DE2258973A1 - PENICILLIN, THE METHOD FOR MANUFACTURING IT AND THEIR USE AS A MEDICINAL PRODUCT - Google Patents

Description

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and licenses

_. , “509 Leverkusen, Bayerwerk

Ib (Ph *) 3 0 NOV. 1972

Penicillins, processes for their production and their use as a medicine

/ i

The present invention relates to new penicillins, several Process for their production and their use as pharmaceuticals in human and veterinary medicine, as therapeutic Agents for poultry, mammals and fish, as feed additives and as growth-promoting agents for animals, in particular their oral and parenteral use as antibacterial agents, especially when used by bacteria Families of the Enterobacteriaceae, Pseudomonas and Aeromonas bacteria caused infectious diseases »

These penicillins are those 6-acylureidoacetamido) -penicillanic acids in which the hydrogen atom of the nitrogen atom in the 3-position of the acylureido group is replaced by hydrocarbon radicals and the Ot position of the acetamido group is replaced by a hydroxy, dihydroxy or 2,5-Dihydrophenylrest is substituted.

It has already become known that 6 - (<X-3-Acylureidoacetamido) -penicillanic acids are synthetically accessible and can be used as antibacterial agents. This is possible in detail from the following sections:

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6- (A ^ -acylureidoacetamidoJ-penicillanic acids are in Dutch patent applications 69, 01646 and 69, 08909 and US Patents 3,479,339 and 3,481,922, but all of them described in these patents have claimed 3-acylureidoacetamldopenicillanic acids in the Acylureido group on the nitrogen atom located in the 3-position is a hydrogen atom. The presence of this Hydrogen atom and the absence of another substituent at this point of the acylureido group inevitably results from the different synthetic route of these penicillins.

6- (o6-3-Acylureido-acetamido) -penicillanic acids, in which the hydrogen atom of the nitrogen atom in the 3-position of the acylureido group by hydrocarbon radicals is replaced, are in the German Offenlegungsschriften 2 o25 414 and 2 1o4 58o as well as in the Belgian patent specification 767 647, but contain those described there and penicillins did not claim any hydroxy, dihydroxy or 2,5-dihydrophenyl radicals in the cc position of the acetamido radical.

6- (od-3-acylureido-acetamido) -penicillanic acids, in which the hydrogen atom of the nitrogen atom in the 3-position of the acylureido group is replaced by hydrocarbon radicals and which have a hydroxyphenyl or 2,5-dihydrophenylreet in the OC position of the acetamido group are already mentioned in the German Offenlegungsschriften 2 o25 415 and 2 1o4 579 and in the Belgian patent specification 767 648.

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

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A-CO-NH-CH-CONH B

COOH

wherein A is a group X-CO-N- or C N -,

J ^

X hydrogen, alkyl with up to 10 carbon atoms, Alkyl with up to 6 carbon atoms, where a hydrogen atom of the alkyl group is replaced by a nitro, Amino-, mono-lower alkylamino-, di-lower alkylamino- or substituted by a 1-pyridinium group is, alkenyl with up to 10 carbon atoms, vinyl, cycloalkyl and cycloalkenyl with up to 10 carbon atoms, Aryl vinyl, mono-, di- and trihalo-lower alkyl, Mono-lower alkylamino, di-lower alkyl lamino, monoary lamino, ary llowalky lamino, alkoxy with up to θ carbon atoms, cycloalkoxy with up to 7 carbon atoms, aralkoxy with up to 8 carbon atoms, aryloxy,

(CH

Vo-

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J- O

or

Rr

η is an integer from zero to two inclusive and R ^, R ₂ and R, each hydrogen, nitro, nitrile, amino, di-lower alkylamino, di-lower alkylaminocarbonyl, lower alkanoylamino, lower alkoxycarbonyl, lower alkanoyloxy, lower alkyl, lower alkoxy, sulfamyl, chlorine, bromine, iodine, fluorine or trifluoromethyl, Y alkyl with up to 4 carbon atoms, alkenyl with up to 4 carbon atoms, vinyl, eropenyl, cycloalkyl and cycloalkenyl with up to 6 carbon atoms, mono-, di- and trihalo-lower alkyl, aralkyl with up to 8 carbon atoms, aryl, «- Z - a divalent group

2, 3 or 4

O or 1

O or 1

2 or 3

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G denotes hydrogen or lower alkyl with up to 3 carbon atoms, the arrow in the divalent

Group ^ - Z is intended to express that

the connection of the two free valences of 4-Z-with the N and the C atom of group CE N-

not arbitrarily, but in the manner indicated by the arrow,

E oxygen or sulfur, B H

or

means, and those with respect to the chiral center C in the two possible R and S configurations and as mixtures of the resulting diastereomers and their non-toxic pharmaceutically acceptable salts have strong antibacterial properties.

The above-mentioned non-toxic, pharmaceutically acceptable salts include salts of the acidic carboxyl group such as sodium, potassium, magnesium, calcium, aluminum and ammonium salts and non-toxic substituted ammonium salts with amines such as di- and tri-lower alkylamines, procaine, dibenzylamine, N, N ^f -dibenzylethylenediamine, N-benzyl-ß-phenylethylamine, N-methyl- and N-ethylmorpholine, 1-ephenamine,

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Dehydroabietylamine, N.N'-bis-dehydroabietylethylendlamine, N-lower alkylpiperidine and other amines that lead to formation of salts of penicillins have been used.

With the term "lower alkyl" in the present Invention understood both a straight-chain and a branched alkyl group with up to 6 carbon atoms. in the Relation to other groups, as in "Diniedrigalkylamino" the term "-lower alkyl-" refers to that only Alkyl part of the group concerned.

It has also been found that the penicillins of the general formula I are obtained if

/ ~ a_7 compounds of the general formula II

^CH

B-Sh-CO-NH-CH CH ^ \ / ^CH 3

I TT N

I T

NH _? CN

² ^

T-T CL II

he

COOH

in which B and C have the meaning given above, with compounds of the general formulas VI or VII,

E X-CO-N-CO-W II

I C N-CO-W

VI VII

wherein X, Y, Z and E are as defined above, and W is halogen, azide, a group

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-0-N = O

/ ^H 3

CH,

-0-N

Cl, -S-CH ₂ , -0-Ν

or

-S-lower alkyl means O

in anhydrous or hydrous solvents in the presence of a base at a temperature in the range of about -2o to + 5o ° C, or

£ ~ \> _ J compounds of general formula III, the condensation products of compounds of general formula II are compounds having carbonyl,

b-6h

H ^ \ / ^CH 3 C

III

CH ^ 00H

in which B, G and C have the meaning given above, with compounds of the general formulas VI or VII in

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anhydrous or hydrous solvents in the presence of a base at a temperature in the range from about -2o to + 5o ° C, or

/ ~ c__7 compounds of the general formulas IV and V

B-CH-CO-NH-CH CH

ι I 1

/ ^CH 3

CO-O-Si-

IV

B-CH-CO-NH-CH-

Si

CH

CO-O-Si: R

in which B has the meaning given above or

Re-Si-O— (/

R,

, R ₅ - ^ Si-O M /

or

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means, C has the meaning given above and R ,, Rc and Rg is alkyl of up to 6 carbon atoms, in anhydrous and hydroxyl group-free solvents with or without the addition of a base at a temperature * "in the range converts from about -2o to + 5o ° C,

and the penicillins obtained in this way, if applicable, in theirs transferred non-toxic, pharmaceutically acceptable salts.

The penicillins according to the invention surprisingly show a significantly higher antibacterial © effect especially against bacteria from the group of enterobacteria and Pseudomonads as e.g. B. those known from the prior art Commercial penicillins ampicillin and carbenicillin. The substances according to the invention are thus an asset in pharmacy.

If one uses D-cjC-amino-p-hydroxy-benzylpenicillin and 1-Chlorcarbony1-2-0X0-imidazolidine as starting materials, see above the course of the reaction can be represented by the following equation:

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(R)

H-CONH

ϊ-COCl

Tetrahydrofuran / HgO 0-2o ° C, pH 7-8

mJ /

In formulas II and III, B preferably represents

and

in formulas IV and V, B preferably represents

and

R _c - Si-O— // \

The compounds of the general formulas II, III, IV and V are preferably present at C in the D = R form.

The compounds of the formula II and some of the formula III which can be used according to the invention are already known and are described in J. Chem.

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Sog. (C), 1971 , 192ο; J. med. Chem. H, 117 (1971) and in Belgian patent 737,451.

The compounds of the formula III used as starting materials are only partially known and, if they are not in are described in the literature, by condensation of compounds of the general formula II with CarbonyIverbindungen

G-tf-G

(where G has the meaning given above) with elimination of water getting produced.

The compounds of the general formulas IV and V used as starting materials can be obtained by reacting compounds of the general formula II with silylating agents such as trimethylchloroilane or hexamethyldisilazane in the presence acid-binding agents such as triethylamine are produced.

All crystal forms and salts of the compounds of the general Formulas II and III are used as "starting materials for the present." Invention suitable.

The configuration of the asymmetric centers of the 6-aminopenicillanic acid core in en srbindungen of the general formulas II, III, IV and V should be matched with that of the corresponding asymmetric centers of 6-aminopenicillanic acid, the z. B. obtained from penicillin-G by fermentative processes would be identical.

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The compounds of the formulas VI and VII used as starting materials were, as far as W halogen is produced by processes described in German Offenlegungsschrift 1 793 287, in German U.S. Patents 1,259,871, U.S. Patents 3,275,618 and 3,337,621, Japanese Application No. 12,921/64, in the German disclosure documents 2 o25 414 and 2 1o4 58o, in Belgian patent specification 767 647 and in Doklad, Akad. Nauk, SSSR, ^ 92, 1o56-59 (197o) are described. the The preparation of compounds of the formulas VI and VII is also described in the examples.

As the diluent, there are those in the following Sections mentioned substances in question.

If the starting materials used for the synthesis of the penicillins according to the invention are compounds of the general formulas II or III and they are combined with compounds of the general formulas VI or VII, these reactions can be carried out, for example, in mixtures of water with such organic solvents that are miscible with water, such as acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, Carry out dimethyl iso, ifoxide or isopropanol. Included the pH of the reaction mixture is kept between 6.5, for example, by adding bases or using buffer solutions and 8.0. The reaction according to the invention can, however, also be carried out in a different pH range, for example between 4.3 and 9.0 or at pH 2.0 to 3.0. It is also possible to carry out the reaction in water-immiscible solvents, e.g. B. To carry out chloroform or methylene chloride with the addition of preferably triethylamine, diethylamine or N-ethylpiperidine. Furthermore, the reaction can be carried out in a mixture of water and a water-immiscible solvent, such as. B.

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Run ether, chloroform, methylene chloride, carbon disulfide, isobutyl methyl ketone, ethyl acetate, benzene, it is advisable to stir vigorously, and the pH value by adding base or using buffer solutions between 4.5 and 9.0 or e.g. B. 2.0 and 3.0 to hold.

If compounds of the general formulas IV or V are used as the starting material and these substances are combined with compounds of the general formulas VI or VII, then one usually has to work in solvents free of water and hydroxyl groups, work for example in methylene chloride, chloroform, benzene, tetrahydrofuran, acetone or dimethylformamide. The addition of bases is not necessary here, but in individual cases this can improve the yield and purity of the products to enhance. However, the opposite effect is also possible. Any bases added must either be tertiary Amines, such as pyridine or triethylamine, or secondary amines which are difficult to acylate due to steric hindrance, such as dicyclohexylamine be. The number of usable bases is therefore hardly limited.

The amount of bases used is e.g. B. determined by the gewUnselite compliance with a certain pH. If a pH measurement and adjustment does not take place or is not possible or useful because there are insufficient amounts of water in the diluent, 2 molar equivalents of base _{9 are} preferably used if the compounds of the general formulas II or III are used represents compounds of the general formulas IV or V either no base at all or preferably 1 molar equivalent of base added.

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The reaction temperatures can be varied over a wide range. As in general, preferably carried out between about -20 and about +50 ⁰ C, between 0 and + 2O ⁰ C. at most chemiechen reactions can be used as those specified in the examples, higher or lower temperatures. However, if one goes well beyond the values given there, an increasing number of side reactions will take place which reduce the yield or adversely affect the purity of the products. On the other hand, excessively lowered reaction temperatures reduce the reaction rate so much that reductions in yield can occur.

The reaction can be carried out under normal pressure, but also under reduced or increased pressure. Generally works one at normal pressure.

When carrying out the method according to the invention can the reactants are made to react with one another in equimolecular amounts. However, it may be useful Use one of the two reactants in excess in order to purify or purify the desired To facilitate penicillins and increase the yield. For example, you can use the general reactants Use formulas II or III with an excess of 0.1 to 0.3 molar equivalents and thus less decomposition reach the reactants of the general formulas VI or VII in the water-containing solvent mixture. The excess the reactants of the general formulas II or III can be used because of their good solubility in aqueous mineral acids Easily remove when working up the reaction mixture. On the other hand, the reactants of the general formulas VI or VII can also be used with advantage in an excess

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use, for example, 0.1 to 1.0 molar equivalents. This makes the reactants, for example, the general Better use of formulas II or III and the side reaction in aqueous solvents Decomposition of the reactants of the general formulas VI or VII. Compensated. Since the compounds added in excess of the general formulas VI or VII rapidly convert into neutral amides, ureas or thioureas in water, which can be easily removed, the purity of the penicillins is hardly affected.

The reaction batches for the preparation of the penicillins according to the invention and their salts are worked up throughout in the manner generally known from penicillins.

If the starting material used is compounds of the general Formula III, the hydrolytic cleavage of the fragment takes place

in the form of the orarbony compound originally used to prepare the compound of the general formula III

J-,

already immediately after the implementation of the connection general formula III with the compounds of general formulas VI or VII, if water is present in the reaction medium is or in the course of the aqueous work-up of the reaction batches if no water is present in the reaction medium.

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If compounds of the general formulas IV or V, βο are used as starting materials, hydrolytic cleavage takes place of the silyl residues

in the course of the aqueous work-up of the reaction batches.

The following new active ingredients are mentioned in detail:

D- <? C- (3-acetyl-3-methyl-ureido) -p-hydroxybenzy! Penicillin:

(D) CHjCON-CONH-CH-CONH

CH,

CH,

COOH

D-oC (3-i ¹ onnyl-3-methyl-ureido) -p-hydroxybenzylpenicillin:

(D) H-CO-N-CONH-CH-CONH

N CH

OH

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D- oC - (3-methylaminocarbonyl-3-meth.yl-ureido) -p-hydroxybenzy! -Penicillin:

(D) CH ₅ NH-CON-CONH-CH-CONh.

CH,

CH,

COOH

OH

D-i? C- (3-dimethylamino-carbonyl-3-niethyl-ureido) -p-hydroxy " benzylpenicillin;

Λ ⁽⁾

J ₂ N-CO-N-CONH-CH-CONh 1

.CH,

CH,

COOH

3- (Piperidin-1-y1-carbony1) -3-methyl-ureido_7-p-foydroxy benzylpenicillin:

-CON-CONH-CH-CONH-

CH,

■ OH.

COOH

OH

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D- ° L- (3-allyloxy carbony1-3-methy1-ureido ) -p-hydroxy-benzy 1-penicillin:

(D)
• O-CO-N-CONH-CH-COHN-

CH

0 '

CH,

CH,

COOH

D- <26- ^ ~ 3- (ß-nitropropionyl) -3-methyl-ureido_7-p-hydroxy-benzylpenicillin:

(D)
O ₂ N-CH ₂ -CH ₂ -COn-CONH-CH-CONH-

CH _x

N.

CH,

CH,

COOH

D-c ^^ "3- (m-Nitro-p-methoxy-benzoyl) -3-methyl-ureido_7-phydroxy-benzylpenicillin:

(D)
CON-CONH-CH-CONH-

CH,

CH, CH,

COOH

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? -Oxo-py rrolidln-1 -y 1) -carbony lamino__7 "P-ny droxy-l) enzy 1-penicillin:

(D) N-CO-NH-CH-CONH-

Cr

OOOH

OH

D- o6- / ~ (2-0xo-imidazolidin-1 -yl) carbony lamino__7-p-hydroxybenzylpenicillin:

LJ

(D) -CONH-CH-CONH-

.N

CH,

CH,

COOH

OH

J) -oC- £ ~ (2-Oxo-3-methy 1-imidazolid in-1 -y 1) -car bony lamlno_7-p-hydroxy-benzylpenicillin:

CH ₃ -

(D) -CONH-CH-CONH-

COOH

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D-GC- / ~ (Imidazolidin-2-thion-1-yl) -carbonylamino_7-p-hydroxybenzy! Penicillin:

(D) -CONH-CH-CONH

COOH

D- et - (3-dimethylaminocarbony1-3-n-propy1-ureido) -p-hydroxylbenicillin:

CH,
CH,

N-CO-N-CONH OHo νΉ

(D)
3H-C0NH-

p V / Xl ^ r

.N.

COOH

D- <ak- (3-acetyl-3-methyl-ureido) -oC '- (1,4-methylpenicillin:

(D) CH ^ CON-CONH-CH-CONH-

CH,

.N.

CH,

CH,

COOH

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D- οι- (3-FOrIDy 1-3-methyl-ureido) - oC- (1,4-cyclohexadien-i-yl) -methy! Penicillin:

(D)
HCO-N-CONH-CH-CONH.

CH,

COOH

D-o6_ (3-methylaminocarbony1-3-methyl-ureidoJ-hexadien-1-yl) -methy! Penicillin:

- (I, 4-cyclo-

(D) CH ₅ M-GON-CONH-CH-CONh.

CH, 1 Y N.

CH, CH,

COOH

D-i> t- (3-dimethylaminocarbonyl-3-methyl-ureido) -Ä -_ (i, 4-cycloh.exadiene-1 -yl) -methylpenicillin:

(D)

₅ J ₂ N-CO-N-CO-NH-CH-OH-

CONH-

CH, CH

3

COOH

D- oC - / "" 3- (Piperidin-1 -y 1-carbony 1) -3-methyl-ureido__7-cyclohexadien-1-yl) -methy! Penicillin:

(D)

( N-CO-N-CONH-CH-CONH-

CH, CH,

COOH

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D- ° t- (3-allyloxycarbonyl-3-methyl-ureido) - <3t- ( 1,4-cy clohexa dien-1-y1) -methy! Penicillin:

(D)
O-CON-CONH-CH-CONH

CH

OOH

D- <3L- / ~ 3- (ß-nitropropionyl) -3-niethyl-ureido_7- -O, 4-cyclohexadien-1-yl) -methylpenicillin:

(D) O ₂ N-CH ₂ -CH ₂ -COn -CO-NH-CH-CONH

CH ₃

COOH

D-Ä- / ~ 3- (m-nitro-p-methoxy-benzoyl) -3-methyl-ureido_7 - ^ - (1,4-cyclohexadien-1-yl) -methy! Penicillin:

(D) CON-CONH-QH-CONH-

CH ₅

COOH

D- et - £ ~ (2-Oxo-py rr olid in-1 -y 1) -car bony lamino__7-hexadien-1-y1) -methy! Penicillin:

(D)
N-CONH-CH-CONH

, 4-cyclo-

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D-oC-jT (2-Oxo-imidazolid in-1 -y 1) -carbony lamino__7- <* - (1 »4-cy clohexadien-1-yl) -methy! Penicillin:

w.

(D) -CONH-CH-CONH

COOH

D-öC- / _i ~ (imidazolidin-2-thion-1-yl) -carbonylamino_7- < ^? i '- (1,4-cyclohexadien-1-yl) -methy! penicillin:

(D) -CONH-CH-CONH.

CH,

CH,

COOH

D_u6_ ^ ~ (2-Oxo-3-methyl-imidazolidin-1-yl) -carbonylamino__7 (1,4-cy clohexadien-1-yl) -methy! Penicillin:

CH, -

(D) N-CONH-CH-CONH

.CH,

COOH

D- <? U- (3-dimethylaminocarbonyl-3-n-propyl-ureido) -öC- (1,4-cyclohexadien-1-yl) -methy! Penicillin:

(CHj) ₂ N-CON-

(D)
3H-C0NH-

o CHn

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oL- (2-oxo-imidazolidin-1-yl-carbonylamino) -3 »4-dihydroxybenzy! penicillin:

-CONH-CH

CONH

)H

COOH

CH,

The new active ingredients have strong antibacterial effects on. They can be used in human and veterinary medicine for the treatment and prevention of all diseases caused by Bacteria are caused, which are inhibited by the new penicillins with the appropriate dosage.

The new active ingredients can be converted into the usual ones in a known manner Formulations Transferred and applied in the usual way will. So they can be used alone or in combination with a pharmaceutically acceptable carrier substance according to the usual pharmaceutical procedure formulated and administered.

For oral administration they can be in the form of tablets, e.g. B. may additionally contain starch, lactose, certain types of clay, etc., or be given in the form of capsules, drops or granules, alone or together with the same or equivalent additives . They can also be given orally in the form of juices or suspensions, which may contain flavorings or colorings customary for such purposes.

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Furthermore, the new active ingredients can be administered parenterally, z. B. intramuscularly, subcutaneously or intravenously, possibly as a continuous drip infusion. In the case of the For parenteral administration, this is best done as a sterile solution that contains other components of the solution, such as Sodium chloride or Gluco & e may contain to make the solution isotonic close. In order to prepare such solutions, one can expediently use the new active ingredients in the form of dry ampoules. For oral and parenteral administration, one is Dosage from 25,000 to 1 million U / kg body weight / day expedient. It can be given as a single dose or as a continuous drip infusion or divided into several doses. For one local treatment, the new active ingredients can be prepared and applied as ointments or powders.

In veterinary medicine, the new penicillins can be used with the Be administered via food, preparations or drinking water.

The penicillins according to the invention have an antibacterial effect. This is demonstrated by the following experiment, the one with the penicillin of Example 1 has been shown:

The penicillin of Example 1 was diluted to a content of 100 / Ug / ml with Müller-Hinton nutrient broth with the addition of 0.1 # glucose. The nutrient solution contained 1 χ lo ^ ⁵ to 2 χ 1o ⁵ bacteria per milliliter. The tubes with this mixture were each incubated for 24 hours and then the degree of turbidity was determined. Freedom from haze indicates effect. At a dosage of 100 / Ug / ml, the following bacterial cultures were free of turbidity:

*) 1 mole of penicillin is known to correspond to 5.9514.1ο ⁸ Β. Le A 14 739 - 25 -

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E. coil H; E. coil c165; Proteue vulgarie 1o17; Klebeiella E 1o; Klebsiella 63; Salmonella ep .; Shigella ep .; Enterο-bacter sp .; Serratia ep .; Proteus, indole negative, ep .;

Proteue, indolpoBitiv, ep .; Pasteurella pseudotuberculoeie; Bruceila sp .; Haemophilue influenzae; Bordetella brochiseptica; Bacteroides ep .; Staphylococcus aureus 133; Neisseria catarrhalis ep .; Diplococcus pneumoniae sp .; Streptococcus pyogenes W; Enterococcus sp .; Lactobacillus sp .; Corynebacterium diphteriae graviθ; Corynebacterium pyogenes M; Clostridium botulinium; Clostridium tetani; Borrelia sp .; Peeudomonas aeruginosa sp .; Aeromonas hydrophila ep ..

The following table 1 shows the effect of one of the penicillins according to the invention against a broad spectrum of bacteria in animal experiments with the white mouse. The white mice of strain CF ₁ were infected intraperitoneally with the specified type of bacteria.

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NJ I

Tabel Animal experiments with the white mouse

Germ Dose in units
of penicillin from
Example 1 per kg
subcutaneous 1. after
2. Survivor animal "
treatment
3rd 5th day 7o 9 after infection
Infection control
1st 2nd day 15th E. coli C 165 1 χ 200,000 7o 7o 7o 15th 15th Klebsiella 63 2 χ 150,000 loo 7o 2o 80 15th 4o Staphylococcus
aureus 1 χ I0.000 loo 80 80 3o 5o 1o Pseudomonas
aeruginosa W 4 x 150,000 5o 3o 3o 3o 15th ¹⁰ . .5 Pseudomonas
aeruginosa F 41 4 x 150,000 80 3o 3o 15th

Therapy: once: 30 minutes after infection

Twice: 3o and 90 minutes after infection

4 times: 30 minutes, 2 hours, 4 hours and 6 hours after infection

example 1

(R) -CONH-CH-CONH

COOH

2, o parts by weight of D-it-amino-p-hydroxy-benzylpenicillin trihydrate were dissolved in 25 parts by volume of 8o 56% aqueous tetrahydrofuran by adding triethylamine to a pH of 8.5. With stirring, 0.7 parts by weight of 1-chlorocarbonyl-2-oxoimidazolidine were added in portions and the pH was kept at 7 to 8 by adding triethylamine Tetrahydrofuran on a rotary evaporator, extracted the aqueous solution once with vinegar, covered with fresh ethyl acetate and acidified to pH = 1.5 with dilute hydrochloric acid while cooling with ice to pH = 1.5, whereby the penicillin was mainly obtained as a crystalline free acid that was sparingly soluble in water and ethyl acetate, which was sucked off and washed out with water. The ethyl acetate solution remaining in the mother liquor was separated from the aqueous phase, washed with a little water, dried over MgSO., Mixed with 2.0 parts by volume of a 1 molar solution of sodium 2-ethylhexanoate in methanol-containing ether, evaporated in the vacuum almost to dryness, dissolved in a little methanol and poured a face amount of ice-cold ether into one of the 1o i "contained methanol. It was filtered off with suction, washed with methanol-containing ether and then with pure ether, and dried over Pp ^ 5 paraffin chips in a vacuum exiccator. Yield: 0.3 parts by weight = 12.5 #.

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The penicillic acid sucked off was dissolved in 10% parts of dimethylacetamide, 4 parts by volume of sodium ethylhexanoate solution were added and the mixture was stirred into ice-cold ether (70 parts by volume). The deposited precipitate was filtered off with suction and washed out with methanol-containing ether and then with pure ether and dried in a desiccator ^{over ^ 0 S and paraffin chips.}

Yield: 1.9 weight st ei = 8o 56 D-o (, - / ~ (2-oxo-imidazolidin-1-yl) -carbonylamino-7-p-hydroxy-benzylpenicillin-sodium.

The two fractions of the penicillin sodium salt obtained in this way were identical according to the IR spectra.

ß-lactam content: 88 to 90% (the content was taken from the IR and NMR spectrum taken).

IR bands at 328o, 1765, 1722, 1660, 16o5, 1538, 133o and 1284 cm " ¹ (in Nujol).

NMR signals at T = 2.7 (2H), 3.2 (2H), 4.5 (2H), 4.55 (1H),

5.8 (1H), 5.9-6.35 (2H), 6.4-6.8 (2H), 8.4 (3H) and 8.5 ppm (3H).

1-chlorocarbony1-2-oxo-imidazolidine:

-COCl

For the vigorously stirred solution of 3.5 parts by weight of imidazolidones) (prepared according to Piseher and Koch, Ann. 232, p. (1886)) in 50 parts by volume of absolute tetrahydrofuran one 4 parts by weight of phosgene in to parts by volume of absolute

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Tetrahydrofuran increased over the course of 15 minutes. The mixture was then stirred at 10 ° C. for 3 hours and then a stream of dry air was passed through the reaction mixture in order to blow out the hydrochloric acid and residues of phosgene formed. It was then evaporated to dryness on a rotary evaporator in vacuo and the solid residue was dried over concentrated sulfuric acid and at about 12 torr. Yield: $ 93>. Mp = 150 ° C. after recrystallization from acetone-pentane.

Calcd .: C 32.3 H 3.4 N 18.8 Cl 23.9 found: C 32.3 H (4.5) N 18.7 Cl 23.9

NMR signals at T = 5.7 to 6.1 (2H) and 6.3 to 6.7 (2H), (acetone-dg as solvent) symmetrical A ₂ B ₂ system.

IR bands at 323o, 179o, 17oo, 127o and 115o cm Example 2

! H-CO-NE

-1

CH,

COONa

2.0 parts by weight of D-öt-amino- <X- (1,4-cyclohexadien-i-yl) -methyl-penicillin (epicillin) were in 45 parts by volume 80% aqueous tetrahydrofuran suspended. Sann were

Le A14 739

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1.4 parts by weight of imidazolide in-2-on-1-car bony chloride with stirring entered and the pH by means of triethylamine held at 7.5 - 8, o. The mixture was then stirred until no triethylamine was maintained until the pH 7.5-8.0 was maintained more had to be admitted. After diluting with. About 80 parts by volume of water was the tetrahydrofuran in Rotary evaporator removed, the remaining aqueous solution covered with ethyl acetate and under Stirring acidified to pH 1.5 using 2N hydrochloric acid. The majority of the penicillin formed fell as crystalline precipitate from.

Yield: 1.2 parts by weight = 43,96 of theory D- (X- (imidazolidin-2-on-i-yl-carbonyl-amino) -öt- (1,4-cyclohexadien-i-yl) methylpenicillin-sodium. ■>

ß-lactam content: 80 96

calc .: C 49.5 H 5, ο N 14.4 S 6.6 found: C 49.9 H 5.9 N 14.2 S 6.6

IR bands in the carbonyl region at: 1785, 173o, 1680 and 1635 cm " ¹ (Nujol).

To convert the penicillin into the sodium salt, it was concentrated as much as possible in methanol or dimethyl acetamide dissolved, the calculated amount of an ethereal sodium 2-ethylhexanoate solution containing a few percent methanol added and then stirred the mixture into about 6 times the amount of ether. The precipitated sodium salt was sucked off, with methanol-containing ether and then with ether washed and dried.

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NMR signals at T: 4.1 (1H), 4.2-4.5 (4H), 5, ο (1Η),

5.7 (1H), 5.9-6.7 (4H), 7.3 (4H) and 8.2-8.6 ppm (6H).

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Claims (1)

Claims A is a group X-CO-N- or X is hydrogen, alkyl with up to to carbon atoms, alkyl with up to 6 carbon atoms, where a Hydrogen atom of the alkyl group by a nitro, Substituted amino, mono-lower alkylamino or di-lower alkylamino group or 1-pyridinium group is, alkenyl with up to to carbon atoms, vinyl, cycloalkyl and cycloalkenyl with up to 1o carbon atoms, aryl vinyl, mono-, di- and trihalo-lower alkyl, mono-lower alkylamino, Di-lower alkylamino, monoarylamino, aryl-lower alkylamino, Alkoxy with up to 8 carbon atoms, cyeloalkoxy with up to 7 carbon atoms, aralkoxy with up to 6 carbon atoms, aryloxy, R, ' . (0H ₂ , χι ie A 14 739 (IF ^R öf- 409823/1001 ο- or η is an integer from zero to two and inclusive R ₁ , R ₂ and R _{5 are} each hydrogen, nitro, nitrile, amino, di-lower alkylamino, di-lower alkylaminocarbonyl, lower alkanoylamino, lower alkoxycarbonyl, lower alkanoyloxy, lower alkyl, lower alkoxy, sulfamyl, chlorine, bromine, iodine, fluorine or trifluoromethyl, Y alkyl with up to 4 carbon atoms, alkenyl with up to 4 carbon atoms, vinyl, propenyl, cycloalkyl and cycloalkenyl with up to 6 carbon atoms, Mono-, di- and trihalo-lower alkyl, aralkyl with up to 8 carbon atoms or aryl, (—.Ζ— a divalent group 0 or 1 2 or Le A H 739 409623/1081 Gr is hydrogen or lower alkyl with up to three carbon atoms, the arrow in the divalent group £ Z- to Is intended to express that the connection of the two free valences of <—- Z— with the N- and the C atom of group E N- not arbitrary, Bonder should be done in the manner indicated by the arrow, E oxygen or sulfur, B HO- / 7 or means, and those with respect to the chiral center C in the two possible R and S configurations and as mixtures of the resulting diastereomers and their non-toxic, pharmaceutically acceptable salts. 2.) Compounds according to claim 1, in which the group B is. Le A H 739 - 35 - 409823/1081 3.) Compounds according to claim 1, in which the group B is. 4 ·) Compounds according to claim 1, in which the group A is. 5.) Compounds according to claim 1, in which C is in the D = R configuration is present. 6.) D-öt- / ~ (2-oxo-imidazolidin-1-yl) -carbonylamino7-phydroxy-benzylpenicillin: (R) -CONH-CH-CONH- CH, CH, COOH iH 7.) Ώ-oC - / "" (2-0xo-imidazolidin-1-yl) -carbonylamino _- 7-2,5-dihydro-benzylpenicillin: (R) r-CONH-CH-CONH- CH, CH, OOH Le A14 739 409823/1081 8.) D-cC- (3-acetyl-3-methyl-ureiäo) -p-hydroxy-benzylpenicillin: (D) OH ₅ CON-CONh-QH-CONH.- CH, JI. CH, CH, COOH 9.) D- <X> - (3-Foriny 1-3-methyl-ure id o) -p-aydr oxy benzylpenicillin: "(D) H-CO-N-CONH-CH-CONH- CH ₃ XX " ¹ - ^Ά - ~ Υ ^X CH, ο '"1 ³ COOH OH 1 ο.) D- ^ - (3-Methylaminocarbony1-3-methyl-ureidο) -phydroxy-benzylpenicillin: (D) CH * NH-CON-CONH-CH-CONH CH, CH, CH, COOH OH Le A H 739 - 37 - 409823/1081 11.) Di- (X-- (i-Dimethylamino-carbonyl-J-methy l-ureid ο) -phydroxy-benzy! Penicillin: (D) (CH ₃ J ₂ N-CO-N-CONh-CH-CONH. CH, .N, CH, CH, COOH 12.) D- <τ (- / ~ 3- (piperidin-1-yl-carbonyl) -3-methyl-ureido__7-p hydroxy-benzylpenicillin: (D) -COp-CONH-CH-CONH CH, COOH 13.) D-oC- (3-allyloxycarbonyl-3-methyl-ureido) -ß-hydroxy benzylpenicillin: (D) ^ 0-CO-N-CONH-CH-CONH- -N-C CH, CH, CH, COOH Le A14 739 - 38 - 409823/1081 14.) D-o £ - / ~ 3- (ß-Nitropropionyl) -3-methyl-ureido_7-phydroxy-benzylpenicillin: (D) O ₂ N-CH ₂ -CH ₂ -GON-CONh-CH-CONH- CH * CH, CH, COOH 15.) D- <Jt- / f "3- (m-Nitro-p-methoxy-benzoy 1) -3-methy l-ureid £ 7-p-hydroxy-benzylpenicillin: O ₂ N (D) -CON-CONH-CH-CONH- CH ₃ CH CH, COOH OH 16.) D- öt- / ~ (2-Oxo-pyrrolidin-1-yl) -carbonylamino_7-phydroxy-benzylpenicillin: -w (D) "li-CO-NH-CH- CONH COOH Le A H 739 -39 - 0 9823/1081 17.) D - «, - / ~ (2-Oxo-3-methyl-imidazolidin-1-yl) -carbonyl amino_7-p-hydroxy-benzy! penicillin: CH ₃ -. (D) -CONH-CH-CONH- CH, OH, COOH 18.) D - <? C - / "* (Imidazolidin-2-thion-1-yl) -carbonylamino _- _7-phydroxy-benzylpenicillin: (D) -CONH-CH-CONH CH, COOH 19.) D-öC- (3-dimethylaminocarbonyl-3-n-propyl-ureido) -phydroxy-benzy! Penicillin: N-CO-N-CONH 'CH CH - (D)
- CH-CONH- Il J ο CH, CH, COOH Le A14 739 - 4o - 40982 3/1081 2ο.) D-ot- (3-acetyl-3-methyl-ureido) -öi '- (1,4-cyclohexadien-1-yl) -methy ! penicillin: - (D)
CH ₃ CON-CONh-CH-CONH- CH, CH, COOH 21.) D - (? I- (3-Forinyl-3-methyl-ureldo) -ix :-( 1,4-cyclolixadiene-i yl) methylpenicillin: (D) _s HCO-N-CONH-CH-CONH- . f ^ \ / ^CH 3 .CH, CH JS: COH 22.) I) -iC- (3-Methylaffiinocarbonyl-'3-methyl-ureido) -od- (1,4-Glycloh63cadien> -1-yl) -methy !penicillin: CH, CH ₅ NH-CON-CONH-GH-CONE 0OH 23 ») D-cfc- (3-Dimethy! Aminoc ^^» 4- (D) Ö GOOH Le A14 739 41 - 4098 2 371 oar D- <XU ^ ~ 3- (Piperidin-1-yl-carbonyl) -3-methyl-ureido_7 ~ ^Α - (1 ^ -cyclohexadien-i-ylj-methylpenicillin: Sf-CONH-CH-CONH- -CO-N-CH 9 < COOH CH, CH, 25.) D - ^ (3-Allyloxycarbonyl-3-methyl-ureido) - <? C- (1,4-cyclohexadien-1-y1) -methylpenicillin: (D) O-COB-CONH-CH-COKH- CH ₅ CH, CH, COOH 26.) D-oC - / '"3- (ß-Nitropropionyl) -3-methyl-ureido _- 7-cyclohexadien-1-yl) -methy! Penicillin: (D) O ₂ N-CH ₂ -CH ₂ -CON-CO-Nh-CH-CONH. CH, CH, COOH 27. ) D-u6 - / "" 3- (m-nitro-p-methoxy-benzoyl) -3-ethy 1- oL - (1,4-cyclohexadien-1-yl) -methy! Penicillin: O ₂ N ^(D) \ V-CON-CONH-QH-CONH CH ₅ .N. CH, ch! COOH Le A14 739 409823/1081 28.) D- <£ - / "(2-Oxo-pyrrolid in-1-yl) -carbony lamino__7-cyclohexadien-1-yl) -methy! Penicillin: CH, OOH 29.) D-oC- / ~ (Imidazolidin-2-thion-1-yl) -carbonylamino_7- ⁰ ^ - (1 »4-cyclohexadien-1-yl) -methy! Penicillin: 0OH D-öC - / "" (2-0xo-3-methyl-imidazoliäin-1-yl) -earbonylamino- <3t- ( 1,4-cy clohexadien-1-yl) -methy! Penicillin: (D) N-CONH-CH-CONH COOH 31.) D-o £ - (3-Dimethylaminocarbonyl-3 ~ n-propyl-ureido) -oC- (1,4-cyclohexadien-i-ylj-methylpenicillin: (D) 3H-CONH (CH _{5) 2} N-C0N-C0NH - CH ₂ CH ₂ CH ₃ CH, COOH Le A14 739 - 43 - 409823/1081 32.) ot- (2-Oxo-imidazolidin-1-yl-carbonylamino) -3,4-di hydroxy-benzylpenylcillin: rS -CONH-CH-CONH )H 00H CH, 33.) Process for the preparation of penicillins of the general formula I. a-co-nh-8h-conh- COOH CH, CH, (D or wherein A is a group X-CO-N- X hydrogen, alkyl with up to 10 carbon atoms, Alkyl with up to 6 carbon atoms, where a hydrogen atom of the alkyl group is replaced by a nitro, Amino, mono-lower alkylamino or di-lower alkylamino group or 1-Iyrldiniumgruppe substituted is, alkenyl with up to 10 carbon atoms, vinyl, cycloalkyl and cycloalkenyl with up to 10 carbon atoms, arylvinyl, mono-, di- and trihalo-lower alkyl, mono-lower alkylamino, di-lower alkylamino, monoarylamino, aryl-lower alkyl amines, alkoxy Le A14 739 - 44 - 409823/1081 with up to 8 carbon atoms, cycloalkoxy with up to 7 carbon atoms, aralkoxy with up to 8 carbon atoms, aryloxy, - (CH ₂ ) _n -, R ₁ -U- -ff- (CH ₂ ) ₂ ) _n R ₂ O
R. or η is an integer from zero up to and including two and R ₁ , R ₂ and R ^ are each hydrogen, nitro, nitrile, amino, bin lower alkylamino, di lower alkylaminocarbonyl, lower alkanoylamino, lower alkoxycarbonyl, lower alkanoyloxy, medrigalkyl, lower alkoxy, sulfamyl, chlorine, bromine, iodine, fluorine or trifluoromethyl, Y alkyl with up to 4 carbon atoms, alkenyl with up to 4 carbon atoms, vinyl, bropenyl, Cycloalkyl and cycloalkenyl with up to 6 carbon atoms, mono-, di- and trihalo-lower alkyl, Aralkyl with up to 8 carbon atoms or aryl, _Α a divalent group lie A 14 739 40S82 3/1081 2, 3 or 4 / «Λ O or 1 / Eq 0 or 1 2 or 3 G denotes hydrogen or lower alkyl with up to 3 carbon atoms, the arrow in the divalent Group f - Z - is intended to express that the Linking the two free valences of ^ -Z - with the N and the C atom of group E N- not arbitrarily, but in the manner indicated by the arrow, E oxygen or sulfur B HO - // \ V-, . HO - // OH HO or Le A H 739 409823/1081 and which, with respect to the chiral center C, can be present in the two possible R and S configurations and as mixtures of the distereomers resulting therefrom and of their non-toxic
pharmaceutically acceptable salts, characterized in that one / ~ a_7 compounds of the general formula II B-CH-CO-NH-CH-Cir " ^S \ / CH, NH JI ^ ⁰ C ^(II) // ¹ ^ OT ^CH 5 COOH wherein B and C have the meanings given above
to have, with compounds of the general formulas VI or VII X-CO-N-CO-W ^ _{0 H} _ _{0 (W} Y
(VI) (VII) wherein X, Y, Z and Έ have the meaning given above have, and W halogen, azide, a group Cl -OV / Vy-NOo, _Λ - «, , -Cl Le A 14 739 - 47 - 409823/1081 / CH ₃
-0-N = C, -0-Ν 1 -0-ΒΓ Y ^ I or -S-lower alkyl means
0 in anhydrous or water-containing solvents in the presence of a base at a temperature in the range from about -20 to +50 ⁰ C, or f / ~ b_7 compounds of the general formula III, the Condensation products of compounds of general Formula II with Carbony! Compounds are (III) 0OH in which B, G and C have the meaning given above, with compounds of the general formulas VI or VII in anhydrous or water-containing solvents in the presence of a base at a temperature in the range from about -20 to +50 ⁰ C, or £ O_J compounds of the general formulas IV or V B-Sh-CO-NH-CH CH ^ ^S \ / CH, NH ₂ w "--CH co-o-si—: Le A 14 739 - 48 - 409823/1081 B-CH-CO-NH-CH- O' -N- CH ■ / 00-0-Si-R , / ^CH 3 (V) in which B has the meaning given above or H-Z ^ Si-O- ^ "\ , R Si- 0- or means, C has the meaning given above and Rc and Alkyl of up to 6 carbon atoms means, in anhydrous and hydroxyl group-free solvents, or water-containing or hydroxyl group-containing solvents with or without addition of a base at a temperature in the range from about -20 to +50 ⁰ C, and the penicillins obtained thereby converted into their nontoxic, pharmaceutically acceptable salts. Medicament, characterized by a content of at least one penicillin according to claims 1 to 32, Le A14 739 - 49 - 409823/1081 BATH so 35.) Method for the division of ant! Bacterial Agents, characterized in that one penicillins according to claims 1 to 32 with inert, non-toxic, pharmaceutically suitable carriers mixed. rrani thereby kerniZeichn ^ ggeiteirman penicillins according to Claim 1 Jii «^! Ji applied to humans or animals, the Le A H 739 - 5o - 409823/1081