DD201904A5 - PROCESS FOR PRODUCING NEW PENICILLINE - Google Patents

Abstract

There are described novel penicillins of the general formula I and their salts, in which A represents the phenyl group, the p-hydroxyphenyl group, the 2-thienyl group or the cyclohexa-1,4-dien-1-yl, 3,4-dihydroxyphenyl or 3 -Chlor-4-hydroxyphenyl group and R groups of the formulas II, wherein R deep 1 and others the ureido group, the nitro group, an aminocarbonyl group optionally substituted by methyl radicals, the acetyl group or groups of the formulas -SO deep 2 R deep 4; -SOR deep 4; -SO deep 2 NH deep 2, -SO deep 2-NHR deep 4, -SO deep 2N (R deep 4) deep 2 and R deep 2 and / or R deep 3 represent the hydroxyl group, the aminosulfonyl group, the aminocarbonyl or methylaminocarbonyl group In addition, two ways of preparing the compounds of general formula I are given. The compounds of general formula I show a very strong action against Gram-positive, but especially against Gram-negative bacteria.

Description

Anwendungsiingsgeliiet the invention

The invention relates to a process for the preparation of new penicillins. They are used as medicaments for the treatment of diseases caused, in particular, by gram-positive and gram-negative bacteria.

Characteristic of the known technical solutions

By DE-OS 2,535,655 and 2,450,668 and by the US-PS JTr * 4 031 230 hydroxy-pyridylureidobenzyl penicillins the general lermel

R-CH-COM -

CO t

OH

CH ₃ CH ₃

COOH

which, however, do not do justice to the demands placed on them, especially in their action against gram-negative germs. "

The same applies to those compounds which instead of the group ~ M - CO- KH group -KH -. Hold CO- ", -said with the CO group, a ¹ pyrimidines ing is associated (see BE-PS 828 933 and DE -OS 2 347 533) »

- 1a -., 59 939 11

06/04/82

The most effective of all ureidopenicillins was the piperacillin with the group

-BH - CO - MH - Ii 'N - C ₀ H ₁ -,

\j 20

IJ W ο ο

but even this compound did not satisfy, for it showed only mediocre effects against a number of germs ^.

Object of the invention

The aim of the invention is the provision of new penicillins with a broad spectrum of activity against Gram-positive and Gram-negative bacteria and good tolerability in humans »

Explanation of the invention of the invention

The invention has the object zugrundej new penicillins having the desired properties and processes for their preparation locate _e

The novel penicillins according to the invention having the pyrimidine group substituted on the ureido group in the 2-position are clearly superior to piperacillin both in vitro and in vivo,

- 1b -

59 93.9 6,4o82

According to the invention, new penicillins of the general formula I

A-CH-COBH-

HH i GO

0 *

OH

CH ₃ CHO

COOH

(D

and their physiologically tolerated salts with inorganic or organic bases *

the above general - 2 - J ^Λ , (ID il 2 It J the groups In A is the phenyl group and Formula I means: in which n = 0 or 1 and R. if n = 0, 0 0 -C-N (CH); a) 0 Il -NH-C-NH ₂ ; " ^N0 2 ^; -SO-R ₄ ; -SO ₂ -NH ₃ ; 0 R is the group of general formula II, -So ₂ -NR ₄ -NH- (CH ₂ ) _n - ^ -PC-CH ₃ ; -SO ₂ -R ₄ ; · ^H 0

or -SO ₂ -N (R 1) ₂ and, if n = 1, it means the abovementioned groups and additionally a hydrogen or fluorine atom, the hydroxy, methyl or methoxy group, wherein R ^ ₊ in the above formulas is an alkyl group having 1 to 4 carbon atoms, or R is a group of general formula III,

-NH- / V-

R-

, (III)

in which one of the radicals R ₂ or R _{3 is} the hydroxy group and the other of these radicals is a group of the formulas

-C-NH-CH.,

-C -NH ₀ ; Ji 2

or the two radicals R ₂ and R _{3 represent} the group -CONH ₂ or it means

b) A.the p-hydroxyphenyl group and

R is the group of general formula II in which n is 0 or 1 and R-, if n = 0, are the groups of the formulas

-NH-C-NH ,,; -C-NH-CH ,; -CN ^- (CH); -OC-CH; Jl " a "^> · j * a 3

0 0 0 0.

-SO-R ₅ ; -SO ₂ -R ₅ ; -SO ₂ -NR ₄ ; -SO ₂ -N (R ₄ J ₂ or

H -

the meta-permanent group -SO _{3 represents} -NH and, when n = 1, it means the above-mentioned groups and additionally a fluorine atom, the hydroxy group, the nitro group, the group H ₂ NCO-, the groups -SO-CH ₃ , -SOp-CH ,, .oder p-HpN-SO, -, or the methyl or methoxy group wherein in the above formulas R, as defined above is defined and R ₁ . an alkyl group having 2 to 4 carbon atoms, or

R is a group of the general formula III, in which one of the radicals Rp or R, the hydroxy group and the other of these radicals is a group of the formulas

-SO -MH _n ; -C-NH ,; -C-NH-CH ,, or in which the two 2 2 j) 2 ij 3

0 0

Radicals R ₀ and R, the group -CONH, represent, or means

c) A represents the 2-thienyl group, the cyclohexa-1,4-dien-1-yl group,

the 3,4-dihydroxyphenyl or the 3-chloro-4-hydroxyph.enyl group and

R is a group of the general formula II in which n is 0 or 1 and R _{1 is} a fluorine atom, the methyl or methoxy group or a group of the formulas

HNC-NH-; H _n NC; CH, -NH-C-; (CH,), NC; -SO-R .; 2 (| 2 11 3 _{l {} 3 2; / 4

0 0 0 0 "

-SO ^ -R-; -SO-NH ₇ , -SO ₇ -NR ,, or -SO ₇ -N (R) represents

being in 'this. Formulas R. is defined above, and R .. can also be a hydrogen atom, if then A is the 2-thienyl, 3,4-dihydroxyphenyl or 3-chloro-4-hydroxyphenyl group or R _{1 is} the hydroxy group or the methylcarbonyloxy group, if A represents the 2-thienyl group, the cyclohexa-1,4-dien-1-yl group or the 3-chloro 4-hydroxyphenyl group, or

R is a group of general formula III, in which R _{2 is} the hydroxy group and -R, the hydroxy group or the groups -CONH ₂ , -CO-NHCH ,, -SO ₂ -NH ₂ , both radicals R ₂ and R, can also mean the group -CONH ₂ simultaneously.

Preferred are those compounds of the general

Formula I, wherein

R "the groups of formulas -NH

-NH-

-NH-f V> -SO-CH · -NH-Z ^ -SO ₇ -CH ₇ ; -NH) H - ^W

; -NH-f3 '

SO ₂ NH ₂ ; -NH-CH ₂ -Z ^ ·

-NH-CH - (Λ) -SO ₇ NH ₇

or -NH-CH

mean. Particularly valuable compounds of the general formula I have proved, in which R is the group -NH-ZJv-SO ₃ NH ₂ and A is the phenyl, 2-thienyl, 3-chloro-4-hydroxyphenyl or the 3, 4-Dihydrox

phenyl group, r '"^

or R is the group -NH- ^ y -SO ₇ NH ₀ and A is the phenyl, ρ-

Hydroxyphenyl ,. 2-thienyl, 3-chloro-4-hydroxyphenyl or 3,4-dihydroxyphenyl group,

or R is the group -NH-CH ₂ - </ y-SO ₂ NH ₂ and A is the phenyl or p-hydroxyphenyl group.

 - 5 -

The penicillin compounds of the general formula I can exist in two tautomeric forms (namely of the lactim and of the lactam type). It depends particularly on the particular solvent and on the nature of the substituent R, which predominates of the two formulas I or I ':

A-CH-CONH-I NH CO

NH

OH

'.COOH

'COOH

, (I ¹ )

It goes without saying that the type I compounds mentioned above always comprise both tautomers.

The compounds of general formula I may be present with respect to the chiral center C + in the two possible R 'and S configurations, but also as a mixture of these two configurations. Particularly preferred are those compounds for which the D = R configuration is true.

59 93.9 11 6.4.82

The new semi-synthetic penicillins of the general formula I show a broad spectrum of action against 'gram-positive and gram-negative bacteria with a very good compatibility in humans.'

Penicillin antibiotics are known to inhibit the growth of various Gram-positive and Gram-negative bacteria. It is also known that only a few penicillins have good activity against important Gram-negative problematic pathogens, especially in the V-hospital area, such as Pseudomonas and Klebsiella However, in recent years, the incidence of infection caused by these germs, particularly Pseudomonas species, has steadily increased. Penicillin derivatives such as carbenicillin (U.S.Patent 3,142,673), sulbenicillin (U.S.P. 660,379) and ticarcillin (U.S. Patent 3,282,926). Although described as antipseudomonal antibiotics, they have only modest potency in vitro and in vivo. An Important Developing Indacylated Derivatives of α-Aminobenzylpenicillins, eg _, Ampicillin and Amoxycillin, From these classes of compounds, which have been extensively studied in recent years, Azlocillin has recently been prepared: Azilillin = 6- ^ D- <- / T2-oxo-imidazolidine ~ 1- * yl ^ carbonylamino7-4-ph. enylacetamido "3 -penicillanoic acid> sodium salt (eg ₍ BE-PS 767 647) as further Antipseudomonas penicillin introduced in." For a successful treatment, however, this penicillin must be highly dosed . Außerdem.ist its effect against Klebsiella and E. coli _e-species only moderately "continue There was therefore a need-to search for new penicillins, the increased activity against bacteria such as - Pseudomonas and Klebsiella and e ^ _e coli, have"

While, as mentioned above, acyl derivatives of cC ~ * aminobenzylpenicillins have been and are being extensively researched, little is known about derivatives in which a heterocycle is attached via a urego bridge (EHCIiH-)

- 7 * 59 939 11

6.4 * 82

The "benzyl" atom of "<Γ-amino" benzylphenylalanic is knoWn "Only in DE-OS 2 450 668 and 2 535 655 and of U3.PS 4 031 230 are hydroxypyridylureido benzylpenicillins of general formula IV

R "CH-COHH-

ir ι - ^CH 3

X ο V

COCOOH, (IV)

HH

OH

However, these compounds are in their antibacterial activity of the compounds of the prepublished European Patent Application No. ₉ 70 100 468 * 2, which differ from the compounds of the invention only by other meanings of the radical R or by other combinations' of the radicals A and R, clearly inferior * The compounds according to the invention have but in comparison to the compounds. this European Patentanmeldung.gegenüber problem microbes _s particular against bacteria, such as E · _e coli, Pseudomonas and Klebsiella, even better activities »

The compounds of general formula I can be represented as follows!

1) By reacting a compound of general formula V,

Ar-GH -COHH- Γ \ L 2 // 0 HH T ^ S ^0H 3 H- "* ~~~ - GH ^ f I f COOH

DO / U

in which A is as defined above, with a pyrimidine derivative of the general formula VI,

(VI)

in which R is as defined above and B is the group -NCO or a reactive derivative of the group NHCOOH, such as e.g.

the groups -NHCOCl, -NHCOBr or -NH-COO-y J-NO _{? r}

wherein the group NHCOCl is particularly preferred. It is also possible to use mixtures of such pyrimidine derivatives of the general formula VI, in which B has one or the other of the abovementioned meanings, for example the groups --NCO and --NCOCl together, side by side.

The starting materials of general formula V can be prepared in Forin their inorganic or organic salts, e.g. as Triäthy ammonium salt or sodium salt, can be used. The reaction can then be in any mixtures of water with such organic solvents which are miscible with water, such as ketones, for example acetone, cyclic ethers, for example tetrahydrofuran, or dioxane, nitriles, for example acetonitrile, formamides, for example dimethylformamide, dimethyl sulfoxide or alcohols, for example isopropanol or in hexametapol, whereby the pH of the reaction mixture is maintained by addition of bases or use of buffer solutions in a pH range of about 2.0 to 9.0, preferably between pH 6.5 and 8.0 also possible to carry out the reaction in anhydrous organic solvents, for example halogenated hydrocarbons such as chloroform or methylene chloride with the addition of bases, 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 ether, e.g. Diethyl ether, halogenated hydrocarbons, e.g. Chloroform or methylene chloride, carbon disulfide, ketones, e.g. Isobutyl methyl ketone, esters, e.g. Ethyl acetate, aromatic solvents, e.g. Benzene, it being difficult to stir vigorously, and to increase the pH by addition of base or using buffer solutions in a range of about pH 2.0 to 9.0, preferably between 6.5 and 8.0 However, the reaction can also be carried out in water alone in the presence of an organic or inorganic base or with the addition of buffer substances.

If the starting materials of the compounds of the general formula V (for example mono- or di-trimethylsilyl derivatives) are used as starting materials for the process according to the invention and are reacted with compounds of the general formula Vi, the reaction is generally expediently carried out in water. and hydroxyl group-free solvents, for example in halogenated hydrocarbons, eg Methylene chloride or chloroform, benzene, tetrahydrofuran, acetone or dimethylformamide, etc. The addition of bases is not necessary in this case, but may be advantageous in individual cases to improve the yield and purity of the products. As optionally added bases tertiary aliphatic or aromatic amines, such as pyridine or triethylamine, or by sterically hindering difficult to acylatable secondary amines, such as dicyclohexylamine, are suitably used.

Instead of the silyl esters, all other carboxylic derivatives of C 1-6 aminobenzylpenicillins known in the art of producing semisynthetic penicillins can also be used. Typical examples are the trityl esters, the p-nitrobenzyl esters or the pheftacyl esters. In connection

/ j A O u /

- 10 -

To the reactions, these derivatives can be converted by known methods into the penicillins according to the invention. The amount of bases used is e.g. determined by the desired maintenance of a specific pH. Where a pH measurement and adjustment is not made or is not possible or useful because of the lack of sufficient amounts of water in the diluent, preferably 1.0 to 2.0 molar equivalents of base are used in the case of using the nonilylated compounds of general formula IV , In the case of using the silylated compounds, it is preferred to use up to one molar equivalent of base.

As bases, in principle, all organic and inorganic bases commonly used in organic chemistry can be used, such as alkali and alkaline earth hydroxides, alkaline earth oxides, alkali and alkaline earth carbonates and bicarbonates, ammonia, primary, secondary and tertiary aliphatic and aromatic amines and heterocyclic bases. Examples include sodium, potassium and calcium hydroxide, calcium oxide, sodium and potassium carbonate, sodium and potassium bicarbonate, ethylamine, methyl-ethylamine, triethylamine, hydroxyethylamine, aniline, pyridine and piperidine. When using the silylated starting materials, however, the abovementioned restrictions regarding the nature of the bases should be taken into account.

As buffer systems, all customary buffer mixtures can be used, e.g. Phosphate buffer, citrate buffer and tris (hydroxymethyl) amino-methane buffer.

The reaction temperatures can be varied within a substantial range. In general, one works between about -20 and about +50 C, preferably between 0 and +20 C.

- 11 -

The reactants of the general formulas IV and V can be reacted with each other from the outset in equimolar amounts. However, it may be quite appropriate in individual cases, to use one of the two reactants in excess, in order to facilitate the purification of the final product or to increase the yield.

2) By reacting ureidocarboxylic acids of the general formula VII,

A-CH-COOH

NH ι CO

NH

, (VII) OH

in which A and R have the meanings given above, their salts or reactive derivatives, with the 6-aminopenicillanic acid of the formula VIII,

, (VIII)

'' <coon

or their inorganic or organic salts or derivatives, which are easily convertible into the 6-aminopenicillanic acid. The resulting reaction product is optionally subsequently hydrolyzed to a penicillin of the general formula I or catalytically hydrogenolated.

- 12 -

As reactive derivatives of Ureidocarbonsäuren the general formula VII, for example, their acid anhydrides such. those derived from chloroformates, e.g. Chloroformic acid ethyl or -isobutylester, deduce, or their reactive esters, such as the p-nitrophenyl ester or the N-hydroxysuccinimide, or their reactive amides, such as the N-carbonylimidazole, but also their acid halides, such as the corresponding acid chloride or their acid azides in question. In principle, however, all the linking methods known from β-lactam chemistry can be used.

The 6-aminopenicillanic acid is advantageously used in the form of one of its derivatives. As derivatives there are e.g. in question: their trimethylsilyl ester, trityl ester, p-Nitrobenzy! ester, phenacyl esters and their Ο, Ν-bis-trimethylsilylderivat. These derivatives are preferably reacted in an aprotic solvent such as methylene chloride or tetrahydrofuran. However, it is also possible to use 6-aminopenicillanic acid in the form of its salts, for example its triethylammonium salt; in this case one uses e.g. Methylene chloride or a protic solvent or an aqueous medium or an aqueous-organic solvent, e.g. Tetrahydrofuran-water mixtures.

The ureidocarboxylic acid, its salts or its reactive derivative, if necessary, reacted with the 6-aminopenicillanic acid or its derivatives in a solvent at temperatures between -40 ° C and + 4O ⁰ C, in the presence of a base ·. If, for example, an 'anhydride of the ureidocarboxylic acid, for example the anhydride with the ethyl chloroformate, is reacted with a derivative of 6-aminopenicillanic acid, the reaction is carried out under cooling, for example at -10 C to +10 ⁰ C in the presence of a tertiary amine, such as triethylamine or Ν, Ν-dimethylaniline, in a solvent such as acetone, tetrahydrofuran, dimethylformamide, chloroform,

- 13 -

Dichloroethane, hexametapol or in a mixture of these solvents. If, for example a N-hydroxysuccinimide ester of the ureidocarboxylic with the 6-aminopenicillanic acid in a way, the reaction is preferably carried out at 0 to 20 ⁰ C in the presence of a base, such as triethylamine, in a solvent such as dimethylformamide, dichloromethane, dioxane, or in a mixture of such Solvent carried out.

The reaction of an ureidocarboxylic acid of the general formula VII itself or its salts with the 6-aminopenicillanic acid or with its salts is advantageously carried out in the presence of a condensing agent, for example in the presence of N ₁ N'-dicyclohexylcarbodiimide.

If a derivative of 6-aminopenicillanic acid is used, for example one of its abovementioned esters, a reaction product, which may be obtained, for example, depending on the reaction conditions, is optionally obtained. still contains the ester function. However, such a reaction product is readily convertible into the penicillin of general formula I. If, for example, the carboxyl group of 6-aminopenicillanic acid is in the form of its silyl ester, it may also be in the form of its silyl ester after the reaction in the resulting penicillin of the general formula I. In this case, subsequent to the actual reaction, this silyl ester group is hydrolyzed off, whereby the compound of general formula I is formed. In other cases, e.g. in the presence of a p-nitrobenzyl ester, this p-Nitrobenzylestergruppe is split hydrogenolytically after the actual reaction, in which case the penicillin of the general formula I is obtained.

- 14 -

The workup of the reaction mixture obtained according to both methods after the reaction is carried out according to the methods customary in β-lactarn antibiotics; the same applies to the isolation and purification of the end products, for example for the release of the acid from its salts and the conversion of the free acid into other salts by means of inorganic or organic bases. The precipitation of these salts from an alcoholic-ethereal solution of the free acid by the addition of potassium or sodium 2-ethylhexanoate proves particularly useful for the preparation of potassium or sodium salts.

The compounds of general formula V used as starting materials are known from the literature, cf. e.g. E. H. Flynn, Cephalosporines and Penicillines, Academic Press, New York and London (1972).

The starting materials of general formula VI can be prepared, for example, by reacting the corresponding 5-aminopyrimidines

the general formula IX,

NH,

OH

R in which R is as defined above, can be obtained with phosgene.

This reaction is preferably carried out in a non-hydroxyl-containing solvent, such as tetrahydrofuran, methylene chloride, chloroform, Dimethoxyäthan · or hexametapol at temperatures between -40 ° and + 6O ⁰ C, preferably between -10 ° and + 20 ° C. It is advisable to bind the resulting hydrogen chloride by equimolar amounts of an inert organic base, such as triethylamine or pyridine. As a solvent, pyridine can also be used in excess. Should the relevant aminopyrimidines of the

- 15

general formula IX be sparingly soluble in one of the solvents mentioned, the phosgenation can also be carried out in a heterogeneous phase. Furthermore, the aminopyrimidines of general formula IX by treatment with a silylating agent such as hexamethyldisilazane or trimethylchlorosilane / triethylamine or N, O-Bistrimethylsilylacetamid, in a generally very readily soluble in the solvents mentioned, simply or, according to the existing exchangeable hydrogen atoms, several times silylated aminopyrimidine, which then reacts with phosgene to give the corresponding compounds of general formula VI. Depending on the type of solvent, the amount of temperature, the amount and type of base used either predominantly the corresponding isocyanate or Carbaminsäurehalogenid or a mixture of these two compounds. Depending on the reaction conditions, the compound of the general formula VI may also be present in a small amount or partially as a diisocyanate isomeric dihydrooxazolo-pyrimidine of the general formula VIa

HN -f

, (VIa) 0

R "

or in the case of previous silylation, depending on the nature of the substituent R, as a mono- or multi-silylated analog. ·

The starting materials of the general formula VI or their mixtures formed by phosgenation are generally readily soluble in the abovementioned solvents and can, after removal of the excess phosgene, without further purification with the corresponding penicillin derivatives of the general

- 16 -

my Formula V directly implemented. However, it is also possible to isolate the intermediate of general formula VIa, optionally desilylate it with a protic solvent, for example water or methanol. to purify it on the basis of its solubility properties and to implement it in the manner set out above.

The illustration of the 2-substituted-5-amino-4-hydroxypyrimidines of the general formula IX, unless they are already described in the laid-open European patent application no. 79 100 468.2, is specified in more detail in the examples below. The reaction of 2-chloro-4-hydroxy-5-nitro-pyrimidine with anilines or benzylamines in aqueous solution is particularly well suited, in which case the nitro group is subsequently reduced by methods known per se, or the reaction of 5-benzoylamino-4 ' hydroxy ~ 2-methylmercapto-pyrimidine with the corresponding anilines or benzylamines in the melt or in a high-boiling solvent, such as SuIfolan.

The ureidocarboxylic acids of the general formula VII can be easily prepared by reacting the pyrimidine derivatives of the general formula VI with glycine derivatives of the general formula X,

NH.

- COOH

in which A is as defined above. The reaction takes place at temperatures between -20 and + 40 C, preferably between 0 ° and + 20 °, in a solvent. As a solvent, e.g. Mixtures of water and organic solvents which are miscible with water may be used, for example acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, ethanol, dimethyl sulfoxide. Possibly

- 17 -

the use of a hydrogen halide-binding agent is necessary, as such are, for example, trialkylamines, such as triethylamine or inorganic bases, such as dilute sodium hydroxide solution.

It has been found that the compounds of general formula I have valuable pharmacological properties with good compatibility. The active compounds according to the invention can therefore be used for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine. As diseases which can be prevented or cured by the compounds according to the invention, for example, those of the respiratory tract, the pharynx and the urinary tract are called; in particular, the compounds are active against pharyngitis, pneumonia, peritonitis, pyelonephritis, otitis, cystitis, endocarditis, bronchitis, arthritis and general systemic infections. Further, these compounds can be used as substances for preserving inorganic or organic materials, especially organic materials such as Polymers, lubricants, paints, fibers, leather, paper and wood as well as food.

This is made possible by the fact that the compounds of general formula I, both in vitro and in vivo against harmful microorganisms, in particular against gram-positive and gram-negative bacteria and bacteria-like microorganisms act very strong, being particularly characterized by a broad spectrum of activity. In addition, the compounds of general formula I after parenteral administration show high levels in tissue, serum, organs and urine.

Typical, particularly effective penicillins according to the present invention are listed in the following Table 1. The abovementioned penicillins can be prepared by the process 1 or 2:

- 18 -

These are compounds of general formula I in which A and R are defined as follows:

Table 1

R = -NH- /

R>

1) PH ₂ NSO ₂ -

2) PH ₂ NSO ₂ -

3) PH ₂ NSO ₂ - 4) PH ₂ NSO ₂ - 5) IH-H ₂ NSO ₂ - 6) IH-H ₂ NSO ₂ - 7) P-CH ₃ NHSO ₂ 8th) P-CH ₃ NHSO ₂ 9) P-CH ₃ NHSO ₂

10) P-CH ₃ NHSO ₂ -

11) P-CH ₃ NHSO ₂ -

12) PH ₂ NSO ₂ -

13) P-CH ₃ NHSO ₂ -

14) ρ- (CH ₃ ) ₂ NSO ₂ -

15) p- (CH ₃ ) ₂ NSO ₂ -

16) PC ₂ H ₅ NHSO ₂ -

17) PC ₂ H ₅ NHSO ₂ -

p ~ hydroxyphenyl phenyl

ρ-hydroxyphenyl phenyl

m, p-dihydroxyphenyl

HO-i ^

phenyl

ρ-hydroxyphenyl phenyl

p-hydroxyphenyl

^R 1 - 19 - Cl • A PC ^ IL NSO _{7 0} 3 ι ι 2 HO p-hydroxyphenyl 18) I H HO P- (C ₂ H ₅ J ₂ NSO ₂ HO p-hydroxyphenyl 19) PC ₄ H _{9 2} NHSO p-hydroxyphenyl 20) P-SOCH ₃ Phenyl ". 21) P-SOCH ₃ "7 \ 22) P-SOCH ₃ 23) P-SO ₂ CH ₃ Phenyl - .. ..: · ' 24) P-SO ₂ CH ₃ m-chloro-p-hydroxy-phenyl 25) P-SO ₂ CH ₃ m, p-dihydroxyphenyl j 26) P-SOC ₂ H ₅ ' p-hydroxy-phenyl 27) • PC ₂ H ₅ SO phenyl 28) PC ₃ H ₇ SO p-hydroxyphenyl 29) PC ₄ H ₉ SO p-hydroxyphenyl 30) PC ₂ H ₅ SO ₂ p-hydroxyphenyl 3D PC ₄ H ₉ SO ₂ ' p-hydroxyphenyl 32) p-CH ^ CO 3 | ή p-hydroxyphenyl 33) PH ₂ NCO phenyl 34) PH ₂ NCO m-chloro-p-hydroxy-phenyl 35) PH ₂ NCO m, p-dihydroxyphenyl 36) p-CH-, NHC0 HO-HO- p-hydroxy-phenyl 37) P-CH ₃ NHCO phenyl 38) p- (CH ₃ ) ₂ NCO p-hydroxy-phenyl 39) P »(C ₂ H ₅ ) ₂ NC0 p-hydroxy-phenyl 40) 'P-NO ₂ phenyl 41) P-NO ₂ 42) PH ₂ NCONH- p-hydroxy-phenyl 43)

L ·

U /

- 20 -

R =

44) 45) 46)

-47) 48)

49)

-OH

-OH> 0H

, -0H '.-0H

-OH

-SO ₂ NH ₂ -SO ₂ NH ₂ -SO ₂ NH ₂

-SO ₂ NH ₂ -SO ₂ NH ₂

-SO ₂ NH ₂

p-hydroxy-phenyl

phenyl

m, ρ-dihydroxyphenyl

m-chloro-p-hydroxy-phenyl

50) -OH 57) p-OH , _: -CONH ₂   p-hydroxy-phenyl A 51) '~ 0H _; 58) p-OH -COIiH ₂ · phenyl p-hydroxy-phenyl 52) -OH 59) p-OCOCH, -CONHCH, p-hydroxy-phenyl phenyl 53) -GONH ₂ 60) p-F -OH p-hydroxy-phenyl p-hydroxy-phenyl 54) -OH 61) H -OH p-hydroxy-phenyl p-hydroxy-phenyl 55) CONH ₂ 62) P-SOCH ₃ -CONH ₂ p-hydroxy-phenyl phenyl 56) -CONH ₂ 63) P-SOCH ^ -CONH ₂ phenyl p-hydroxy-phenyl c) R = -NH-CH ₂ - < 64) P-SO ₂ NH ₂ f \ ^R 1 phenyl ^R 1 65) P-SO ₂ NH ₂ p-hydroxy-phenyl phenyl

R ₁

66) P-SO ₂ NH ₂

67) p-CH 2 O 'p -hydroxy-phenyl

- 22 -

With these penicillin derivatives, for example, local and / or systemic diseases caused and / or prevented by the following pathogens or by mixtures of the following pathogens can be treated and / or prevented: Micrococcaceae, such as staphylococci; Lactobacteriaceae, such as streptococci; Neisseriaceae, like Neisseria; Corynebacteriaceae, such as Corynebacteria; Enterobacteriaceae, such as Escherichiae bacteria of the Coli group, Klebsiella bacteria, e.g. K. pneumoniae; Proteae bacteria of the Proteus group, e.g. Proteus vulgaris; Salinonella bacteria, e.g. S. typhimurium; Shigella bacteria, e.g. Shigella dysenteriae; Pseudomonas bacteria, e.g. Pseudomonas aeruginosa; Aeromonas bacteria, e.g. Aeromonas ligue faciens.

Spirillaceae, such as Vibrio bacteria, e.g. Vibrio cholerae; Parvobacteriaceae or Brucellaceae, such as Pasteurella bacteria; Brucella bacteria, e.g. Bruceila abortus; Haemophilus bacteria, e.g. Haemophilus influenzae; Bordatella bacteria, e.g. Bordetella pertussis; Moraxella bacteria, e.g. Moraxella lacunata; Bacteroidaceae, such as Bacteroides bacteria; Fusiform bacteria, e.g. Fusobacterium fusiforme; Sphaerophorus bacteria, e.g. Sphaerophorus necröphorus; Bacillaceae, such as aerobic spore formers, e.g. Bacillus anthracis; anaerobic spore-forming chlostridia, e.g. Chlostridium perfringens;

Spirochaetaceae, such as Borrelia bacteria; Treponema bacteria, e.g. Treponema pallidum; Leptospira bacteria, such as Leptospira interrogans.

The above enumeration of pathogens is merely exemplary and by no means limiting.

- 23 -

The effectiveness of the penicillins according to the invention can be exemplified by the following tests:

1. In vitro experiments

For the investigations, the method of the serial dilution test in the microtiter system was used. The testing of the substances for bacteriostasis was carried out in liquid medium. The bacteriostatic effect was examined at the following concentrations.

> 64; 64; 32; 16; 8th; 4; 2; 1; 0.5; 0.25; 0.125; 0.06; 0.03; 0.015 and 0.007 yug / ml.

A nutrient medium of the following composition was used: 10 g peptone, 8 g meat extract oxoid, 3 g sodium chloride, 2 g sec. Sodium phosphate are mixed with dist. Water made up to 1000 ml (pH 7.2-7.4). Only in the test for streptococci 1% glucose was added. The age of the primary cultures was about 20 hours. The seed suspension was adjusted on the photometer (according to "Eppendorf") (test tube diameter 14 mm, filter 546 nm) on the basis of the turbidity of a barium sulfate comparative suspension, which was produced by a barium sulfate suspension, which by the addition of 3.0 ml of 1% barium chloride solution in 9 7 ml of 1% sulfuric acid was formed. After adjustment, Streptococcus Aronson was diluted 1:15 and the remaining test germs diluted 1: 1500 with saline.

16 mg of the respective substance were weighed into 10 ml volumetric flasks and made up to the mark with the solvent. The further dilution series was prepared with distilled water or the respective solvent.

The wells of the microtiter plates were mixed with 0.2 ml of nutrient medium, 0.01 ml of the appropriate substance dilution

- 24 -

and one drop of seed suspension (0.01 ml) and incubated at 37 ° C for 18 to 20 hours. A solvent control was always carried.

The reading was made macroscopically, whereby the respective Grenkonzentration (= lowest still bacteriostatic effective concentration) was determined.

As test organisms were used:

Staphylococcus aureus SG 511, Escherichia coli ATCC 11,775, Pseudomonas aeruginosa Hamburgensis and Walter, Serratia marcescens ATCC 13,880, Klebsiella pneumoniae ATCC 10 031 and BC 6, Proteus mirabilis Hamburgensis, Proteus rettgeri BC 7 and Enterobacter cloacae ATCC 13,047.

Table 2 below lists the minimum inhibitory concentrations (MIC) determined for typical representatives of the compounds according to the invention, the numbers referring to the penicillins of Table 1 page 1β.

• CD O- τ- in CM in · "- _u in T- • 25 - m τ- OJ OJ - in -cf OJ -cf τ- OJ CD -ί Ο O OJ • OJ O ο O O O O O β CD in in OJ in ΙΛ -P Oh, I T- O ιη in in in in in τ- in CM OJ O r \ O ω in ο " co O OJ O O O τ- O O Ο O O O O. bfl co OJ O VO in in CM OJ in VO CM VO VO P * -P O PX. T- O ο OJ O O CM τ- τ- T- OJ O τ- ο O O J. -P O co O O O Ο Ο CM O O Ο O O iH U _Q O in O · O O O V VO in in H t I ε CM OJ O T- O* τ- ο CM VO in O in S O PQ O _α τ- • in OJ OJ OJ in OJ T- OJ CM O τ- τ- <f H Ft O ε O O τ- O • CD ιη in in - m in in OJ in CM ιη ft β OJ OJ OJ T ~ CNJ CM CM in τ- OJ τ- OJ jh O CM ο O O CM O O O O Ο ο Ο ο CO W ATCC τ- τ- H CD Ο * Ο ε • Üj. jh CNJ Fl xi cd ε CD ^ 5 -P OJ τ- OJ O OJ OJ CM CM OJ CM τ- OJ (D ω • iH -P CQ CD τ- OJ U P! T- ω χ] jh is CD CD <} * CNJ OJ τ- OJ CM CM τ- CM CVJ τ- , ι CO CD , Ω in I ie ώ τ- O .T- •H in in in m CM in OJ ιη H ω m ιη OJ OJ CM OJ in τ- OJ CM O o CD OJ ο " O τ- OJ O O O O Ο ο O ο • τ- T τ τ- β T- ο " OJ Ο in in in OJ ιη ft O T- m CM OJ in m CM OJ τ- CM cd -P in OJ ο O OJ O O O O ο Ο ο cn co O τ- O τ- Ο Ο χ] CD in Ö CD CM • Η OJ in O m OJ -cf in OJ OJ £> τ- τ- OJ OJ OJ m Sh τ- co CD '. r- _Ω CO

cd C-

ο -cf

cd O

-P-PC-O -P ί-ι <ΰ O CU U CQ

-P " • ro o O J-. Fl SU • Η O CU a W a ' O H VO CO φ CO CJ ϋ ^Ά PQ Ü T " H φ O a Ü • φ O O φ j ^ O CO CD ε  d φ -P φ ΐΗ

OT Φ Cdα. cd: ==

φ & ω φ CU co

• η ιη

η ιη

ο ο C

H <γ

si ft cd -μ co

φ ιη

cd co

ιη in VO O ιη m oy ιη - 26 - CM ιη τ- -cf OJ CM -cf CO . Cf ο " ο " O ο " ο ο ο " m ιη ιη νο ο ιη CM ιη CM νο ο OJ τ- OJ OJ τ- τ- ιη OJ ο " τ- CD OJ τ- τ- ο ο CD" CO ο ο Ο ιη ιη ιη VO O ο CM OJ τ- VO O ιη m oy ιη OJ ιη OJ ιη νο ο ο ο ο ο O ο Ο O ο ο O ο ο OJ O CO ο Τ " τ- VO o OJ τ- VO O OJ tr- ιη OJ ιη ιη ιη ο Ο O -cf OJ CO -cf OJ -cf OJ CO ο CM ο " ο τ- ο " τ- OJ. • ιη CM ιη CM τ- ιη CM OJ -cf CO -cf ιη τ- -cf -cf OJ ΓΛ -cf OJ m -cf O ο " τ- Ο ο ιη ο ιη m oy ιη ιη. ιη CM' OJ τ- ιη Ο3 OJ -cf ο ο " τ- Tf ο OJ ο " CD" ο -cf τ- ο τ- Ο ο " CM CM • ιη OJ OJ ιη ιη ιη ο ο τ- OJ OJ CM T- ω CM co CO ο OJ ο ο " τ- CM OJ ιη OJ ιη ιη OJ ιη CM τ- τ- τ- OJ ιη OJ OJ CM OJ CO VO τ- co -cf -cf ο OJ ο ο " ° O ιη O ιη OJ ιη OJ τ- ιη OJ τ- OJ τ- OJ ιη OJ τ ~ OJ ο ιη OJ ο ο Ο νο τ- Ο] OJ CM OJ ο Ο Ο O ο ιη CM ιη OJ ιη OJ ιη ο ιη OJ ιη ιη OJ ιη CM ιη OJ ιη C-m m oy m oy ιη CTi -Cf ο ο O ο ο οο ο ο ο ο ο 1 α ο O ο ιη ιη OJ ιη CM σ \ ιη τ-VO CM VO -Cf VO " ο P ιη τ- ο ο O O ο ιη m ιη C- ιη ιη m

- 27 -

A number of compounds of the invention have been studied in vivo in experimental infections in mice. E.coli ATCC 11 77 5 and Pseudomonas aeruginosa Walter were used as pathogenic bacteria. An intraperitoneal infection with 0.2 ml of a 5% mucin suspension of the bacteria was set. This corresponds to about 2x10 germs E. coli or 8x10 germs Pseudomonas / mouse. NMRI strain female mice were divided into groups of 10 animals each, two groups were left untreated, the remaining groups were treated with different doses of the respective penicillins of the invention for the determination of ED (dose at which 50% of the animals survive). The E.coli infection was treated once. The Pseudomonas infection was treated three times.

The observation period was 7 days in both cases. The results of these tests with representative representatives of the penicillins according to the invention are shown in Table 3.

As comparison substances served the known penicillins of the general formula

^ COONa

- 28 - : Azlocillin mg / kg - ^A With : Mezlocillin E. coli ATCC = B R = H. the _e further that 1175 R = SO ₂ CH ₃ THsC- / (4-hydroxy-3-pyridyl) aureido 3.9 Benzylpenicillin sodium (see DE-OS 3.7 2 450 668) 6, -1 ₌ Q 3.4 = D and piperacillin (T 1220) 5.0 Table 3 4.2 in vivo values 6.6 s.c. Appl. 3.0 Pseudo, aerug. Walter Connection. 4.7 3.2 8.2 1 2.8 10.4 3 8.3 - 4 5.6 6.6 7 2.1 • - 12 8.5 14 - 20 6.6 21 7.5 24 - 34 8.0 37 - , 41 - 43 3.6 44

- 29 -

^ED 50 connection

(Mg / kg)

s.c. Appl.

E. coli ATCC 1175

Pseudo, aerug. Walter

45 50 62 57 64

3.2 4.0 5.9 7.2 2.4

5.2 18.3 12.4

A B D

> 100> 100

89

225

186 '

The acute toxicity was determined by peroral and subcutaneous application of the compounds of Table 1 to white laboratory mice in increasing doses.

j.

is the dose, after its application 50-% of the animals

die within 8 days. All substances show

with oral administration one

above 4 g / kg, with subcutaneous administration

an LD ₅₀ of over 3 g / kg, ie at 3 g / kg no animals died, the substances are thus nontoxic in practice.

The reported values indicate that representative representatives of the penicillins of the present invention are valuable antibiotics because of their broad antibiotic spectrum, their high antibacterial activity, their low toxicity and their high serum content after subcutaneous and oral administration.

It is another object of the present invention to provide pharmaceutical agents which are valuable in the treatment of infectious diseases in both human and animal.

As preferred pharmaceutical preparations are tablets, j dragees, capsules, granules, suppositories, solutions, suspensions

- 30 -

ions, emulsions, ointments, gels, creams, powders and sprays. Advantageously, in human or veterinary medicine, the active ingredient or a mixture of the various active compounds of general formula I in a dosage between 5 and 500, preferably 10 - 200 mg / kg body weight administered per 24 hours, optionally in the form of several individual doses. A single dose contains the active ingredient (s) according to the invention, preferably in amounts of about 1 to about 100, in particular 5 to 60 mg / kg of body weight. However, it may be necessary to deviate from the stated dosages, depending on the type and body weight of the object to be treated, the nature and severity of the disease, the method of preparation and the application of the drug as well as the period or interval within which the administration takes place. Thus, in some cases it may be sufficient to make do with less than the abovementioned amount of active ingredient, while in other cases the abovementioned amount of active ingredient must be exceeded. The definition of 'each required optimal dosage and mode of administration of the active ingredients can be done easily by any person skilled in his expertise.

For parenteral administration, it is preferred to dissolve the penicillin compound of the invention in a non-toxic liquid medium for injection and to inject the solution intramuscularly, intravenously or subcutaneously.

It is also possible to dissolve or mix the penicillin compound of the invention in a non-toxic liquid medium or in an ointment base, and apply the solution or mixture directly to the damaged site. The compounds may also be used as suppositories after mixing with a suppository base or after dissolving therein.

- 3T-

Examples of non-toxic liquid media which can be used for the preparation of injectable preparations containing the penicillin compound as the active ingredient are sterilized deionized water, saline, glucose solution for injection, Ringer's solution and amido acid solution for injection.

The penicillin compound can also be dissolved in other injectable preparations and administered parenterally.

For oral administration, the penicillin compounds of the invention are used in the form of a pharmaceutical preparation containing the compound (s), optionally in admixture with pharmaceutically acceptable carriers, e.g. an organic or inorganic solid or liquid excipient suitable for oral administration. If desired, these preparations may also contain auxiliary substances, stabilizers and other commonly used additives.

When used as a feed additive, the new compounds may be given in the usual concentrations and preparations together with the feed or with feed preparations or with the drinking water. Thereby, infection by Gram-negative or Gram-positive bacteria can be prevented, ameliorated and / or cured, as well as promotion of growth and improvement of the utilization of the feed can be achieved.

-32 - 59 939 11

Example 1

The following examples are intended to explain the invention in more detail: (The indication of the Rf values relates to the system n-butanol-water-glacial acetic acid = 60: 25: 15, SiO _p plate). With "ampicillin" is the "^ -Aminobenzylpenicillin, with" amoxycillin "that c ^ -Amino-p-hydroxy-benzylpenicillin and with" epicillin "that - ^ - amino ^ T- (1 _f 4-cyclohexadien-1-yl ) -methylpenicillin with the D = R configuration in the side chain

Example A

- 33 - -

I. Representation of starting compounds

5-Amlno-4 ~ hydroxy ~ 2-tD methylsulfonylanilino-pyrimidine

3.2 g (0.019 mol) of 4-methylthio-nitrobenzene are dissolved in 20 ml of formic acid and added at room temperature 0.05 mol of hydrogen peroxide as a 30% solution. The solution heats up. After standing for 1 hour at room temperature, it is precipitated with ice water, the precipitate is filtered off with suction and dried at 50 C in vacuo. This gives 2.9 g (76.2 % of theory) of p-nitrophenyl methylsulfone.

3.42 g (0.017 mol) of p-nitrophenyl-methyl-sulfone are dissolved in 100 ml of methanol and in the presence of 1 g of Raney nickel at 50 ⁰ C.

5 bar hydrogenated. The solution is filtered off from the catalyst and evaporated to dryness. The residue is dissolved in 40 ml of dioxane and a solution von.3? 77 g (0.0175 mol) of 2-chloro-4 ~ hydroxy-5 ~ nitro-pyrimidin-Natriunisalzx 1H ^ O i _n 120 ml of water. The solution is heated for 3 hours on the steam bath. After cooling, the precipitate is filtered off, washed with water and dried at 50 ⁰ C in a vacuum.

Yield: 3.1 g (58.7 % of theory) of 4-hydroxy-2-p-methylsulfonylanilino-5-nitropyrimidine.

3.3 g (0.01063 mol) of hydroxy-Z-p-methylsulfonylanilino-5-nitropyrimidine are dissolved in 50 ml of water by addition of 6 ml of concentrated ammonia and heating in solution. With stirring, 7.83 g (0.045 mol) of sodium dithionite are added in one portion. Then it will be

- 34 -

Stirred at 6O ⁰ C for 15 minutes. After cooling, the resulting precipitate is filtered off with suction, washed with water

/t.-

Yield: 2.4 g (80.6 % of theory) of 5-amino-4-hydroxy-2-p-methylsulfonylanilino-pyrimidine.

NMR spectrum (DMSO + CD ^ OD) signals at ppm: 3.15 (s, 3H), 7.2 (s, 1H), 7.8 (broad s, 4H).

Example B

5-amino-4-hydroxy- 2-p-methylsulfinylanilino-pyrimidine

3.8 g (0.014 mol) of 4-hydroxy-2-p-methylthio-anilino-5-nitropyrimidine are slurried in 50 ml of glacial acetic acid, added 2.3 g (0.02 mol) of 30% hydrogen peroxide and stirred for 10 minutes heated on the steam bath. After cooling, the precipitate formed is filtered off with suction and dried in vacuo.

Yield: 2.28 g (55% of theory) of 4-hydroxy-2-p-methylsulfinylanilino-5-nitro-pyrimidine.

2.1 g (0.0079 mol) of 4-hydroxy-2-p-methylsulfinylanilino-5-ni-tropyrimidine are slurried in 60 ml of water and dissolved by adding 7 ml of concentrated ammonia and heating. 8 g of sodium dithionite are added all at once and the solution is heated on the steam bath for 20 minutes. After cooling, the solution is brought to pH 7 with glacial acetic acid and allowed to stand for several hours in the refrigerator. After suction, the crude product is purified by chromatography on a silica gel column (eluent chloroform / methanol 5: 1).

Yield: 0.8 g (38.2 % of theory).

NMR spectrum (DMSO + CD ^ OD) signals at ppm: 2.75 (s, 3H), 7.15 (s, 1H), 7.7 (q, 4H).

- 35 -

Analogously, starting from the appropriately substituted aniline and 4-hydroxy-2-p-methylthioanilino-5-nitro-pyrimidine or 2-chloro-4-hydroxy-5-nitropyrimidine and, subsequently, the reduction, the synthesized in the following table pyrimidines.

Pyrimidines of the general formula

Yield NMR spectrum (DMSO + signals at

in %

a) m-S0 ₂ NH ₂ > 2 55 7, Ks, 1H), 7.25-7.8 (m, 3H), 8.2 (s, 1H) b) P-SO ₂ NHCH ₃ 60 2.45 (s, 3H), 7.05 (s, 1H), 7.7 (Q, 2H) c) P-SO ₂ NHC ₂ H ₅ 56 1,3O (t, 3H), 3,5 (m, 2H), 7,1 (s, 1H), 7.75 (m, 4H) d) P-SO ₂ N (C ₂ H ₅ 68.5 1.35 (gi, 6H), 3.55 (m, 4H), 7.05 (s, 1H), 7,70 (q, 4H) e) P-SO ₂ NHC ₄ H ₉ 62 • 1.05 (t, 3H), 1.90 (m, 4H), 3.55 (m, 2H), 7.0 (s, 1H), 7.75 (m, 4H) f) P-SOC ₂ H ₅ 48 1,1 (t, 3H), 3, Km, 2H), 7,15 (s, 1H), 7,7 (q, 4H) g) P-SOC ₃ H ₇   54.5 1.0 (t, 3H), 1.7 (q, 2H), 3.1 (m, 2H), 7.10 (s, 1H), 7.75 (q, 4H)

-Ϊ

Yield NMR spectrum (DMSO + CD ₃ OD) signals at ppm:

ti) P-SOC ₄ H ₉

i) P-SO ₂ C ₂ H ₅

k) P-OCOCH ₃

CL) P-CONHCH ₃

m) P-CON (CH ₃ ) ₂

n) P-CON (C ₂ H ₅ ) ₂

o) p-NHCONH

42.5 60.5

42 64

48 68 O, 9.5 (t, 3H), 1.5-1.8 (m, 4H), 3.15 (m, 2H), 7.15 (s, 1H), 7.70 (m, 4H)

1.15 (t, 3H), 3.35 (m, 2H), 7.2 (s, 1H), 7.8 (broad, 4H) 1.1 (t, 3H), 1.6-1, 8 (m, 4H), 3,4 (m, 2H), 7,15 (s, 1H), 7,8 (broad s, 4H) 3,8 (s, 3H), 7,15 (s, 1H ), 7.7 (d, 2H), 7.9 (d, 2H) 2.8 (s, 3H), 7.25 (s, 1H), 7.6 (d, 2H), 7.85 ( d, 2H) 2.9 (s, 6H), 7.2 (s, 1H), 7.6 (d, 2H), 7.9 (d, 2H) 1, i (t, 6H), 2, 5 (q, 4H), 7.15 (s, -1H), 7.7 (d, 2H), 7.9 (d, 2H) 7, O5 (s, 1H), 7.2-7.6 ) m, 4H).

Pyrimidines of the general formula

R ₂ R ₃ - 37 - NMR spectrum (DMSO + CD ^ OD) 7, Ks, 1H), 7,35- 7.5 to 7, S (m, 3H) yield Signals be OH -SO ₂ NH ₂ in % 6.9 (d, 1H), 7.2 (s, 1H), 7.4 P) , 59 7.6 (m, 2H) 75 (d, 1H OH -CONH ₂ 6.9 (d, 1H), 6.9 (dd, 1H), q) 47 (s, 1H), 7, , 7.35 (d, 1H), OH -CONHCH ₃ 2.8 (s, 3H), r) 71 7.15 (s, 1H) , 7.0 (s, 1H), 7.5 7.7 (d, 1H) , O ^ ^ U, ill J -CONH ₂ -OH 6.85 (d, 1H) 6.7 (s, wide, 2H), 7.05 (s, s) 53 (dd, 1H), 7 broad, 2H), OH OH 7, Ks, 1H), t) 40 -CONH ₂ CONH u) 46

Pyrimidines' the R ₁ general formula ppm: CD ₃ 0D) NH ₂ 6.7 (d, 2H) -OH nxJ , 7 , 1 (m, ι β 4.4 (d, 2H) --OCOCH ^ NHCH ₂ (/ 5 (m, 2 + 1H) , 6 , 9 yield 7, Km, 3H) -P in % , 7 Λ ν) 59 4.4 (d, 2H) OCH ^ 2H + s, 1H) , 6 , 85 (d, w) 53.5 NMR spectrum (DMSO + χ) 48 Signals at 4.3 (s, 2H), y) 62.5 2 + 1H) 2.2 (s, 3H), (d, 2H), 7,1 4.4 (s, 2H),  (M, 2H) 3.7 (s, 3H), 2H), 7.2 (d,

«Jf V

R,

Yield in %

NMR spectrum (DMSO + CD ^ OD) signals at ppm:

ζ) -SO _n NHo 39.5 4 , 5 (s , 2H), 7.0 (s, 1H), 7 , 5 (d, 2H 7 , 8 (d , 2H) aa) -SOCH, * 44 2 , 75 ( s., 3H) , 4.5 (ie , 2H), 7.1 ( s, 1H 7, 6 (q, 4H)

Example C

DLa / 3- (4-hydroxy-2-p-methylaminosulfonylanilino-5-pyrimidinyl) -uricido-7-thienylacetic acid , "" _Trmmmm .,. "" ^ ,, "^

2.95 g (0.01 mol) of S-amino-p-methylaminosulfonylanilino-4-hydroxy-pyrimidine are refluxed in 100 ml of dry tetrahydrofuran with β g of trimethylsilyldiethylamine for 30 minutes. It is then concentrated to dryness in vacuo and the solid product is dissolved under nitrogen in 60 ml of dry tetrahydrofuran. This solution is added dropwise with ice cooling to 1.05 g of phosgene dissolved in 50 ml of tetrahydrofuran. The mixture is stirred for 5 minutes at room temperature and concentrated in vacuo to about half the volume. This solution is added dropwise with ice cooling to 1.57 g (0.01 mol) of D, L-thienylglycine, which was dissolved with 1 N sodium hydroxide solution in a mixture of 50 ml of tetrahydrofuran and 20 ml of water. The pH is adjusted to 8.0 at the end of the addition. The mixture is stirred for one hour at room temperature, then the tetrahydrofuran is removed under reduced pressure, a little water is added and the mixture is extracted twice with ethyl acetate at pH 7.0. The aqueous phase is then adjusted to pH 2.7 with 2N hydrochloric acid. D _a s precipitated product is filtered off with suction and dried

Yield: 3.3 g (69 %)

- 39

IR spectrum: 3300, 166O, 1555 cm ^-1 ; NMR spectrum (DMSO + CD-.0D) signals at ppm: 2.45 (s, 3H), 5.50 (s, 1H), 7.05 ( m, 2H), 7.40 (m, 1H), 7.80 (q, 4H), 8.35 (s, 1H).

The following ureidocarboxylic acids were synthesized analogously: a) Ureidocarboxylic acids of the general formula

A-CH-COOH

R ₁

Yield IR spectrum. NMR spectrum in % cm ^-1 (DMSO + CD ₃ OD),

Signals at

HO

P-SO ₂ NH ₂

46

P-SO ₂ NH ₂

52

I635 1530 1330 1155 1650 I63O I33O 1150

5.15 (s, 1H), 6.9-7.5 (m, 3H), 7.8 (broad s, 4H), 8.4 (s, 1H). 5.10 (s, 1H), 6.8 (d, 2H), 7, i (m, 1H, 7.8 (broad s, 4H) 1, 8.32 (s, 1H).

fe

- 40 -

R ^ yield

in % IR spect. NMR spectrum cm ^-1 (DMSO + CD ₃ OD), signals at ppm:

Cl

d) HO- / Vp-SOCH,

Cl

P-CONH ₂

V P-CONH ₂ ·

P-NO

64

46

f) HO - / ~ Y P-SO ₂ CH ₃ 52.5

HO g) ΗΟ ~ - <ζ ^ P-SO ₂ CH ₃ 61

44

59.5 1645 1550 1325 1150 3350 1655 1540

3330 1660 1530

3320 1655 1530

3340 1660 1540

3350 1660 1530 3350 1650 1610 1550 3300 1640 1545

2.45 (s, 3H), 5.10 (s, 1H), 7.0-7.45 (m, 3H), 7.8 (q, 4H), 8.38 (s, 1H-j. 2.75 (s, 3H), 5.1 (s, 1H), 6.9-7.4 (m, 3H), 7.75 (m, 4H), 8.36 (s, 1H). '2,7 (s, 3H), 5,10 (s, 1H), 6,80 (d, 2H), 7,15 (m, 1H), 7,8 (m, 4H), 8,35 ( s, 1H), 3, O5 (s, 3H), 5.10 (s, 1H), 7 _? 0-7.5 (m, 3H), 7.8 (q, 4H), 8.35 (s , iH), 3,1O (s, 3H), 5,10 (s, 1H), 6,80 (d, 2H) 7,15 (m, 1H), 7,7 (q, 4H), 8 , 30 (s, 1H) 5.15 (s, 1H), 6.85-7.40 (m, 3H), 7.7 (q, 4H), 8.35 (s, 1H) 5.10 ( s, 1H), 6.75 (d, 2H), 7.10 (m, 1H), 7.7 (dd, 4H), 8.38

5.10 (s, 1H), 6.80 (d, 2H), 7.15 (broad s, 1H), 7.55 (d, 2H), 7.90 (d, 2H), 8.40 (s, 1H).

Yield IR spectrum. NMR spectrum in % cm ^-1 (DMSO + CD ₃ OD) signals at ppm

"If) Ureidocarbonsauren the general formula

A-CH-COOH

NH ι

CO I

NH

P-SO ₂ NH ₂ 3340 1655 1560

5.45 (s, 1H), 7.0 (m, 2H), 7.40 (m, 1H), 8.35 (s, 1H).

NH-A Vr

Yield IR spectrum. NMR spectrum 'in % cm ^-1 (DMSO + CD ₃ OD)

Signals beippm

-OH -

50.5

HO

45

ο) Γ \ -OH -SO ₂ NH ₂ 56.5 3320 1650 1545

3330 1655 1540

3340 1650 1540

2.50 (m, 4H), 4.55 (s, 1H), 5.65 (m, 3H), 7.2-7.8 (m, 3H), 8.3 (s, 1H). 5.15 (s, 1H), 6.80 (d, 2H), 7.1- (m, 1H), 7.2-7.8 (m, 3H), 8.35

5.45 (s, 1H), 7.0 (m, 2H), 7.2-7.8 (m, 5H), 8.36

- 42 -

R, yield IR spectrum. NMR spectrum ^ -1

in %

cm

(DMSO + CD ^ OD) signals

-SONH,

3350 1655 '1550

5.10 (s, 1H), 6.9-7.8 (m, 6H), -8.35 (s, 1H).

c) Ureidocarboxylic acids of the general formula

A-CH-COOH NH

Yield IR spectrum. NMR spectrum

in %

-1

(DMSO + CD ₃ OD) signals at ppm

Cl q) HO HO r) HO

-SO ₂ NH ₂

52.5

53

3340 5.15 (s, 1H) , 6,9-7, ' 1650 (m, 3H), 7, 8 (q, 4H), 1540 8.36 (s, 1H) • 3330 4.45 (s, 2H) , 5,10 1655 (s, 1H), 6, 75 (d, 2H) 1540 7.10 (m, 1H) , 7,35 (5H).

II Presentation of the end products Example _1_ "

D-a- ^ 3- (4-hydroxy-2-p-methylaminosulfonylanilino-5-pyrimidinyl) -ureidoZ-pr-hydroxybenzylpenicillin sodium

1j47 g (0.005 mol) of S

_j ε onylanilino-pyrimidine are slurried in 50 ml of dry tetrahydrofuran and heated with 4 g of trimethylsilyldiathylamine until complete solution to reflux (10 to 30 minutes). The solution is concentrated to dryness in vacuo, added dropwise again in 50 ml of tetrahydrofuran'aufgenominen and with ice cooling to a solution of 530 mg of phosgene in 35 ml of dry tetrahydrofuran. The mixture is stirred for 10 minutes at room temperature and then concentrated in vacuo to about Halftb. , ,

2.1 g (0.005 mol) of amoxicillin are suspended in a solvent mixture of 40 ml of tetrahydrofuran and 10 ml of water. Under ice-cooling, triethylamine is added until the solution has dissolved. To this solution, the solution prepared above is added dropwise, wherein the pH is maintained by the addition of triethylamine to about 7.0. The mixture is stirred for one hour in an ice bath, allowed to come to room temperature, mixed with 20 ml of water and the tetrahydrofuran is removed in vacuo. The aqueous phase is extracted by shaking once with ethyl acetate at pH 7.0 and adjusted to pH 2.8 with 1N hydrochloric acid while cooling with ice. The precipitated penicillin is filtered off and dried in vacuo.

By adding the calculated amount of sodium ethylhexanoate in methanol, the sodium salt is prepared and precipitated with ether.

- 44 - Yield: 2, 16 g (62%); • : 1.55 (d, 6H), I '' 'C NH I CH ₃ 00Na - IR spectrum: 1765, 1650, 1610 cm " ¹ NMR spectrum (DMSO + CD ₃ OD) signals at ppm , 3H), 6.75 (d, 2H), 7.30 N ^ 'N j // ^ v-- ^ M NH- C ν of the following 2.55 (s, 3H), 4.05 (s, 1H), '5.45 (d + s At- A R yield (d, 2H), 7.85 (q, 4H), 8.35 (s, 1H). After this method were the penicillins game in % IR spec. Synthesis formula: cm A-CH-CONH ^ s ^s ^^ 2 phenyl p-S0 ₂ NH ₂ 74 NH 176Ο I • 1655 1590 1525 NT4R spectrum 3 p-hydroxy-m-S0 ₂ NH ₂ 63 (DMSO + CD ₃ OD) ', phenyl 1755 Signals at ppm 1660 1.55 (d, 6H), 4.1 1600 (s, 1H), 5.45 (q + s, 1530 3H), 7.4 (m, 5H), 7.75 (d, 2H), 8.0 (d, 2H), 8.35 (s, 1H) 1.55 (d, 6H), 4.0 (s, 1H), 5.45 (q + s, 3H), 6.7 (d, 2H), 7.2 (d, 2H), 7.4 (cL, 2H), 7.8 (m, 1H), 8.25 (s, 1H), 8.4 (s, 1H).

- 45 -

Yield IR-Spek. NMR spectrum

Signals at ppm

phenyl

m-S0 ₂ NH ₂

68

Phenyl P-SO ₂ NHCH ₃ 64

phenyl

P-SO ₂ N (CH ₃ ) ₂ 59

1765 1650 1600 1520

1765 1655 1610 1520

cyclohexanone P-SO ₂ NHCH, 49.5 1765 dienyl 1650 1600 • 1510 cyclohexanone P-SO ₂ NH ₂ 52 1765 dienyl 1655 I6OO

1.55 (d, 6H), 4.05 Cs, 1H), 5.45 (q + s, 3H), 7.5 (m, 7H), 7.8 (m, 1H), 8.25 (s , 1H), 8.4 (s, 1H) 1.55 (d, 6H), 2.45 (s, 3H), 4.05 (s, 1H |) 5.4 (q + s, 3H), 7.4 (in, 5H), 7.75 (q, 4H 8.35 (s, 1H), 1.55 (d, 6H), 2.45 (s, 3H), 2.55 (m, 4Hi ) 4.10 (s, -1H), 4.90 (s, 1H), 5.35 (q, 4H), 5.65 (m, 3H), 7.75 (q, 4H), 8, 35 (s, 1H 1.55 (d, 6H), 2.60 (m, 4H), 4.05 (s, 1H [4.85 (s, 1H), 5.30 (q, 4H), 5 , 70 (πι, 3Ηί) 7,80 (q, 4H), 8,37

1.55 (d, 6H), 2.45 (d, 6H), 4.05 (s, 1H), 5.40 (m, 3H), 7.35 (s, broad, 5H), 7.75 (q, 4H), 8.35

- 46 -

In-A game

Yield IR-Spek. NMR spectrum in % cm ^-1 (DMSO + CD ₃ OD),

Signals at ppm

10

12

• 13

p-hydroxy P-SOpN (CHj ₂ 65.5 1765 - 1765 1.55 (d, 6H), 2.4 phenyl Cm »^ C * m 1655 ' 1660 (d, 6H), 4.10 (s, 1600 1610 1H), 5.45 (q + s, 3 6.80 (d, 2H), 7.3 (d, 2H), 7.75 (q, 4H), 8.35 (s, 1H) phenyl P-SO ₂ NHC ₂ H ₅ 69 1765 1.20 (t, 3H), 1.5 1650 1765 (d, 6H), 3.55 (m, 1610 1655 2H), 4.05 (s, 1H) 1605 5.45 (m, 3H), 7.3 (m, 5H), 7.80 (q, 4H), 8.36 (s, 1H) p-hydroxy p-SOpNHC pHj- 66.5 1.20 (t, 3H), 1.5 phenyl Xd, 6H), 3.5O (m, 1765 2H), 4,10 (s, 1H) 1650 5.40 (q + s, 3H), 1600 6.75 (d, 2H), 7.3 (d, 2H), 7.80 (m, 4H), 8.36 (s, 1H) p-hydroxy P-SO ₂ NHC ₃ H ₇ 61 1, O5 (t, 3H), 1.5 phenyl (d, 6H), 1.90 (s, 2H), 3.55 (m, 2H) 4.05 (s, 1H), 5.4 (m, 3H), 6.80 (d, 2H), 7.35 (d, 2H) 7.75 (q, 4H), 8.3 p-hydroxy * 2 2 5 2 73 1.25 (m, 6H), 1.5 phenyl (d, 6H), 3.5O (m, 4H). 4.05Cs.1H)

5.45 (q + s, 3H), 6.75 (d, 2H), 7.3 (d, 2H), 7.75 (q, 4H), 8.35 (s, 1H)

- 47 -

At- A 'game

Yield IR-Spek. NMR spectrum in % cm ^-1 (DMS)

Signals at ppm

14 p-hydroxy-P-SO ₂ NHC ₄ H ₉ phenyl 68.5

15 phenyl

p-SOCH, 60

16 phenyl

/ owii

ζ 60

17 p-hydroxy phenyl 66

18 phenyl 65

1765 1655 1605

1765 1650 1610

1765 1660 1600

1765 1650 1610

1765 1650

1610

1.0 (t, 3H), 1.6-2.0 (m, 4H), 3.50 (m, 2H), 4.05 (s, 1H), 5.45 (m, 3H), 6 , 75 (d, 2H), 7.25J (d, 2H), 7-, 80 (m, 4H), 8.35 (s, 1H).

1.55 (d, 6H), 2.7! (s, 3H), 4.20 (s, 1H), 5.40 (q + s, 3H), 7.35 (m, 5H), 7.65 (d, d, 4H), 8.20 ( s, 1H). 1,5O (d, 6H), 3,1C (s, 3H), 4,10 (s, 1H), 5,40 (q + s, 3H),

(d, d, 4H), 8.30 s, 1H).

1,1 (t, 3H), 1,55 (d, 6H), 3,10 (m, 2H), 4,2 (s, 1H), 5,40 (q + s, 3H), 6,75 (d, 2H), 7.25 (d, 2H), 7.65 (d, c, 4H), 8.2 (s, 1H). 1, i (t, 3H), 1.55 (d, 6H), 3.10 (m, 2H), 4.2 (s, 1H), 5.4 (q + s, 3H), 7.35 (m, 5H), 7.7 (q, 4H), 8.20

- 48 At- A R. C- Yield IR-Spek. - 53 1765 - game 20 p-hydroxy-p-SOC ^ Hg in % cm 1650. NMR spectrum phenyl 1610 (DMSO + CD ₃ OD), 19. p-hydroxy-p-SOC ^ E, Signals "at ppm phenyl 1.0 (t, 3H), 1.55 ( (6H), 1.70 (q, 2H) 62 1765 3.10 (m, 2H), 4.05 1650 6.75 (d, 2H), 7.2 = 1610 (d, 2H), 7.65 (d, d 4H), 8.2 (s, 1H). O, 95 (t, 3H), 1.5- -1, ο ^ d, lUti), J ₉ l ^ (m, 2H), 4.2 (s, 1F 5.4 (q + 3H), 6.75 (d, 2H), 7.25 (d, 2H), 7.65 (d _s d, 4l · 8.2 (s, 1H).

21

p-hydroxy phenyl

60

1765 1660 1600

1.1-5 (t, 3H), 1.55 (d, 6H), 3.35 (m, 2.405 "(s, 1H), 5.5 (q + s, 3H), 6, 75 (d, 2H) x, 7.3 (d, 2E 7.9 (d, d, 4H), S, L

22

p-hydroxy phenyl

57

1765 1660 1600

1.10 (t, 3H), 1.5f (d, 6H) x, 1.6-1.8 (m, 4H), 3.4 (m, 2l x 4.2 (s, 1H), 5 , 5 (cs, 3H), 6.75 (d, 2l x 7.3 (d, 2H), 7.9 (d, d, 4H), 8.4 (s ₃ 1H).

In-A game

- 49 -

Yield IR spectrum

j

in% cm

NMR spectrum (DMSO + CD ^ OD), signals at ppm

p-hydroxy-P-OCOCH ₃ 79 phenyl ^:

phenyl

P-CONH ₂ 63

p-hydroxy-p-CONHCH, 51-phenyl

phenyl

P-CONH

p-hydroxy-P-CON (CH ₃ ) _£ 66 phenyl

1765

(Shoulder) 1755 1660 1610 1520 1765 1660 1610

1765 1650 I6OO

1765 1660 1610

1765 1650 1610

p-hydroxyphenyl

p-G0N (C _£ H _{5) 2} 53 1765

1655 1605 1.55 (d, 6H), 2.1 (s, 3H),

4.0 (s, 1H), 5.45 (m, 3H), 6.7 (d, 2H), 6.9 (d, 2H), 7.2 (d, 2H), 7.75 (i.e. , 2H), 8,2

1.55 (d, 6H), 4.05 (1H), 5.45 (m, 3H), 7.4 (m, 5H), 7.85 (m, 4H), 8.4 (s, 1H )

1.5 (d, 6H), 2.8 (s, 3h), 4.0 (s, 1H), 5.4 (m, 3H), 6.75 (d, 2H) ,. 7.25 (d ^,! 2H), 7.65 (m, 4H), 8.2 (s, 1H).

1 _s 5 (d, 6H), 2.8 (s, 3H), 4.0 (s, 1H), 5.45 (m, 3H), 7.4 (m, 5H) _s 7.7 (m , 4H), 8.25 (s, 1H). 1.5 (d, 6H), 2.85 (s, 6H), 4.0 (s, 1H), 5.45 (q + s, 3H), 6.75 (d, 2Ht), 7.25 (d, 2H), 7.75 (m 4H), 8.3 (s, 1H). 1.25 (m, * 6H), 1.55 (d 6H), 2.9 (m, 4H), 4.05 (s, 1H), 5.45 (q + s, 3H), '6, 7 (d, 2H), 7.2 (d, 2H), 7.7 (m, 4H),

8.2 (s, 1H).

- 50 -

At- A R-, yield IR-Spek. NMR spectrum

negative yl t,

Signals at ppm

Phenyl p-N0 ₂ 78 1760 1.55 (d, 6H), 4.0 (s,

1655 - 1H), 5.45 (m, 3H), * * 1600 7.35 (m, 5H), 8, i (m,

4H), 8.4 (s, 1H).

-30 p-hydroxy-P-HNCONH ₂ 62 1765 1.55 (d, 6H), 4.0 (s, phenyl '166O 1H), 5.4 (m, 3H),

1600 6.75 (d, 2H), 7.35

(m, 6H), 8.2 (s, 1H).

p-hydroxy-m-HO, 80 1765 1.55 (d, 6H), 4.05 phenyl p-S0 ₂ NH ₂ 1655 (s, 1H), 5.4 (m, 3H),

1600 6.75 (d, 2H), 7.45 1525 (in, 6H), 8.35 (s, 1H).

Phenyl m-OH, 76 1765. 1.55 (d, 6H), 4.0 (s, '

P-SO ₂ NH ₂ 1650 5.45 (m, 3H), 7,3-7, «

1610 U, 8H), 8.35 (s, 1H)

p-hydroxy - m-OH, 68 I76O 1.55 (d, 6H), 4.0 (s, phenyl p-C0NH ₂ 1655 1H), 5.4 (m, 3H), 6, '

-1605 (d, 2H), 7.2 (m, 3H),

7.6 (m, 2H), 8.3 (s, 13 phenyl m -OH, 71 1765 1.55 (d, oH), 4.0 (s,

P-CONH ₂ 1660 1H), 5.45 (q + s, 3H),

1600 7,35-7,7 (m, 8H), 8 ,:

p-hydroxy-m-OH, 67 1765 1.55 (d, 6H), 2.8 (s, phenyl P-CONHCH ₃ I65O3H), 4, 'o (s, 1H), 5, t

1600 "(m, 3H) *, 6.75 (d, 2H) * 1530 7.25 (m, 3H), 7.65

(m, 2H), 8.3 (s, 1H).

In-A game

- 51 Yield IR-Spek. NMR spectrum ¹

in % cm

" ¹

(DMSO + CD ^ OD) signals at ppm

p-hydroxy-m-CONH, phenyl p-OH

37 phenyl

m, p-di-OH

38 p-hydroxy-, p-di-CONH ^ phenyl

39 phenyl

m, P-Di-CONH ₉ 52 1765 1655 1605 1540

1760 1650 1600

1765 1655 1610 1510

1765 1660 1605

1.5 (d, 6H), 4.0 (s, 1H), 5.45 (m, 3H), 6.7 (d, 2H), 7.25 (d, 2H), 7.4-7 , 8 (m, 2H), 8.0

1.5 (d, 6H), 4.05 (s, 1H), 5.45 (q + s, 3H), 7.3-7.7 (m, 7H), 8.2 s, 1H).

1.5 (d, 6H), 4.1 (s, 1I 5.4 (q + s, 3H) -, 6.75 (d, 2H), 7 _s 25 (m, 3H), | 7.6 (m, 1H), 8 _? 0 (s, 1H), 8.25 (s, 1H), 1.55 (d ₅ 6H), 4.05 (s, i 1H), 5.45 (m, 3H ), 7.35-7.8 (m, 6H), 8.05, 8.2 (s, 1H). '

Furthermore, penicillins of the formula

A-CH-CONE ^

NH CO NH

CH

'COONa

N.N

NHCH ₂ -

R.

4m * - 52 - A ^R 1 yield p-hydroxy-p-OH 42 IR spec. NMR spectrum prepared in an analogous manner: game in % phenyl cm"" (DI4S0 + CD ₃ OD) ' J ** $% J w t m? at Signals at ppm 40 1765 1.5O (d, 6H), 3.95 1660 (s, 1H), 4.25 (s, 2H) Phenyl p-OH 50 1610 5.3 (q + s, 3H), 6.65 (d, 4H), 7, i (m, 4H), 7.95 (s, 1H). 41 1765 1.50 (d, 6H), 3.95 1660 (s, 1H), 4.25 (s, 2H) p-hydroxy-p-OCOCH ^ 58 1610 5.3 (q + s, 3H), 6.7 (i.e. phenyl 2H), 7, Km, 2H), 7 ,. ' (m, 5H), 7.95 (s, 1H) 42 1760 1.55 (d, 6H), 2.15 (s 1660 3H), 4,10 (s, 1H), 4

1600 (d, 2H), 5.3 (q + s, 3H 6.7 (d, 2H), 6.9 (d, 2H), 7.2 (m, 4H), 7, 43 p-hydroxy-ρ-F 55 1765 1.5O (d, 6H), 3.95 (s phenyl 1660 1H), 4; 4 (s, 2H), 1600 5.35 (q + s, 3H), 6.70 (d, 2H), 7.2 (m, 6H), , 8.05 (s, 1H). 44 phenyl H 54 1765 1.55 (d, 6H), 4.1 (s, 1660 1H), 4,4 (s, 2H), 5, 1600 (q + s, 3H), 7.2 (br.s 9H), 8.0 (s, 1H). 45 p-hydroxy-p-SOCH, 51 1765 1.5 (d, 6H), 2.7 (s, 3] phenyl 1655 4.1 (s, 1H), 5.35 (q + 1600 s, 3H), 6.75 (d, 2H), 1040 7.25 (d, 2H), 7.55 (q, 4H), 8.0 (s, 1H).

- - Phenyl p-SOCH, - • 53 - IR Spekt. NMR spectrum yield cm" (DMSO + CD ^ OD) At- .A PL in % Signals at ppm 1 game 1765 1.5 (d, 6H), 2.7 (s, 56 1655 3H), '4, Ks, 1H), 46 1600 4.55 (s, 2H), 5.35 p-hydroxy-P-SO ₂ NH ₂ 1040 (q + s, 3H), 7.35 (m, phenyl 5H), 7.55.Cq, 4H), 8.0 (s, 1H). 1765 1.5 (d, 6H), 3.95 (s, 40 1660 1H), 4.4 (br.s, 2H), 47 1600 5,35Cm, 3H), 6 _} 6 (d, Phenyl p-SO ₂ NH ₂ 1325 2H), 7,15Cd, 2H), 1160 7,5Cd, 2H), "7,8Cd, 2H), 7.95Cs, 1H). 1765 1.5Cd, 6H), 3.95 43 1660 Cs, 1Ή), 4,4 (br. 48 1600 2H), 5.35Cm, 3H), p-hydroxy-p-OCH ^ 1325 7,35Cm, 5H), 7,5 phenyl 1160 Cd, 2H), 7.8Cd, 2H), 7,95Cs, 1H). 1760 1, 5 (d, 6H), 3,7Cs, 51 1650 3H), 3.95Cs, 1H), 49 1600. 4.4 (br.s, 2H), 6.8 Cm, 4H), 7.2Cd, 4H), 8.0 (s, 1H).

D, L- (X- / 3- (2-p- Aminosulfonylanilino ) -hydroxy -S-pyrimidinyl) -ureido-1-thienyl-methyl-penicillin sodium

A solution of 2.3 g (5 mmol) of D, La- / 3- (2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl) -ureido-J7-thienylacetic acid in 50 ml of dimethylformamide and 25 ml of methylene chloride is added with P »52 g (5.1 mmol) of N-methylmorpholine and cooled to -20 ° to 25 ⁰ C.

To this is added 0.54 g (5 mmol) of ethyl chloroformate, dissolved in 20 ml of methylene chloride and the mixture is stirred for 45 minutes at -20 °. (Solution A).

To a suspension of 1.1 g (5 mmol) of 6-aminopenicillanic acid in 50 ml of methylene chloride are added dropwise 3 * 1 g (30 mmol) of triethylamine, then stirred for 1-2 hours at room temperature until dissolved and dam cooled to -20 ⁰ C. (Solution B),

Priority solution B to solution A - wobei- the temperature at -20 ⁰ C is maintained, and allowing the reaction mixture to react at room temperature for 45 minutes at -20 ° and 2 hours.

Then, 150 ml 'of water are added, the pH-W _e rt the aqueous phase to 7.2 provided, the organic layer separated and extracted 3 times with .Wasserphase Essigester. The ethyl acetate extracts are discarded. The aqueous phase is covered with ethyl acetate and the pH is adjusted to 3.0 by addition of 2N hydrochloric acid. The organic layer is separated, dried with sodium sulfate and concentrated. The resulting penicillin is dissolved in methanol and the sodium salt precipitated by addition of an equimolar amount of sodium ethyhexanoate.

- .55 -

Yield: 2.9 g (84 % of theory),

IR spectrum: 176O _; 1β55, 1β00 cm " ¹ , NMR spectrum (DMSO + CD ^ OD) signals at ppm:

1.55 (d, 6H) _} 4.0 (s, 1H), 5.45 (m, 3H), 7.1 (m, 2H), 7.45 (m, 1H),

7.85 (q, 4H), 8.35 (s, 1H).

Following the method of presentation of Example 50, the following penicillins were synthesized:

a) the formula

A-CH-CONH ^

NH (JO

NH

-N-

-CH, CH-

'COONa

NH-

In-A game

with the Ausb. IR spec. NMR spectrum

Ureido-in % cm ^-1 (DMSO + CTuOD), carbons signals at ppm

d. Ex.

'HO, 51 HO- / ~ A

cb

1760

1650

- 1605

1.55 (d, 6H), 4.05 (s, 1H), 5.45 (q-f s, 3H), 6.80 (d, 2H), 7.05 (m, 1H),

7.85 (q, 4H) ,. 8.35

- 56 -

examples

game

with the output. IR-Spek. NMR spectrum

Ureido in % cm ^-1 (DMSO + CD ₃ OD) carbons.- signals at ppi

d.-Ex.

P-SO ₂ NH ₂ Ca 42

53 f- \ P-SO ₂ NHCH ₃

P-SOCH

CD

P-SOCH ₃ Ce

P-SO ₂ NHCH ₃ Cc 64

1760 1655 1595 1530

1760 1655 1600 1530

1765 1650 1610

1765 1650 1610

1765 1655 1605

1.55 (d, 6H), 4.05

, 6.95 (d, iH), 7.45 (s, 1H), 7.85 (q, 4H), 8.35 (s, 1l 1.55 (d, 6H), 2.45 (s, 3H), 4.1 (s, 1H, 5.45 (q, 2H), 5.9 (s, 1H), 7.1 (m, 2H: 7.45 (d, 1H), 7.85 ( q, 4H), 8.35 (s, 1] 1.55 (d, 6H), 2.45 (s, 3H), 4 ₃ 0 (s, 1H 5.45 (m, 3H), 7, 0 (d, 1H), 7.3 (m, 1H 7.5 (s, 1H), 7.9 (q 4H), 8.3 (s, 1H), 1.55 (d, 6H), 2 , 75. (S, 3H), - 4.05 (S ₁ U 5.4 (q + s, 3H), 6.9! (D, 1H), 7.25 (m, U 7.45 (s , 1H), 7.7 (q, 4H), 8.35 (s, 1I 1.55 (d, 6H), 2.70 (s, 3H), 4.1 (s, 1h, 5.45 ( m, 3H), 6.85 (d, 2H), 7.1 (m 7.65 (q, 4H), 8.3

A R ₁ - 57 Y. IR spec. NMR spectrum examples I with the in % cm" (DMSO + CD-, OD), he? "al Ureide-

carboxylate

 d. Ex.

Signals at ppm!

57 Cl · - ^ P-SO ₂ CH ₃ HO - // W ^D

Η0- / Λ

HO P-CONH ₂ HO ^ Ö-

P-CONH,

P-NO,

Cf

cg

ci

ch

54

47

65

71

74

1765 1660 1600

1765 1650 1610

1765 1660 1610

1765 1660 1605

1760 1655 1600

1.55 (d, 6H), 3 * 1 (s, 3H), 4.1 (s, 1H), 5.4 {q + s, 3H), 6.95 (d, 1H), 7.3 (m, 1H), 7.45 (s, 1H), 7.85 (q, 4H), 8.3 (s, 1H). 1.55 (d, 6H), 3.1 (s, 3H), 4, Ks, 1H), 5.45 (m, 3H), 6.8 (d, 2K), 7.05 (m, 1H ) | 7.8 (q, 4H), 8.35

1.55 (d, 6H), 4.05 (s, 1H), 5.45 (q + s, 3H), 6.85 (d, 2H) ₃ 7.1 (m, 1H), 7.7 (m, 4H), 8.3 (s, 1H). 1.55 (d, 6H), 4.1 (s, 1H), 5.45 (m, 3H) 6.9 (d, 1H), 7.25 (in, 1H), 7.4 (s, 1H), 7.75 (m, 4H), 8.4 (s, 1H).

1.55 (d, 6H), 4.0 (s, 1H), 5.45 (q + s, 3H), 6.8 (d, 2H), 7.15 (m, 1H), 7.6 (d, 2H), 7.9 (d, 2H), 8.4 (s, 1H).

b) the formula

A-CH-CONH ^ NH

CO O ^ NH

-N

NH

-CH, j

CH,

'COONa

In-A game

R

R, with the Ausb. IR spec. NMR spectrum

Ureido in % cm ^-1 (DMSO + CD ₃ OD) carbons, signals at ppm

d. BeisO.

OH

-SO ₂ NH ₂

OH

-SO ₂ NH ₂

_C1 OH

-SO ₂ NH ₂

OH -SO ₂ NH ₂ Cm Cn Cp Co

42

58

45

52

1765 1.55 (d, 6H), 2.5 1655 (M, 4H), '4, Ks, IH 1600 4.9 (s, 1H), 5.35 (q, 4H), 7.6 (m, 3H 8.3 (s, 1H). 1760 1.55 (d, 6H), 4.05 1660 (s, 1H), 5.4 (m, 3H 1610 6.8 (d, 2H), 7, i (m 1H), 7.6 (m, 3H), 8.35 (s, 1H). 1765 1.55 (d, 6H), 4.1 1660 (s, 1H), 5.45 (m, 3 1600 6.95 (d, 1H), 7.1- 7.9 (m, 5H), 8.4 1765 1.55 (d, 6H), 4.1 1655 (s, 1H), 5.45 (q + s 1600 3H). 7.0 (m.2H).

7.4 (m, 1H), 7.8 (q 4H), 8.3 (s, 1H).

- 59 -

c) the formula

j example

HO HO

A- (JH-CONE ^

NH

NH

0 ·

'COONa

NHCH ₀ -

with the Ausb, IR-Spek, NIiR-spectrum

Ureido in% cm ^-1 (DMSO + CD ₃ OD), j

carbons. , · Signals at ppm!

d. Beisn. I

P-SO ₀ NH ₀ Ca

Cr

1765. 1.55 (d, 6H), 3.95 (s, 1H), 4.4 (broad s, 2H), 5.45 (q + s, 3H), 7.0 (d, 1H), 7, 3 (m, 1H), 7.5 (s, 1H), 7.8 (q, 4H), 8.4 (s, 1H)

 1765 1.55 (d, 6H), 4.0

(s, 1H), 4.4 (broad s, 2H), 5.45 (m, 3H) |, 6.75 (d, 2H), 7.1 (m, 1H), 7.4 (broad .s, 5H).

- 60 -

The compounds of the general formula I and I 'can be incorporated into the customary pharmaceutical application forms, such as tablets, Drag6es, capsules, cdsr ampoules. The single dose in adults is generally between 50 and 1000 mg, preferably 100 to 500 mg, the daily dose between 100 and 4000 mg, preferably 250 to 2000 mg.

Example I

Tablets containing Da - /> - (2-p-Aminosulfonylanilino ~ 4 ^~; hydroxy-5-pyrimidinyl) -ureido7-'benzylpenicillin - sodium

A mixture consisting of 2 kg of active substance, 5 kg of lactose, 1.8 kg of potato starch, 0.1 kg of magnesium stearate and 0.1 kg of talc is compressed in the usual way to tablets, so that 'each tablet contains 200 mg of active ingredient.

Dragees containing Da- / 3- (2-p-Aminosulfonylanilino-4-hydroxy -5- pyrimidin yl) -u reido7-benzylpenicillin - sodium

Tablets are pressed analogously to Example I, which are then coated in the usual way with a coating consisting of sugar, potato starch, talc and tragacanth.

- 61 - 59 939 11

6 * 4 * 82

Capsules- containing D- <χ ~ / 5- (2-ρ-aminosulfonylanilino ~ 4- <hydroxy-pyridimide inyl) acid ido7-benzylphenyl-1-naphthalene

5 kg of active ingredient are filled in the usual way, in hard gelatin capsules, such that each capsule contains 500 mg of the active ingredient.

Example IV

Dry ampoules containing D ~ <- ^ - (2-p-Aminosulfonylanilino-4-hydroxy-5-pyrimidinyl) -ureido-benzylpenicinine sodium

In an aseptic area, 251 g of active ingredient was dissolved in 200 ml of distilled water for injection. The solution ^: was filtered through a Millipore filter (pore size 0.22 mm). "The solution was added in each case in an amount of 2 _? The vials were then sealed with a rubber stopper and aluminum cap. Thus, vials (Hr * A) were each obtained with 250 mg of active ingredient

A physiological saline for injection was filled in an amount of 2 _f 0 ml in vials and the vials were sealed, "In this way, vials were (Ur ₀ B) get * The physiological saline in • the vials. (Hr · B) was poured into the vials (Hr * A) to obtain an injectable preparation for intravenous administration _β

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Distilled water for injection was poured into the vials (No. A) in an amount of 20 ml and the solution was dissolved in a 5% solution of glucose for injections (25 ml). In this way, solutions for continuous infusion were prepared.

Analogously, tablets, dragees, capsules and ampoules are available which contain one or more of the other active ingredients of the formula I or the physiologically acceptable salts of these compounds.

Claims (1)

59 93.9 11 6.4.82 invention claim 1. A process for the preparation of new penicillins of the general formulas A-CH-COHH-I m 'a COOH i CO OH A-CH-coira. IH CH ₃ 3 COOH (D in which A and R have the following meanings σ a) A is the phenyl group and R is the group of general formula II, ^R 1 (II) in which n = 0 or 1 and R ₁ , if n = 0, the groups 0
η NO ₉ ; -C-NH ₉ ; -C-NHCH _x ; -CN (CEL) ₀ ; 0 0 0 -O-C-CH ₃ ; -SO ₂ -R ^; -SO-R ₄ ; -SO ₂ -NH ₂ ; 0 H or -SO ₂ -N (Rr) ₂ and, when n = 1, it means the above-mentioned groups and additionally an hydrogen or fluorine atom, the hydroxy, methyl or methoxy group, wherein R> in the above formulas a Alkyl group having 1 to 4 carbon atoms, or R is a group of general formula III, ,(in) in which one of the radicals R ₂ or R ^ is the hydroxy group and the other of these radicals is a group of the formulas -SO ₉ -NH ₀ ; -C-NH ₉ ; C-NH-GH _x
0 0 or the two radicals R ₂ and R ^ represent the group -CONH ₂ represents <or it means b) A is the p-hydroxyphenyl group and R is the group of the general formula II in which n is Q or 1 and R ₁ , if n = 0, the groups of the formulas -NH-C-NH ₀ ; -C-NH-CH ,; -CN (CH,) -; -OC-CH ,; 00 0 0 -SO-R ₅ ; -SO ₂ -R ₅ ; -SO ₂ -NR ₄ ; -SO ₂ -N (R 1) ₂ or the meta-permanent group -SO ₂ -NH ₂ , and, if n = 1, it means the abovementioned groups and additionally a fluorine atom, the hydroxy group, the nitro group, the group H ₂ NCO-, the groups -SO- CH ₃ , -SO ₂ -CH ₃ , or PH ₂ N-SO ₂ -, or the methyl or methoxy group wherein in the above formulas R 1 is as defined above and R _{5 is} an alkyl group having 2 to 4 carbon atoms, or R is a group of the general formula III in which one of the radicals R ₂ or R _{3 is} the hydroxy group and the other of these radicals is a group of the formulas -SO ₀ -NH ₀ ; ' -C -NH ₀ ; -C-NH-CH ,, or in the two 0 0 Radicals R ₂ and FU represent the group -CONH ₂ , or it means c) A represents the 2-thienyl group, the cyclohexa-1,4-dien-1-yl group, the 3,4-dihydroxyphenyl or the 3-chloro-4-hydroxyphenyl group and R is a group of the general formula II in which n = 0 or 1 and R _{1 is} a fluorine atom, the methyl or methoxy group or a group of the formulas H ₀ NC-NH-; H ₀ NC; CH ^ -NH-C-; (CHO ₀ NC-; -SO-R,; 0000 59 939 11 -SO ₂ -R ₄ ; -SO ₂ -IJH ₂ ; -SO ₂ IR ₄ or ~ £ represents,. - ^H wherein in these formulas R ₄ is defined as indicated above and R _{1 may} also be a hydrogen atom, provided that A is 2-thienyl, 3,4-D, hydroxyphenyl or 3-chloro-4-hydroxyphenyl, or R _{1 represents} the hydroxy group or the methylcarbonyl group, provided that A represents the: 2-thienyl group, the cyclohexa-1,4-diene group or the 3-chloro-4-hydroxyphenyl group, or. R is a group of general formula III in which R _? the hydroxy group and Ro denote the hydroxy group or the groups -COMi ₂ , -CO-HHCHo, -SO ₂ -IiH ₂ , both radicals R and Ro may also simultaneously denote the group -COIuH ₂ and their "salts with inorganic or organic bases , characterized in that a) a compound of general formula V, *. "" - ^GH ~ A-CH-COUH- ^m 2 / '' if, COOH, (V) in which A is as defined above, with a pyrimidine derivative of the general formula VI, OH, (VI) where R is as defined above and B is the group. ICO or a reactive derivative of this group or the groups -NHCOCl, -NHCOBr or -NH-COO ~ ^ _ ₌ 5'-NO ₂ means or with mixtures of such pyrimidines of the general formula VI, in which B partly has one and partly the other of the meanings mentioned above, in a solvent and a pH range between 2.0 and 9.0 at temperatures between -20 ⁰ C and +50 ⁰ C is reacted, or b) a ureidocarboxylic acid of the general formula VII A-CH-COOH NH CO NH , (VII) OH  in which A and R have the meanings given above, or theirs. Salts or reactive derivatives, with 6-aminopenicillanic acid of the formula VIII, , (VIII) or with their inorganic or organic salts or with their derivatives, which are easily convertible into the 6-aminopenicillanic acid, between -40 ° and + 40 ⁰ C in the presence of a solvent and, optionally, a base is reacted and / or a compound thus obtained of general formula I or I 'is converted into their salts with inorganic or organic bases. 59 93.9 11 co IU1J.UUXUU 2, OUiCtW χ 1-u.i.j.i. U icij g, t; λ. υιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιι a) in water or in water-miscible solvents in the presence of water in a pH range of 6.5 to 8.0 or. , b) in anhydrous solvents ^or:; c) in a mixture of water and immiscible with water. Solvents in a pH range between 6.5 and 8.0. , , .... - .. .. · is reacted, or that a compound der.general formula V ₅ . in which the hydrogen atom of the carboxyl group is replaced by a silyl group or another readily cleavable protecting group, with a compound of the general formula VI in a water- and hydroxyl groups bsv /. aprotic solvent, if appropriate in the presence of a base, is reacted » The method of item 1 b, characterized in that as reactive derivatives of the ureidocarboxylic acids of general formulas VII their acid anhydrides, their reactive ^esters: or reactive amides or their Saurehal0gen3.de as derivatives of compound VIII der.Formel the diphenylmethyl ester, the t-butyl ester, the trimethylsilyl ester or the Ν, Ο-bis-trimethylsilyl derivative are used and the reaction is carried out in the presence of a base and / or an organic solvent and / or .a condensing agent. and, if desired, the product so obtained. of the general formula I ₅ in which the hydrogen atom, the carboxyl group is replaced by a removable protective group, is subsequently converted into an acid of the general formula I or »I ¹ *