-toxic salts, in which R, the least of one carboxylic acid or sulfonic acid (acyl radicals) with up to 26 carbon atoms, R _? a hydrogen atom, an optionally substituted or interrupted by heteroatoms alkyl radical or an optionally substituted cycloaliphatic, araliphatic aromatic or heterocyclic radical i3t, R-, has the same meaning as Rp without the two radicals in individual cases and R, iden have to be at the table - and in which Rp and R, also under training a cycloaliphatic or heterocyclic ring with three to seven ring members can and in which the starred carbon atom in the racemic or one of the two optically active forms are present. Le A 11 483 - 60 - 1 09846/1879 BATH 177062C 2) Process for the preparation of penicillins of the general formula I. IR _t -NH-CO-NH-C-CO-NH / VR ₂ R ₃ . "T — COOH and their non-toxic salts, wherein R ₁ . the radical of a carboxylic acid or sulfonic acid (acyl radical) with up to 26 carbon atoms, R _{2 is} a hydrogen atom, an optionally substituted or interrupted by heteroatoms alkyl radical or an optionally substituted cycloaliphatic, araliphatic aromatic or heterocyclic radical, R _{3 has} the same meaning as R ₂ has - without the two radicals R ₂ and R ₃ having to be identical in individual cases - and in which R ₂ and R _{3 can} also be connected to form a cycloaliphatic or heterocyclic Ring ™ with three to seven ring members and in which that with an asterisk provided carbon atom is present in the racemic or one of the two optically active forms, characterized in that either a) compounds of the general formula IX or III, or their salts, or IV, V, VI or VII 1 09846 A1 879 177062C II H ₂ - C - CO - NH COOH CH, III H ₂ N — CO— NH- C — CO — NH- R ₂ R ₃ -N- JH, -COOH IV CH, H ₂ NC — CO-NH- / \ R ₂ R ₃ -N- ■ COOSi — R, R ₅ - Si— HH- C CO — NH- N- CH, CH, -COOSi-R, VI H ₂ N CO — NH- C - CO— NH- R ₂ R ₃ -N- CH, -COOSi-R ₃ Le A 11 483 - 62 109846/1879 ^BATH VII R ₃ —Si-NH-CO-NH- * or H ₂ NCNI or HNeC-NH- -C-CO-NH R ₂ R ₃ wherein R ₂ . Rj and C have the meaning given above and in which R *, R ₃ and R {are identical or different, substituted or interrupted by heteroatoms, alkyl, aralkyl or cycloalkyl radicals or optionally substituted aryl radicals, with acyl isocyanates of the general formula VIII R, - N = "C = O or with N-Acylcarbaminaäurederivaten of the general Formula IX or X R__NH— C R ₁ -NH-C A. - ™ Kn wherein R _{1 has} the meaning given above, X is a radical as it is in Ieocyanatabspaltena. Le A 11 483 ^ -10 9846/1879 bath occurs, A stands for -0- or -S- and R _{7 is} an optionally substituted or interrupted by heteroatoms alkyl, aralkyl or cycloaliphatic radical or optionally substituted aryl or heterocyclic radical, or by reacting b) Compounds of the general formulas III, VI or VII, in which Rp, RI, R4 »Rg and C are as defined above, with acylating agents or mixtures, such as carboxylic acids of the general formula XI XI R ₈ -GO OH where Rg-CO equals R-, in the presence of dehydrating agents Agents or with acylating functional derivatives of the acids of the general formula XI or other acylating functional derivatives of carboxylic acids, as known in peptide chemistry are, or with isocyanates of the general formula XII XlI R ₉ ff = C = 0 wherein R "is the radical of a primary amine, for the reaction brings, or by Le A 11 483 - 64 - 109848/1879 BATH ORIGINAL c) 6-aminopenicillanic acid, or its salts or derivatives of general formulas XIII or XIV H ₂ N- -N- CH ₃ -COOSi-R ₃ ♦> s. COOSi ^ -R ₃ wherein R *, R ₃ and R $ have the meaning given above, with acids of the general formula XV R _t - NH - CO - NH - C - COOH in which R ₁ , R _2, R, and C have the meaning given above, in the presence of a carbodiimide, carbonyldiimidazole or carbonylditriazole or with furious derivatives of the acids of the general formula XV or other functional derivatives of the acids of the general formula XV with an aoy ~ 1 action "as used in peptide chemistry, or jm Le A 11 48-5 - t 846/1879 SAD ORIGINAL 177062G Case of the non-silylated 6-aeinopenicillanic acid fermentative route with the glycine, glycolic acid or Thioglycolic acid derivatives of the acids of the general formula XVI XVI R ₁ NH-CO-NH CO-B-CH ₈ COOH wherein R ₁ , R ₄ , Rj and C have the meanings given above and B stands for -NH-, -0- and -S-, brings about the reaction. 5) The method according to claim 2, characterized in that as functional «* derivatives of the acids of the general formula XV pseudosaccharin esters or amides of the general formula XVII XVII wherein R _{10 is} the acid of the general formula KNf, can be used. j for λ II 4βί 109846/1879 ORIGINAL BATHROOM