DE2933142A1 - Antibacterial alpha-ureido penicillin derivs. - prepd. by reaction of a 1-amino-cycloalkane-carboxamido-penicillanic acid cpd. with e.g. a 4-hydroxy-5-pyrimidinyl isocyanate - Google Patents

Abstract

New ureido-substd. penicillin derivs. are cpds. of formula (Ia) and their tautomers of formula (Ib) and, when E is H, their pharmacologically tolerable salts with organic and inorganic bases: n is 1 or 2; R is H, Me, Et, (substd.)cyclopropyl, -NH-Z-X (where Z is opt. branched 1-6C alkylene or 3-6C cycloalkylene; X is CN, OH, SH, -CO-N(R3)(R4), -CO-R3, -COOR4, -N(R3)(R4), -NH-COR3, -NH-CO-N(R3)(R4), -NH-CS-N(R3)(R4), -NH-SO2-R3, -OR3, -O-COR3, -SR3, -SOR3 or -SO2R3, (where R3 is 1-4C alkyl or phenyl; R4 is H or 1-4C alkyl, or N(R3)(R4) is 3- to 6-membered heteromonocyclic ring), -NH-(CH2)m-C6H2-(R5)(R6)(R7) (m is 0 or 1; R5, R6, R7 are H, halogen, Me, Et, i-Pr, NH2, NHMe, NMe2, NEt2, NEt2, morpholino, OH, OMe, OEt, NO2, acetamido, -SO2-Me, acetyl, -O-CO-Me, -COOMe, -COOH, -CONH2, -CO-NHMe, -CO-NMe2, CN, -SMe, -SOMe, -SO2-NH2 or CF3, at least one of R5-R7 being other than H), -NH-(CH2)m-Het, where Het is a heterocyclyl gp., and E is H or a protecting gp. which is readily cleaved off in vitro or in vivo. (I) are antibacterials useful in the prophylaxis and treatment of local and systemic infections in human and veterinary medicine. They can also be used as preservatives for inorganic and organic materials (including foodstuffs).

Description

New penicillins, their salts, processes for their production

and medicaments containing these compounds. The invention relates to new penicillins of the general formula their physiologically compatible SaJow with inorganic or organic bases, if E denotes a hydrogen atom, processes for egg production of these compounds and drugs containing these compounds.

In the above general formula I, n denotes the numbers 1 or 2, R denotes a hydrogen atom, a methyl or ethyl group, the cyclopropyl group, which can optionally be substituted with one or two methyl groups or an ethyl group or a phenyl group, the cyclobutyl group, the hydroxyl group, the methoxy or ethoxy group, the mercapto, methyl mercapto or ethyl mercapto group, a group of the general formula where R1 and R2 can be the same or different and are hydrogen atoms, aliphatic, branched or unbranched hydrocarbon radicals, which may contain one or two double bonds or a triple bond and 1 to 6 carbon atoms, cycloalkyl radicals with 3 to 7 carbon atoms, with one or two methyl groups or Ethyl group can be substituted and can contain one or more double bonds, alkyl groups substituted by a cycloalkyl radical with 3 to 7 carbon atoms in the cycloalkyl and 1 to 3 carbon atoms in the alkyl part, but R1 and R2 can also together form an alkylene chain with two to 6 carbon atoms, so that a three to seven-membered heterocyclic ring is formed, which may contain one or two double bonds, R also denotes a group of the general formula NH-ZX, in which Z is a straight-chain or branched alkylene group with 1 to 6 carbon atoms or a through the Su Substituent X denotes a substituted cycloalkyl group having 3 to 6 carbon atoms and X denotes the cyano group, the hydroxyl group, the mercapto group or a group of the general formulas -COR3, -COOR4, NHCOR3, -NHSO2R3, -OR3, -OCOR3, -SR3, -SOR3 and -SO2R3, where in these formulas P 3 is a straight-chain or branched alkyl group with 1 to 4 carbon atoms or the phenyl group and R is hydrogen or an alkyl group with 1 to 4 Represent carbon atoms or R3 and R4 together with the intermediate nitrogen atom can also form a 3 to 6-membered monocyclic, heterocyclic ring, R furthermore denotes a group of the general formula in which m the numbers 0 or 1 and one, two or three of the radicals R5, R6, R7 halogen atoms, in particular bromine, chlorine or fluorine atoms, methyl, ethyl, isopropyl, amino, methylamino, dimethylamino, Diethylamino, morpholino, hydroxy, methoxy, ethoxy, nitro, acetylamino, methylsulfonyl, acetyl, methylcarbonyloxy, methoxycarbonyl, carboxyl, aminocarbonyl, methyl and dimethylaminocarbonyl, cyano, methyl mercapto , Methylsulfoxy, methylsulfonyl, aminosulfonyl, or trifluoromethyl groups and optionally the other radicals R5, R6 and R7 represent hydrogen atoms, R furthermore represents a group of the general formula NH (CH2) mHet in which the radical - (CH2) mHet represents the 3-pyridyl, 2-, 3-, or 4-pyridylmethyl, 5-pyrimidinyl, 2-methyl-5-pyrimidinylmethyl, 5-ethoxycarbonyl-2-thienyl, 5-methyl-2-thienyl, 5-thoxycarbonyl-2-furyl-, 2-thienylmethyl-, 3-thienylmethyl-, 5-methyl-2-thienylmethyl-, 5-chloro-2-thienylmethyl-, 2-furylmethyl-, 3-furylmethyl-, 5-nitro -2-fu rylmethyl-, 5-methyl-2-furylmethyl-, 2-tetrahydrofurylmethyl-, 2-pyrrolylmethyl-, 2-imidazolylmethyl-, 3-methyl-5-pyrazolylmethyl-, 3-methyl-5-isothiazolylmethyl- 3-methyl-4- isothiazolylmethyl-, 3-isothiazolylmethyl-, 3-methyl-5-isoxazolylmethyl-, 2-thiazolyl-, 4-methyl-2-thiazolyl-, 2-methyl-5-thiazolylmethyl-, 4-methyl-2-thiazolyl-methyl- , 2-thiadiazolylmethyl, 2-methyl-5-triazolylmethyl, 1,3,4-triazol-2-ylmethyl, 1,2,3-triazol-4-ylmethyl or tetrazolylmethyl, P also denotes the acetylamino or propionylamino group, E denotes hydrogen or a protective group which can be easily cleaved in vitro or in vivo. For the purposes of the invention, suitable carboxyl protective groups are those which have already been used in the field of penicillins and cephalosporins, in particular ester-forming groups that can be removed by liydrogenolysis or llydrolysis or other treatments under mild conditions, or ester-forming groups that are easily found in the living organism can be split off.

Examples of easily cleavable protecting groups in vitro are e.g.

B. the benzyl, diphenylmethyl, trityl, t-butyl, the 2,2,2-trichloroethyl or the trimethylsilyl group.

Examples of protecting groups that can be easily cleaved in vivo are e.g. alkanoyloxyalkyl groups, such as the acetoxymethyl, propionyloxymethyl, 2-acetoxy-ethyl or pivaloyloxymethyl group or the phthalidyl or indanyl group.

If E is hydrogen, the claim also includes pharmaceuticals compatible salts, such as alkali or alkaline earth salts, e.g. sodium, potassium, Magnesium or calcium salts, ammonium salts, organic amine salts, e.g. those with Triethylamine or dicyclohexylamine.

Those compounds of the general formula I are preferred in which n is the number 2 and R is a hydrogen atom, the cyclopropyl group which can be substituted by a methyl or ethyl group, the hydroxyl group, the methoxy group, a group of the general formula denotes in which R1 has the meaning given above; or a group of the general formula -NH-ZX denotes, in the case of -Nli-Z- in particular a group of the formulas and X represents the hydroxy, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl, ethylcarbonyl, methyl mercapto or ethyl mercapto group, or in the denotes the 4'-hydroxycyclohexylamino group; in addition, R can also be a group of the general formula represent in which m and R5 to R7 have the meanings given above; Another preferred meaning for R is a group of the general formula -NH (CH2) mBet, where - (CH2) mHet stands for the 3-pyridyl, the 3-pyridylmethyl group, the 5-pyrimidinyl, the 5-pyrimidinylmethyl group, the 5-Ethoxycarbonyl-2-thienyl group, the 5-ethyl-2-thienyl group, the 2-thienylmethyl, 3-thienylmethyl, 5-chloro-2-thienylmethyl, 5-methyl-2-thienylmethyl group, the 2- or 3-thienylmethyl group -Furylmethyl group, the 5-methyl-2-furylmethyl group or the 2-pyrrolylmethyl group, and E represents a hydrogen atom or the pivaloyloxymethyl group.

The penicillin compounds of the general formula I can exist in two tautomeric forms (namely of the lactim and lactam type). It depends in particular on the particular solvent and the type of substituent R, which of the two forms I or I predominates: It goes without saying that the compounds of the general formula I given at the outset always include both tautomers.

The compounds of the general formulas I and I 'can be represented as follows: By reacting a compound of the general formula in which n is as defined above, with a pyrimidine derivative of the general formula in which R is as defined above and B is the group -NCO or a reactive derivative of the group -NHCOOH, such as, for example

the groups -NHCOC1, -NIICOBr or the group -NHCOCl being particularly preferred. It is also possible to use mixtures of those pyrimidine derivatives of the general formula III in which B has partly one and partly the other of the meanings given above, e.g. the groups -NCO and at the same time next to each other.

The starting materials of the general formula II can be in the form of their inorganic or organic salts, e.g. as triethylammonium salt or sodium salt, can be used. The reaction can then take place in any mixtures of water with such organic solvents that are miscible with water, such as Ketones, e.g. acetone, cyclic ethers, e.g. tetrahydrofuran or dioxane, nitriles, e.g. acetonitrile, Formamides, e.g.

Dimethylformamide, dimethyl sulfoxide or alcohols e.g.

Isopropanol or in hexametapol. One stops at that the pH of the reaction mixture by adding bases or using buffer solutions in a pH range from about 2.0 to 9.0, preferably between pH 6.5 and 8.0. But it is also possible to carry out the reaction in anhydrous organic solvents, e.g. halogenated hydrocarbons such as chloroform or methylene chloride under To carry out the addition of bases, preferably triethylamine, diethylamine or N-ethylpiperidine. Furthermore, the reaction can be carried out in a mixture of water and one with water immiscible solvents such as ethers, 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 is advisable to stir vigorously, and the pH value by adding a base or Use of buffer solutions in a range from about pH 2.0 to 9.0, preferably between 6.5 and 8.0. 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 carry out.

Used as starting materials for the process according to the invention the silyl derivatives of the compounds of general formula II (e.g. mono- or di-trimethylsilyl derivatives) and if they react with compounds of the general formula III, then one works in generally expediently in anhydrous and hydroxyl group-free solvents, for example in halogenated hydrocarbons, e.g.

Methylene octiloride or chloroform, benzene, tetrahydrofuran, acetone or dimethylformamide, etc. The addition of bases is not here necessary, can also be advantageous in individual cases in order to reduce the yield and Improve product purity. As optionally added bases are expediently tertiary aliphatic or aromatic amines, such as pyridine or Triethylamine, or secondary amines which are difficult to acylate due to steric hindrance, like dicyclohexylamine.

Instead of the silyl ester, all other carboxyl derivatives of 8-aminobenzylpenicillins, which are used in the field of the manufacture of semi-synthetic Penicillins are known to be used. Typical examples are the trityl esters, the p-nitrobenzyl esters or the phenacyl esters. Following the implementations, you can these derivatives are converted into the penicillins according to the invention by known methods will. The amount of bases used is, for example, due to the desired compliance a certain pH value.

Where pH measurement and adjustment are not carried out or because of the lack of it sufficient amounts of water in the diluent are not possible or not useful is, in the case of using the nonsilylated compounds of the general Formula II preferably used 1.0 to 2.0 molar equivalents of bases. In case of Use of the silylated compounds is preferably used up to one Molar equivalent of base.

Bases that can be used in principle are all commonly used in organic chemistry Organic and inorganic bases used are used, such as alkali and Alkaline earth hydroxides, alkaline earth oxides, alkali and alkaline earth carbonates and hydrogen carbonates, Ammonia, primary, secondary and tertiary aliphatic and aromatic amines as well heterocyclic bases.

Examples are sodium, potassium and calcium hydroxide, calcium oxide, Sodium and potassium carbonate, sodium and potassium hydrogen carbonate, ethylamine, methyl-ethylamine, Triethylamine, Jlydroxyäthylamin, aniline, pyridine and piperidine called. Using the silylated starting materials should, however, meet the restrictions given above with regard to the type of bases.

All customary buffer mixtures can be used as buffer systems e.g. phosphate buffer, citrate buffer and tris (hydroxymethyl) amino methane buffer.

The reaction temperatures can be varied within a relatively wide range will. In general, one works between about -20 and about + 50 ° C., preferably between 0 and + 200C.

The reactants of the general formulas II and III can from are reacted with one another in equimolar amounts from the outset. It can but in individual cases it can be useful to use one of the two reactants to be used in excess in order to facilitate the cleaning of the end product or to increase the yield.

The work-up of the reaction mixture obtained after Implementation is carried out according to the methods customary for ß-lactam 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. For the production of the potassium or sodium salts, the precipitation of these salts has proven particularly useful an alcoholic-ethereal solution of the free acid by adding potassium or sodium 2-ethylhexanoate. The ones used as raw materials Compounds of the general formula II are known from the literature, see e.g. E.H.

Flynn, Cephalosporines and Penicillines, Academic Press, New York and London (1972). For n = 2 it is the well-known antibiotic ciclacillin.

The starting materials of the general formula III can be prepared, for example, by reacting the corresponding 5-aminopyrimidines of the general formula in which R is as defined above, can be obtained with phosgene.

This reaction is preferably carried out in a solvent that does not contain hydroxyl groups, such as tetrahydrofuran, methylene chloride, chloroform, dimethoxyethane or hexametapol at temperatures between -400 and + 600C, preferably between -100 and + 200C. It is recommended that the hydrogen chloride formed is bound by equimolar amounts of an inert organic base such as triethylamine or pyridine. An excess of pyridine can also be used as a solvent. If the aminopyrimidines of the general formula IV in question are sparingly soluble in one of the solvents mentioned, the phosgenation can also be carried out in the heterogeneous phase. Furthermore, the aminopyrimidines of the general formula IV by treatment with a silylating agent, such as hexamethyldisilazane or trimethylchlorosilane / triethylamine, can be converted into an aminopyrimidine which is generally very easily soluble in the solvents mentioned, or, depending on the exchangeable hydrogen atoms present, several times silylated aminopyrimidine then reacts with phosgene to give the corresponding compounds of general formula III. Depending on the type of solvent, the temperature, the amount and type of base used, either predominantly the corresponding isocyanate or carbamic acid halide or a mixture of these two compounds is formed. Depending on the reaction conditions, the compound of the general formula III can also be used to some extent or in part as a tetrahydro-oxazolopyrimidine of the general formula, isomeric to the isocyanates are present.

The starting products of the general Formula III and mixtures thereof are generally used in the solvents mentioned above easily soluble and can, after removing the excess phosgene, without further Purification with the corresponding penicillin derivatives of the general formula II directly implemented.

The 2-substituted 5-aminopyrimidines of the general formula IV are in the German Offenlegungsschrift P 28 08 153 read writings.

It has been found that the compounds of the general formulas t or 1 'have valuable pharmacological properties with good tolerability. The active ingredients according to the invention can therefore be used for prophylaxis and chemotherapy used by local and systemic infections in human and tied medicine will.

As diseases that are prevented by the compounds according to the invention or can be cured, for example those of the respiratory tract, the pharynx and called the urinary tract; the compounds are particularly effective against pharyngitis, Pneumonia, peritonitis, pyelonephritis, otitis, cystitis, endocarditis, bronchitis, Arthritis and general systemic infections. These connections can continue used as substances for the preservation of inorganic or organic materials especially of 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 connections of the general Formulas I and I 'both in vitro and in vivo against harmful microorganisms, especially against gram-positive and gram-negative bacteria and bacteria-like bacteria Microorganisms have a very strong effect, whereby they are particularly characterized by a broad spectrum of activity distinguish. In addition, the compounds of the general formulas I and I 'show parenteral administration high levels in tissue, serum, organs and urine.

With these penicillin derivatives, for example, local and / or systemic diseases can be treated and / or prevented by the following Pathogens or mixtures of the following pathogens: Micrococcaceae, like staphylococci; Lactobacteriaceae such as streptococci; Neisseriaceae such as Neisseria; Corynebacteriaceae such as Corynebacteria; Enterobacteriaceae such as Escherichiae bacteria the Coli group, Klebsiella bacteria, e.g., K. pneumonia; Proteae bacteria of the Proteus group, e.g., Proteus vulgarist Salmonella bacteria, e.g., S. thyphimurium; Shigella bacteria, e.g. Shigella dysenteriae, Pseudomonas bacteria, e.g. Pseudomonas aeruginosat Aeromonas bacteria, e.g. Aeromonas lique faciens.

Spirillaceae such as Vibrio bacteria e.g. Vibrio cholerae; Parvobacteriaceae or Brucellaceae such as Pasteurella bacteria; Brucella bacteria, e.g. Brucella abortus; Oiaemophilus bacteria, e.g., Haemophilus influenzae; Bordetella Bakeries, e.g., Bordetella pertuss is Moraxella bacteria, e.g., Moraxella lacunata; Bacteroidaceae, such as Bacteroides bacteria; Fusiform bacteria, e.g., Fusobacterium fusiforme; Sphaerophorus bacteria, e.g., Sphaerophorus necrophorus; Bacillaceae, such as aerobic spore formers, e.g., Bacillus anthracis; anaerobic spore-forming chlostridia, e.g., Chiostridlum perfringens; Spirochaetaceae, such as Borrelia bacteria; Treponema bacteria, e.g., Treponema pallidum; Leptospira bacteria, like Leptospira interrogans.

The above list of pathogens is only exemplary and by no means to be understood as restrictive.

lgde typical representatives of the penicillins according to the invention show one particularly good effectiveness, where in the general formulas I and I ', n the number 2, E a hydrogen atom and R a hydrogen atom, the cyclopropyl-, 2-methyl-cyclopropyl- (1) -, thylamino, propylamino, isopropylamino, allylamino, isobutylamino, 3'-methylallylamino, Propargylamino, Cyclopentylamino, cyclohexylamino, 2'-hydroxyethylamino, 3'-hydroxypropylamino, 4'-hydroxy-cyclohexylamino, 2'-hydroxypropylamino, 2'-methoxyethylamino, p-hydroxyanilino, p-chloroanilino, p-methoxy-benzylamino, m, p-dimethoxybenzylamino, 3-pyridylmethylamino, 3-pyridylamino, 5-pyrimidinylamino, 5-pyrimidinylmethylamino, 2-methyl-5-thienylamino, 2-thienylmethylamino, 2-furylmethylamino or 2-pyrrolylmethylamino group mean.

The studies on the antibacterial effectiveness in vitro was made after the agar diffusion test and after the serial dilution test based on P. Klein's Bacteriological Basics of Chemotherapeutic Laboratory Practice ", Springer-Verlag 1957, pages 53 to 76 and 87 to 109, described methodology carried out. It was found that the compounds mentioned in the above list of general formulas I and I 'z. Partly still in concentrations of <1 0 pg / ml against Escherichia coli and <5 pg / ml against Pseudomonas aeruginosa and Klebsiella pneumoniae are effective.

Furthermore, excellent effects, e.g. against Proteus vulgaris, Proteus mirabilis, Serratia marcescens and Enterbacter cloaceae were found. the But compounds also work against a number of other germs, those against other penicillins are resistant.

The high in vitro activity could also be confirmed in vivo. The ED50 was one of the above-mentioned compounds in an intraperitoneal E. coli infection in albino mice of the strain MNRI determined. The first day was treated three times (for the first time 1 hour after infection) and twice for 2 more days.

For the connection of the general formulas I and I ', in which n the Number 2, E is a hydrogen atom and R is the 2'-furylmethylamino group infected with E.

coli strain ATCC 11 775 had an ED50 of less than 5 mg / kg subcutaneous application.

The compounds of the general formulas I and I 'are further distinguished characterized by a high level of tolerance. Even at dosages of 2 g / kg, No harmful side effects were observed in test mice.

Ls is another object of the present invention, pharmaceutical To create means useful in the treatment of infectious diseases both in humans as well as are valuable in animals.

Preferred pharmaceutical preparations are tablets, coated tablets, Capsules, granules, suppositories, solutions, suspensions, emulsions, ointments, gels, Called creams, powders and sprays. It is used advantageously in human or veterinary medicine the active ingredient or a mixture of the various active ingredients of the general formulas I or It in a dosage between 5 and 500, preferably 10-200 mg / kg of body weight administered every 24 hours, if necessary in the form of several single doses. A single gift 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 required be to deviate from the dosages mentioned, depending on the Type and weight of the object to be treated, the type and severity of the Disease, the type of preparation and the application of the drug as well as the time period or interval within which the administration takes place. So can In some cases it may be sufficient with less than the above amount of active ingredient get along, while in other cases the amount of active ingredient above is exceeded must become. Determining the optimal dosage and type of application required in each case the active ingredients can easily be made by any person skilled in the art on the basis of his specialist knowledge.

In the case of parenteral administration, it is preferred that the invention Penicillin compound in a non-toxic liquid medium for injections to dissolve and inject the solution intramuscularly, intravenously or subcutaneously.

It is also possible to use the penicillin compound of the invention in to dissolve in a non-toxic liquid medium or in an ointment base or mix with it, and apply the solution or mixture directly to the damaged Place to raise. The compounds can also be used as suppositories after mixing to be used with a basis for suppositoxes or after dissolving in it.

Examples of non-toxic liquid media used to manufacture of injectable preparations containing the penicillin compound as an active ingredient, Can be used are sterilized deionized water, physiological Saline solution, glucose solution for injection, Ringer's solution, and amino acid solution for injection.

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

The penicillin compounds according to the invention are used for oral administration used in the form of a pharmaceutical preparation containing the compound (s), optionally in admixture with pharmaceutically acceptable carriers, such as a organic or inorganic solid or liquid excipient, which is suitable for the oral administration, contains. If desired, these preparations can also Contain auxiliary substances, stabilizers and other commonly used additives.

In the case of application as a feed additive, the new compounds in the usual concentrations and preparations along with be given with the feed or with feed preparations or with the drinking water. This can prevent infection by gram-negative or gram-positive bacteria, be improved and / or cured and also a promotion of growth and a Improvement in the utilization of the feed can be achieved.

The penicillins according to the invention can be used for the purpose of enlargement of the spectrum of activity and an increase in activity, especially in the case of ß-lactamase-forming Achieve bacteria with other antimicrobial agents, e.g. with penicillinase-resistant Penicillins are combined. Oxacillin or dicloxacillin are particularly suitable for this. Furthermore, the penicillins according to the invention can be combined with β-lactamase inhibitors such as e.g. Clavulanic acid can be combined.

The penicillia according to the invention can be used for the purpose of enlargement the spectrum of action and to achieve an increase in effectiveness also with aminoglycoside antibiotics, such as.

Gentamicin, sisomicin, kanamicin, amikacin or tobramicin combined will.

The invention thus also relates to a medicament which at least an inventive penicillin derivative of the general formulas I or I 'or a pharmaceutically acceptable salt thereof and optionally an aminoglycoside antibiotic or a pharmaceutically acceptable acid addition salt thereof, optionally in Mixture with a pharmaceutically acceptable carrier or diluent contains.

The following examples are intended to explain the invention in more detail: All NMR spectra were recorded in a mixture of deuterated dimethyl sulfoxide and perdeuterated Methanol added.

Example 1 Sodium 6-T1- / 3 1- / 3- (2-cyclopropyl-4-hydroxy-5-pyrimidinyl) ureido / cyclohexylcarboxamido penicillinate 9.1 g of 5-amino-2-cyclopropyl-4-hydroxypyrimidine (0.06 mol) are added with heating dissolved in 300 ml of absolute tetrahydrofuran and mixed with 8.25 ml of tristhylamine. At OOC, this solution becomes a solution of 6.1 g of phosgene in 200 ril absolute Tetrahydrofuran was added dropwise. The mixture is then stirred for about 30 minutes while cooling with ice. Afterward nitrogen is blown through the solution to remove unreacted phosgene.

20.5 g of anhydrous ciclacillin are suspended in 700 ml of aqueous 80 Figem tetrahydrofuran and cools down to OOC. Then enough triethylamine is added that a solution arises.

The suspension prepared above is added dropwise within 30 minutes, the pH value is kept at 7.5 with triethylamine. You bet another 100 ml of water zu.und keeps the reaction mixture for one hour at 0-20C. The cooling will removed and it is stirred for one hour at room temperature.

250 ml of water are then added and the tetrahydrofuran is removed Vacuum. The remaining water phase is washed twice with 100 μl of ethyl acetate washed. It is diluted to 1 l with ice water and slowly added with constant stirring 2N hydrochloric acid up to pH 2.0, the temperature being kept below 50C. The unusual one Product is filtered off with suction, washed with a little ice-cold water and dried in vacuo.

A methanolic solution of the calculated amount of sodium hexanoate is then added to, whereby a solution is obtained.

When ether is added, the desired product falls as a colorless one Powder off.

Yield: 23.9 g sodium salt (74%) IR spectrum: 1770, 1655, 1610, 1545 cm; Nuclear Magnetic Resonance Spectrum signals at ppm: 0.85-2.1 (m, lH), 4.05 (s, lli), 5.40 (q, 2H), 8.40 (s, 1H).

Using this method, starting from 6-41-aminocyclohexyl) -carboxymido] penicillanic acid synthesized the following penicillins: Example 2 Sodium 6- {1- [3- (4-hydroxy-5-pyrimidinyl) -ureido] -cyclohexylcarboxamido} penicillinate With the reaction product of 5-amino-4-hydroxypyrimidine and phosgene.

Yield: 56.5% -1 IR spectrum: 1770, 1665, 1610, 1550 cm; NMR spectrum Signals at ppm: 1.1-2.0 (m, 16H), 4.0 (s, 1N), 5.4 (q, 2H), 8.3 (s, 1Ii), 8.55 (s, 1H).

Example 3 Sodium 6- {1- [3- (2- (2'-methylcyclopropyl) -4-hydroxy-5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillinate tlit the reaction product of 5-Amio-2- (2'-methylcyclopropyl) -4-hydroxypyrimidine and phosgene.

Yield: 61%. IR spectrum: 1770, 1660, 1610, 1545 cm -1 NMR spectrum Signals at ppm: 0.85-2.0 (m, 22H), 2.1 (m, 1H), 4.05 (s, 1H), 5.45 (q, 2H), 8.45 (s, 1H).

Example 4 Sodium 6- {1- [3- (2-allylamino-4-hydroxy-5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillinate 01 with the reaction product of 5-amino-2-allylamino-4-hydroxypyrimidine with phosgene.

Yield: 64.5% IR spectrum: 1770, 1669, 1615, 1550 cm NMR spectrum Signals at ppm: 1.15-2.05 (m, 16H), 3.9 (m, 2H), 4.0 (s, 1H), 5.0-5.5 (m, 4H), 5, 85 (m, 1H), 8.1 (s, 1H).

Example 5 Sodium 6- {1- [3- (4-hydroxy-2-propargylamino-5-pyrimidinyl) ureido] cyclohexylcarboxamido] penicillinate With 5-amino-4-hydroxy-2-propargylamino-pyrimidine and phosgene.

Yield: 57% IR spectrum: 1765, 1650, 1615, 1540 cm NMR spectrum-6- {1- [3- (4-hydroxy-2-propylamino-5-pyrimidinyl) -3.95 (s, 1H) , 4.1 (broad s, 2H), 5.45 (q, 2H), 8, a5 (s, 1H).

Example 6 Sodium 6- {1- [3- (4-hydroxy-2-propylamino-5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillinate With 5-amino-4-hydroxy-2-pyropylamino-pyrimidine and phosgene.

Yield: 69.5% IR spectrum: 1770, 1655, 1610, 1545 cm; NMR spectrum Signals at ppm: 1.1-2.0 (m, 21H), 3.3 (q, 2H), 4.0 (s, 1H), 5.40 (q, 2H), 8.10 (s, 1H).

Example 7 Sodium-6 - / 3- (4-hydroxy-2-isopropylamino-5-pyrimidinyl) -ureido] -cyclohexylcarboxamido} penicillinate With 5-amino-4-hydroxy-2-isopropylamino-pyrimidine and phosgene.

Yield: 71% IR spectrum: 1770, 1655, 1610, 1540 cm; NMR spectrum Signals at ppm: 1.15-2.0 (m, 22H), 3.65 (m, 1H), 4.0 (s, 1fl), 5.4 (q, 2H), 8.15 (s, 1H) Example 8 Sodium 6- {1- [3- (4-hydroxy-2-isobutylamino-5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillinate With 5-amino-4-hydroxy-2-isobutylamino-pyrimidine.

Yield: 63% IR spectrum: 1765, 1655, 1610, 1545 cm; NMR spectrum Signals at ppm: 1.0 (d, 6H), 1.15-2.0 (m, 17H), 3.15 (m, 21I), 4.0 (s, 1H), 5.40 (q, 2H), 8.15 (s, 1H) Example 9 Sodium 6- {1- [3- (2-cyclopentylamino-4-hydroxy-5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillinate With 5-amino-2-cyclopentylamino-4-hydroxypyrimidine in 74.5% yield.

IR spectrum: 1770, 1660, 1615, 1550 cm-1; NMR spectrum signals at ppm: 1.15-2.25 (m, 24H), 3.8 (broad signal, 1H), 4.05 (s, 1lI), 5.40 (q, 2H), 8.25 (p. 111).

The following were prepared analogously: Sodium 6-t 3- (2-cyclohexylamino-4-hydroxy-5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillinate, Sodium 6-1- / ~ 3- (2-acetylamino-4-hydroxy-5-pyximidinyl) -ureido] -cyclohexylcarboxamido} penicillinate, Sodium 6- / 3- (2-anilino-4-hydroxy-5-pyrimidinyl) ureido7-cyclohexylcarboxamido} penicillinate; Sodium 6- {1- [3- (2-p-chlorobenzylamino-4-hydroxy-5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillinate; Sodium 6- {1- [3- (2-p-chlorobenzylamino-4-hydroxy-5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillinate; Example 10 Sodium 6 »- (4-hydroxy-2-p-methoxybenzylamino-5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillinate, With 5-amino-4-hydroxy-2-p-methoxybenzylamino-pyrimidine in 68% yield.

IR spectrum: 1770, 1660, 1610, 1540 cm 1s NMR spectrum signals at ppm: 1.2-2.0 (m, 16H), 3.70 (s, 3fl), 4.05 (s, 1H), 4.15 (s, 2H), 5.45 (q, 2H) , 6.9 (d, 2H), 7.5 (d, 2H), 8.25 (s, 1Jf).

Example 11 Sodium 6- {1- [3- (2-p -chlorobenzylamino-4-hydroxy-5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillinate; With 5-amino-4-hydroxy-2-p-hydrobenzylamino-pyrimidine in 44% yield.

IR spectrum: 1770, 1655, 1615, 1545 cm; NMR spectrum signals at ppm: 1.2-2.0 (m, 16H), 4.05 (s, 1H), 4.2 (broad s, 2H), 5.4 (q, 2H), 6.8 (d, 2H ), 7.3 (d, 2H), 8.25 (s, 1H).

Example 12 Sodium 6 "3- (2-p-chloroanilino-4-hydroxy-5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillinate, With 5-amino-2-p-chloroanilino-4-hydroxypyrimidine in 52% yield.

IR spectrum: 1765, 1650, 1610, 1550 cm NMR spectrum signals at ppm: 1.15-1.95 (m, 16H), 4.10 (s, 1H1, 5.35 (q, 2H), 7.35 (d, 2H), 7.85 (d, 2H), 8, 40 (s, 1H), Example 13 Sodium 6- {1- [3- (2- (2'-methoxyethylamino) -4-hydroxy-5-pyrimidinyl) -ureido7-cyclohexylcarboxamidopenicillinate With 5-amino-2- (2'-methoxyAthylamino) -4-hydroxypyrimidine in 66% yield.

-1 IR spectrum: 1770, 1655, 1615, 1555 cm NMR spectrum Signals at ppm: 1.10-1.95 (m, 16H), 3.3 (s, 3H), 3.5 (m, 4H), 4.05 (s, 1H), 5.40 (q, 2H), 8.15 (s, 1H).

Example 14 Sodium 6- {1- [3- (2- (4'-hydroxycyclohexylamino) -4-hydroxy-5-pyrimidinYl) ureido7-cyclohexylcarboxamido-peniclllinate With 5-amino-2- (4'-hydroxycyclohexylamino) -4-hydroxypyrimidine in 51% yield.

-1 IR spectrum: 1770, 1660, 1610, 1545 cm t NMR spectrum signals at ppm: 1.1-2.2 (m, 24H), 3.7 (m, 2H), 4.05 (s, 1H), 5.40 (q, 2H), 8.15 (s, 1H ).

Example 15 Sodium 6-t1- / 3- (2- (32-hydroxypropylamino) -4-hydrOxy-5-pyrimidinyl) -ureidq7-cyclohexylcarboxamidolpenicil linate With 5-amino-4-hydroxy-2- (3'-hydroxypropylamino) -pyrimidine in 52% yield.

-1 IR spectrum: 1765, 1655, 1610, 1550 cm NMR spectrum signals at ppm: 1.1-2.0 (m, 18H), 3.2-3.8 (m, 4H), 4.05 (s, 1H), 5.40 (q, 2H), 8.05 ( s, 1H).

Example 16 Sodium 6- {1- [3- (4-hydroxy-2- (3'-pyridylmethylamino) -5-pyrimidinyl) ureido7-cyclohexylcarboxamidogpenicillinate With 5-Amino-4-hydroxy-2- (3'-pyridylmethylamino) pyrimidine in 55.5% yield.

IR spectrum: 1765, 1640, 1610, 1560 cml t NMR spectrum signals at ppm: 1.1-1.95 (m, 16H), 3.95 (s, 1H), 4.55 (s, 2H), 5.40 (q, 2H), 7.2 (m, 1H) , 7.6 (m, 1H), 8.0 (s, 1H), 8.3 (m, 2H) Analog was prepared: Sodium 6- {1- [3- (4-hydroxy-2- (2'-pyridylmethylamino) -5-pyrimidinyl) - ureido7-cyclohexylcarboxami8o) penicillinate Example 17 Sodium 6- {1- [3- (4-hydroxy-2- (3'-pyridylamino) -5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillinate With 5-amino-4-hydroxy-2- (3'-pyridylamino) pyrimidine in 61% yield.

IR spectrum i 1770, 1645, 1615, 1560 cm-1, NMR spectrum signals at ppm: 1.2-2.0 (m, 16H), 4.05 (s, 1H), 5.40 (q, 2H), 7.4 (1H), 8.2 (m, 3H), 8 , 8 (s, 1H).

Example 18 Sodium 6- {1- [3- (4-hydroxy-2- (2'-pyridylamino) -5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillinate With 5-amino-4-hydroxy-2- (2 | -thienylmethylamino) pyrimidine in 60% yield.

IR spectrum: 1765, 1660, 1620, 1560 cm -1 NMR spectrum Signals at ppm: 1.15 -2.05 (m, 16H), 4.0 (s, 1H), 4.5 (s, 2H), 5.35 (q, 2H), 6.8 (m, 2H), 7.35 (m, 1H), 8.1 (s, 1H).

Example 19 Sodium 6- {1- [3- (4-hydroxy-2- (5'-methyl-2'-thienylamino) -5-pyrimidinyl) ureido] -cyclohexylcarboxamido} penicillinate With 5-amino-4-hydroxy-2- (5'-methyl-2'-thienylamino) pyrimidine in 47% yield.

IR spectrum: 1765, 1655, 1610, 1550 cm-1, NMR spectrum signals at ppm: 1.1-2.1 (m, 16H), 2.55 (s, 3H), 4.05 (s, 1H), 5.35 (q, 2H), 6.5 (m, 2H) , 8.1 (s, 1H), Example 20 Sodium 6- {1- [3- (2- (2'-furylmethylamino) -4-hydroxy-5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillinate With 5-amino-2- (2'-furylmethylamino) -4-hydroxypyrimidine in 68% yield.

IR spectrum: 1770, 1660, 1620, 1550 cm-1; NMR spectrum signals at ppm: 1.1-2.05 (m, 16H), 3.95 (s, 1H), 4.4 (broad s, 2H), 5.40 (q, 2H), 6.3 (m, 2H ), 7.5 (m, 1H), 8.0 (s, 1H).

The following was prepared analogously: Sodium 6- {1- [3- (4-hydroxy-2- (5'-thienylmethylamino) -5-pyrimidinyl) ureido / cyclohexylcarboxamido penicillinate.

Example 21 Pivaloyloxymethyl 6- {1- [3- (4-hydroxy-2- (4'-hydroxycyclohexylamino) -5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillinate 615 mg (0.001 mol) of the compound of Example 14 are suspended in 10 ml of acetone. A solution of 170 mg of pivaloyloxymethyl chloride (0.0011 mol) in 10 ml of acetone is added, and 0.1 ml of a 25% sodium iodide solution in water.

The mixture is then refluxed for 5 hours, cooled and mixed with 15 ml of ice water. It is decanted and the precipitated product again with 10 ml of ice water are added and the mixture is stirred for a short time. Then the colorless one is sucked off Product dissolved in ethyl acetate, with water, sodium hydrogen carbonate solution and washed again with water and then dried in vacuo.

Yield: 420 mg (60%) IR spectrum: 1770, 1700, 1650, 1610 cm t NMR spectrum (CDCl3 + CD30D) signals at ppm: 1.1-2.1 (m, 33H), 3.8 (m, 2H), 4.15 (s, 1H), 5.40 (q, 2H), 5.65 (dd, 2H), 8.1 (s, tH).

The following examples relate to pharmaceutical preparations, which compounds of general formula I contain: Example A Containing tablets Sodium 6- {1- [3- (2- (2'-furylmethylamino) -4-hydroxy-5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillinate A mixture consisting of 2 kg of active ingredient, 5 kg of lactose, 1.8 kg of potato starch, 0.1 kg of magnesium stearate and 0.1 kg of talc is pressed into tablets in the usual way, such that each tablet contains 200 mg of active ingredient.

Example B Dragees containing sodium 6 »/ 3- (2- (2'-furylmethylamino) -4-hydroxy-5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillinate In the same way as in Example A, tablets are pressed, which are then used in the usual manner a coating consisting of sugar, potato starch, talc and tragacanth coated will.

Example C Capsules containing sodium 6- / 3- (2- (2'-furylmethylamino) -4-hydrOxy-5-pyrimidinyl) -ureido7-cyclohexylcarboxamido} penicillinate 5 kg of active substance are in the usual way in hard gelatin capsules filled in such a way that each capsule contains 500 mg of the active ingredient.

Example D Dry ampoules containing sodium 6- {1- [3- (2- (2'-furylmethylamino) -4-hydroxy-5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillinate In An aseptic area was 251 g of active ingredient in 2008 ml of distilled water dissolved for injection. The solution was filtered through a Millipore filter (pore size 0.22 µm, product of Millipore Corporation, Bedford, USA). The solution each was poured in an amount of 2.0 ml into 1000 vials (capacity 10 ml) and it was lyophilized. The tabs were then tied with a rubber stopper and sealed with an aluminum cap. Thus, tabs (No. A) were each with 250 mg of active ingredient received.

A physiological saline solution for injection was given in an amount of 2.0 ml each filled into ampoules and the ampoules were sealed. on ampoules (No. B) were obtained in this way. The physiological saline solution in the ampoules for B) was poured into the vial (No. A), making an injectable Preparation for intravenous administration was obtained.

Distilled water for injection was added in an amount of 20 ml Poured into the vesicles (No. A) and the solution was in a 5% solution of Dissolved glucose for injections (250 ml). In this way solutions were found for the continuous infusion established.

Similarly, tablets, coated tablets, capsules and ampoules are available that one or more of the other active ingredients of the formula I or the physiologically harmless ones Contain salts of these compounds.

Claims (10)

Claims: 1) New penicillins of the general formulas in which n is the numbers 1 or 2, R is a hydrogen atom, a methyl or ethyl group, the cyclopropyl radical, which can optionally be substituted by one or two methyl groups or an ethyl group or a phenyl group, the cyclobutyl radical, the hydroxyl group, the methoxy or ethoxy group , the mercapto, methyl mercapto or ethyl mercapto group, or a group of the general formula mean, where 1 and R2 can be the same or different and hydrogen atoms, aliphatic, branched or unbranched hydrocarbon radicals, which may contain one or two double bonds or a triple bond and 1 to 6 carbon atoms, cycloalkyl radicals with 3 to 7 carbon atoms, which can contain one or two Methyl groups or ethyl groups can be substituted and can contain one or more double bonds, alkyl groups substituted by a cycloalkyl radical with 3 to 7 carbon atoms in the cycloalkyl and 1 to 3 carbon atoms in the alkyl part, but R1 and R2 together can also represent an alkylene chain with two to 6 carbon atoms form, so that a three to seven-membered heterocyclic ring is formed, which may contain one or two double bonds, R also denotes a group of the general formula NH-ZX, in which Z is a straight-chain or branched alkylene group with 1 to 6 carbon atoms or a by the substituent X denotes a substituted cycloalkyl group having 3 to 6 carbon atoms and X denotes the cyano group, the hydroxyl group, the mercapto group or a group of the general formulas -COR3, -COOR4, -NHCOR3, -NHSO2R3, -OR3, -OCOR31 -SR3, -SOR3 and -SO2R3, where in these formulas ei represent a straight-chain or branched alkyl group with 1 to 4 carbon atoms or the phenyl group and R4 represent hydrogen or an alkyl group with 1 to 4 carbon atoms or R3 and R4, together with the nitrogen atom in between, can also form a 3 to 6-membered monocyclic, heterocyclic ring, R also denotes a group of the general formula in which m the numbers 0 or 1 and one, two or three of the radicals R5, R6, R7 halogen atoms, in particular bromine, chlorine or fluorine atoms, methyl, ethyl, isopropyl, amino, methylamino, dimethylamino, Diethylamino, morpholino, hydroxy, methoxy, ethoxy, nitro, acetylamino, methylsulfonyl, acetyl, methylcarbonyloxy, methoxycarbonyl, carboxyl, aminocarbonyl, methyl and dimethylaminocarbonyl, cyano, methyl rercapto , Methylsulfoxy, methylsulfonyl, aminosulfonyl or trifluoromethyl groups and optionally the other radicals R5, R6 and R7 represent hydrogen atoms, p furthermore represents a group of the general formula -NEl (CH2) mHet in which the radical - (CH2) mHet for the 3-pyridyl, 2-, 3-, or 4-pyridylmethyl, 5-pyrimidinyl, 2-methyl-5-pyrimidinylmethyl, 5-ethoxycarbonyl-2-thienyl, 5-methyl-2-thienyl , 5-ethoxycarbonyl-2-furyl-, 2-thienylmethyl-, 3-thienylmethyl, 5-methyl-2-thienylmethyl-, 5-chloro-2-thienylmethyl-, 2-furylmethyl-, 3-furylmethyl-, 5-nitro -2-f urylmethyl-, 5-methyl-2-furylmethyl- 2-tetrahydrofurylmethyl-, 2-pyrrolylmethyl-, 2-imidazolylmethyl-, 3-methyl-5-pyrazolylmethyl-, 3-methyl-5-isothiazolylmethyl-, 3-methyl-4- isothiazolylmethyl-, 3-isothiazolylmethyl-, 3-methyl-5-isoxazolylmethyl-, 2-thiazolyl-, 4-methyl-2-thiazolyl-, 2-methyl-5-thiazolylmethyl-, 4-methyl-2-thiazolyl-methyl- , 2-thiadiazolylmethyl, 2-methyl-5-triazolylmethyl, 1,3,4-triazol-2-ylmethyl, 1,2, 3-triazol-4-ylmethyl or tetrazolylmethyl group, R also denotes the acetylamino or propionylamino group, E denotes a hydrogen atom or a protective group which can be easily split off in vitro or in vivo, and, if E represents a hydrogen atom, its pharmacologically acceptable salts with inorganic or organic bases. 2) New penicillins of the general formula 1 or I 'according to claim 1, characterized in that in the general formulas I and I' n the number 2 and R is a hydrogen atom, the cyclopropyl group, which are substituted with a methyl or ethyl group can, the hydroxyl group, the methoxy group, a group of the general formula denote, in which R1 has the meanings given above, or a group of the general formula -NH-ZX, in the case of -Njj-Z in particular a group of the formulas and X represents the hydroxy, methoxy, sthoxy, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl, ethyl carbonyl, methyl mercapto or ethyl mercapto group, or in the denotes the 4 '-hydroxycyclohexylamino group; in addition, R can also be a group of the general formula represent, in which m and R5 to R 7 have the meanings given above, R can also represent a group of the general formula -NHtCH2) mHet in which - (CH2) Het represents the 3-pyridyl, the 3-, pyridylmethyl group, 5-pyrimidinyl, 5-pyrimidinylmethyl, 5-sthoxycarbonyl-2-thienyl, 5-methyl-2-thienyl, 2-thienylmethyl, 3-thienylmethyl, 5-chloro-2-thienylmethyl, 5 -Methyl-2-thienylmethyl group, the 2- or 3-furylmethyl group, the 5-methyl-2-furylmethyl group or the 2-pyrrolylmethyl group, and E represents a hydrogen atom or the pivaloyloxymethyl group and if E is a hydrogen atom, their pharmacologically acceptable salts with inorganic or organic bases. 3) New penicillins of the general formulas I or I 'according to claim 1 and 2, characterized in that E in residue X as an in vitro and in vivo easily removable group the benzyl, diphenylmethyl, trityl, t-butyl, 2,2,2-trichloroethyl, Trimethylsilyl, an alkanoyloxyalkyl group with 1 to 5 carbon atoms in the alkanoyl radical and 1 to 3 carbon atoms in the alkylene radical, the phthalidyl or indanyl group means. 4) New penicillins of the general formulas I and I 'according to claim 3, characterized in that E is the acetoxymethyl, propionyloxymethyl, 2-acetoxythyl or represents pivaloyloxymethyl group. 5) New penicillins of the general formulas I and I 'according to the claims 1 to 4, characterized in that the D = R configuration applies to these. 6) 6- {1- [3- (2- (2'-Furylmethylamino) -4-hydroxy-5-pyrimidinyl) ureido] cyclohexylcarboxamido} penicillin and its salts with inorganic or organic bases. 7) Medicines containing one or more compounds according to Claims 1 to 6 in addition to one or more inert carriers and / or auxiliaries. 8) Use of the penicillins according to claims 1 to 6 for the preparation of drugs by non-chemical means. 9) Process for the preparation of new penicillins of the general formulas in which n is the numbers 1 or 2, R is a hydrogen atom, a methyl or ethyl group, the cyclopropyl group, which can optionally be substituted by one or two methyl groups or an ethyl group or a phenyl group, the cyclobutyl group, the hydroxyl group, the methoxy or ethoxy group , the mercapto, methyl mercapto or ethyl mercapto group, or a group of the general formula mean, where R1 and R2 can be the same or different and hydrogen atoms, aliphatic, branched or unbranched hydrocarbon radicals, which may contain one or two double bonds or a triple bond and 1 to 6 carbon atoms, cycloalkyl radicals with 3 to 7 carbon atoms, which can contain one or two Methyl groups or ethyl groups can be substituted and can contain one or more double bonds, alkyl groups substituted by a cycloalkyl radical with 3 to 7 carbon atoms in the cycloalkyl and 1 to 3 carbon atoms in the alkyl part, but R1 and R2 together can also represent an alkylene chain with two to 6 carbon atoms form, so that a three to seven-membered heterocyclic ring is formed, which may contain one or two double bonds, R also denotes a group of the general formula NH-ZX, in which Z is a straight-chain or branched alkylene group with 1 to 6 carbon atoms or a byc h denotes the substituent X substituted cycloalkyl group with 3 to 6 carbon atoms and X denotes the cyano group, the ilydroxy group, the mercapto group or a group of the general formulas -COR3, -COOR4, NHCOP3, -NHSO2R3, -OR3, -OCOR3, -SR3, -SOR3 and -SO2R3, where in these formulas R3 is a straight-chain or branched alkyl group with 1 to 4 carbon atoms or the phenyl group and R4 is hydrogen or an alkyl group with 1 to 4 carbon atoms or R3 and R4, together with the nitrogen atom in between, can also form a 3 to 6-membered monocyclic, heterocyclic ring, R also denotes a group of the general formula in which m is the number 0 or 1 and one, two or three of the radicals Rs, P6, R7 halogen atoms, in particular bromine, chlorine or fluorine atoms, methyl, ethyl, isopropyl, amino, methylamino, dimethylamino, Diethylamino, morpholino, hydroxy, methoxy, ethoxy, nitro, acetylamino, methylsulfonyl, acetyl, ethylcarbonyloxy, methoxycarbonyl, carboxyl, aminocarbonyl, methyl and dimethylaminocarbonyl, cyano, methyl mercapto , Methylsulfoxy, methylsulfonyl, aminosulfonyl, or trifluoromethyl groups and, if appropriate, the other radicals R5, R6 and R7 represent hydrogen atoms, furthermore means a group of the general formula -NH (CEl2) mHet in which the radical - (CH2) Het for the 3-pyridyl, 2-, 3-, or 4-pyridylmethyl, 5-pyrimidinyl, 2-methyl-5-pyrimidinylmethyl, 5-ethylcarbonyl-2-thienyl, 5-methyl-2-thienyl , 5-ethoxycarbonyl-2-furyl-, 2-thienylmethyl-, 3-thienylmethyl-, 5-methyl-2-thienylmethyl-, 5-chloro-2-thienylmethyl-, 2-furylmethyl-, 3-furylmethyl-, 5-nitro-2-fu rylmethyl-, S-methyl-2-furylmethyl-, 2-tetrahydrofurylmethyl-, 2-pyrrolylmethyl-, 2-imidazolylmethyl-, 3-methyl-5-pyrazolylmethyl-, 3-methyl-5-isothiazolylmethyl-, 3-methyl-4 -isothiazolylmethyl-, 3-isothiazolylmethyl-, 3-methyl-5-isoxazolylmethyl-, 2-thiazolyl-, 4-methyl-2-thiazolyl-, 2-methyl-5-thiazolylmethyl-, 4-methyl-2-thiazolyl-methyl -, 2-thiadiazolylmethyl, 2-methyl-5-triazolylmethyl, 1,3,4-triazol-2-ylmethyl, 1,2, 3-triazol-4-ylmethyl or tetrazolylmethyl, R also denotes the acetylamino - Or propionylamino group, and E is a hydrogen atom or a protective group which can be easily cleaved in vitro or in vivo and, if E is a hydrogen atom, salts thereof with inorganic or organic bases, characterized in that a compound of the general formula in which n has the meaning given above, with a pyrimidine derivative of the general formula in which R is as defined at the outset and B is the -N = CO or -NHCO-Hal group or the group represents, where Hal is a halogen atom, or with mixtures of such pyrimidine derivatives of the general formula II, in which D has partly one and partly the other of the meanings mentioned above, in a solvent and with a pII range between 2.0 and 9, 0 is reacted at temperatures between -2O0C and + 500C, and, if desired, then, a compound of the general formula I prepared in this way, in which E is a protective group that can easily be split off in vitro, into the free carboxylic acid of the general formula I in which E n Hydrogen atom is converted and / or a compound of the general formula I, in which E denotes a hydrogen atom, is converted into ore esters or, by means of inorganic or organic bases, into the corresponding salts. 10) Method according to claim 9, characterized in that a connection of the general formula II, in which E is hydrogen, or one of its salts with inorganic or organic bases with a compound of the general formula III, a) in water or in water-miscible solvents in the presence of Water in a pH range from 6.5 to 8.0, or b) in anhydrous solvents or c) in a mixture of water and water-immiscible solvents is reacted in a pH range between 6.5 and 8.0, or that a compound of the general formula II, in which E is a silyl group or another easily cleavable group Protective group means with a compound of the general formula III in one anhydrous and hydroxyl group-free or aprotic solvents, if appropriate in the presence of a base.