CS226028B2 - Method of preparing cephalosporine derivatives - Google Patents

Description

The present invention provides a process for making cephalosporin derivatives having antibacterial properties.

The vast majority of therapeutically useful antibiotics on the basis of the penieilin and cephalosporin ring systems carry at position 60 and 60 respectively. 70 acylamino. A large number of other substituents at these positions have been investigated, but the resulting compounds, at best, showed only weak antibacterial activity. An exception to this generalization is the amidine substituent. Penicillin derivatives carrying a 6'-position substituted amidine residue (see, for example, British Patent Nos. 1,315,566 and 1,406,732) have been found to have useful antibacterial activity and two of these compounds, mecillinam and pivmecillinam, are found. on the market. In contrast, however, it has been found that cephalosporin derivatives bearing the corresponding amidine residue at position 70 (see DOS No. 2,430,375) surprisingly have only low antibacterial activity (see FJ Lund, 6 ' -Amidino Penicilnic Acids - Synthesis and Antibacterial Properties in Lactam Antibiotics, ed. J. Elks, The Chemical Society Special Publication No. 28, London 1977, pp. 42-43, and J. Altman et al., J. Med. Chem., 1975, 16 (627-630).

It has now been found that the introduction of a guanidine residue in the 7-beta-cephalosporin core position in which two of the nitrogen atoms are linked by two carbon bridges to form a 2-imidazoline or imidazole ring produces compounds with remarkable antibacterial properties.

Accordingly, the invention provides a process for the preparation of cephalosporin derivatives of formula (I)

in which

R ¹ represents hydrogen or chlorine atom, a methyl group, an acetoxymethyl group,

-methyl-1H-tetrazol-5-ylthiomethyl, 1-carboxymethyl-1H-tetrazol-5-ylthiomethyl, 1- (2-dimethylamino) ethyl-1H-tetrazol-5-ylthiomethyl, 1-sulfomethyl-1H-tetrazol 5-ylthiomethyl, 1-isopropyl-1H-tetrazol-5-ylthiomethyl,

1- (2,2,2-trifluoro) ethyl-11H-tetrazol-5-ylthiomethyl, 1-phenyl-1H-tetrazol-5-ylthiomethyl, 1- (2-methylthio) ethyl-1H-tetrazole- 5-ylthiomethyl, 1,3,4-thiadiazol-2-ylthiomethyl, 5-methyl-1,3,4-thiadiazol-2-ylthiomethyl,

1,2,3-thiadiazol-5-ylthiomethyl, 1H-1,2,3-triazol-4-ylthiomethyl, 5-trifluoromethyl-1H-1,2,4'-triazol-3-ylthiomethyl, 4,6 -dimethylpyrimid-2-ylthiomethyl, 2-thiazolin-2-ylthiomethyl, benzoxazol-2-ylthiomethyl, benzthiazol-2-ylthiomethyl, 2-carboxyphenylthiomethyl, (6-carboxymethyl-7-hydroxypyrrolo [-1,2] b) ] pyridazin-2-yl) thiomethyl, methoxymethyl, hydroxymethyl, azidomethyl, aminomethyl, benzoyloxymethyl, acetylaminomethyl, carbamoyloxymethyl,

2-methylthio-1,3,4-thiadiazol-5-ylthiomethyl, 2-mercapto-1,3,4-thiadiazol-5-ylthiomethyl, 2-acetylamino-1,3,4-thiadiazol-5-ylthiomethyl , 5-methyl-1,2,4-thiadiazol-2-ylthiomethyl, 2-sulfomethyl-1,2,4-oxadiazol-5-ylthiomethyl, 4-methyl-5- (3-carboxypropyl) thiazole-2- ylthiomethyl, 2H-2-methyl-1,2,3-triazol-4-ylthiomethyl, 1H-1,2,4-triazol-2-ylthiomethyl,

4,5-dihydro-6-hydroxy-4-methyl-5-oxo-1,2,4-triazin-3-ylthiomethyl, 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1 2,4-triazin-3-ylthiomethyl, 1-oxidopyrid-2-ylthiomethyl, imidazole [4,5-b] pyridin-2-ylthiomethyl or imidazo [4,5-d] pyrimidin-2-ylthiomethyl,

R represents a carboxyl group or a radical of formula

COOCHgOCOR ^{1 0} r'® wherein denotes methyl, ethyl or tert-butyl, ·

or R is a radical of formula

COOCH ₂ COCH ₃ or coo represents a hydrogen atom, a hydroxyl group, a methyl group, a methoxy group, an acetyl group or a 4-methoxybenzyl group and

A is a radical of formula II or III

R *

(II) (III) wherein each of R ^ and R ^, which may be the same or different, each represents a hydrogen atom, a cyano group, a hydroxyl group, a carboxyl group, a methyl group, a hydroxymethyl group, a 3-hydroxypropyl group, an ethoxycarbonyl group , phenyl, aminomethyl, 2-hydroxypropyl, propyl, butyl or 3-aminopropyl, or _and R ⁵ are taken together to form a cyclohexene, benzene, naphthalene C 1 dihydroacenaphthalene ring together with the carbon atoms to which they are attached wherein the benzene ring is optionally substituted with one or two substituents selected from the group consisting of fluorine and chlorine atoms, hydroxyl group, amino group, carboxyl group, nitro group, methyl group, methoxy group, trifluoromethyl group, hydroxymethyl group, aminomethyl group, acetylamino group, azidomethyl group, acetylamino group group, k yanomethyl and carbsaoylmethyl, and residues of formulas IV, V and VI

CH ₂ -N = CH-N 2 R 2 ^{, CH} 2 e (IV)

CH 2 COCH 3 H 2 (V)

CH 2 COCHCPh 3 NH 4 (VI) wherein

Ph represents a phenyl group and ao and o each of fi, R, R and R, which may be the same or different, each represents a hydrogen atom, a hydroxymethyl group, an aminomethyl group, a carbamoyl group, a methoxy carbonyl group, a methyl group, a n-hexyl group , a phenoxymethyl group, optionally substituted with a diphenylmethyl group, or a phenyl group, optionally substituted with one or two substituents selected from the group consisting of fluorine and chlorine atoms, cyano, hydroxyl, phenyl and dimethylamino;

R and R, when in cis arrangement, are joined together and together with the carbon atoms to which they are attached to form a cyclopropane, cyclobutane, cyclopentene or cyclohexene ring, or g 7 fi O

R is a carboxyl group and R, R and R are hydrogen, and the pharmaceutically acceptable acid or base addition salts of those compounds of formula I that contain free basic or acidic groups;

R ² (VII) wherein

2

R and R are as defined above, reacted with a compound of formula VIII

R ¹⁸ (VIII) in which ^ ***

H and are as defined above and

5

R is halogen, whereupon the optionally obtained compound of formula I containing a free acid group is converted by treatment with a base giving a pharmaceutically acceptable cation to its base addition salt or the obtained compound of formula 1 containing a free base group is optionally converted by reaction e an acid providing a pharmaceutically acceptable anion to its acid addition salt.

It should be noted that in the above general formula (I) and throughout this specification, the stereochemistry of the 3-cephem core of general formula (X) is an absolute configuration. It should further be emphasized that while in formulas I, II and IV the double bond (or double bonds) is always drawn in a certain position, there may be other tautomeric forms in some cases and that these tautomeric forms are also within the scope of the invention. It should be noted, however, that the β-double bond between the carbons bearing the substituents R ¹ and R ² has a fixed position. It should also be noted that when the compounds of formula I contain both an acidic and a basic center, they may exist in the form of a zwitterion.

When A @ 1 is a radical of the aforementioned formula (111), such a compound of formula (I) optionally contains one or two carbon atoms each bearing unequal atoms or radicals R @ 1 and R @ 2, respectively. In the presence of one such carbon atom, R @ 1 and R @ 2 exist in two diastereomeric forms. In the presence of two such carbon atoms, the compound of formula I exists in four diastereomeric forms. It will be understood that useful properties, as defined below, of these diastereomers may vary and therefore, when A is a radical of formula III, the invention includes a mixture of diastereomers of formula 1 and all individual diastereomers having useful properties, how these individual diastereomers can be obtained and how their biological properties can be determined. Similar conclusions apply if the compound of formula I contains an asymmetric center in another part of the molecule.

5

The symbol R ^y in the starting materials of the general formula (VIII) represents, for example, a halogen atom, preferably fluorine or chlorine. The reaction is preferably carried out in the presence of at least one equivalent of an acid so that the compound of formula VIII is present in protonated form. The reaction may be carried out in the presence of a diluent or solvent, for example ecetonitrile, dimethylformamide or tetrahydrofuran, or a mixture thereof, and may be accelerated or terminated by heating, for example by heating to 70 ° C or the boiling point of the diluent or solvent. The compound of formula (VIII) may conveniently be prepared in situ by reacting the corresponding N-triphenylmethyl derivative with p-toluenesulfonic acid. The compound of formula (VII) is then added to the resulting reaction mixture,

If, according to the invention, a compound of formula (I) is obtained in the form of a free acid or free base, or in the form of a zwitterion, and a salt is to be prepared, the compound of formula (I) is reacted with a base providing a pharmaceutically acceptable cation, or a compound of formula I in free base or zwitterion form is reacted with an acid providing a pharmaceutically acceptable anion. When the compound of the formula I is obtained in the form of the acid addition salt and the corresponding zwitterion is to be prepared, the compound of the formula I in the form of the acid addition salt is reacted with a low molecular weight epoxide such as epoxypropane.

Many of the compounds of formula (VII) used in the process of the invention are known. Those of these new compounds can be prepared from known 7-aminocephalosporin derivatives by standard chemical transformations known in the art of cephalosporin chemistry, for example as described in Example 3.

Many of the compounds of formula (VIII) used in the process of the invention are known. Those of the novel compounds can be prepared by standard chemical transformations known in the chemistry of imidazole and 2-imidazoline, for example as described in Examples 4 and 7.

Specific compounds that can be prepared by the process of the invention are described in the Examples. The following is a group of preferred compounds which can be prepared by the process of the invention:

3-acetoxymethyl-7- (5-hydroxybenzimidazol-2-yl) aminocef-3-em-4-carboxylic acid,

7- (5-hydroxybenzimidazol-2-yl) amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethylcef-3-em-4-carboxylic acid,

3-O- (2-dimethylamino) ethyl-1H-tetrazol-5-yl] thiomethyl-7-imidazol-2-ylaminoceph-3-em-4-carboxylic acid,

3- (1-Methyl-1H-tetrazol-5-yl) -thiomethyl-7-imidazol-2-ylaminoceph-3-em-4-carboxylic acid,

3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-7- (imidazol-2-yl) aminoceph-3-em-4-carboxylic acid,

3- (1H-1,2,3-triazol-4-yl) thiomethyl-7- (imidazol-2-yl) aminoceph-3-em-4-carboxylic acid,

3- (1-carboxymethyl-1H-tetrazol-5-yl) thiomethyl-7- (imidazol-2-yl) aminoceph-3-em-4-carboxylic acid,

7- (imidazol-2-yl) amino-3- (1,3,4-thiadiazol-2-yl) thiomethylcef-3-em-4-carboxylic acid,

7- (imidazol-2-yl) amino-3- (1-methyl-1H-tetrazol-5-yl) thlomethylcef-3-em-4-carboxylic acid; 7- (imidazol-2-yl) amino-3- (1-Sulfomethyl-1H-tetrazol-5-yl) thiomethylceph-3-em-4-carboxylic acid,

7- (imidazol-2-yl) amino-3- (1-isopropyl-1H-tetrazol-5-yl) thiomethylceph-3-em-4-carboxylic acid,

7- (imidazol-2-yl) amino-3-L- (2,2,2-trifluoro) ethyl-1H-tetrazol-5-yl) thiomethylceph-3-em-4-carboxylic acid,

7- (imidazol-2-yl) amino-3-Q- (2-methylthio) ethyl-1H-tetrazol-5-yl] thiomethylceph-3-em-4-carboxylic acid,

7- (imidazol-2-yl) amino-3- (5-trifluoromethyl-1H-1,2,4-triazol-3-yl) thiomethylceph-3-em-4-carboxylic acid,

7- (4-methylimidazol-2-yl) amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethylceph-3-em-4-carboxylic acid,

7- (4-methylimidazol-2-yl) amino-3- (1H-1,2,3-triazol-4-yl) thiomethylceph-3-em-4-carboxylic acid,

7- (4,5-dimethylimidazol-2-yl) amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethylcef-3-em-4-carboxylic acid

3-Acetoxymethyl-7- (4-hydroxymethylimidazol-2-yl) -fflinocef-3-em-4-carboxylic acid,

7- (2-imidazolin-2-yl) amino-3-methylceph-3-em-4-carboxylic acid,

7- (4-phenyl-2-imidazolin-2-yl) amino-3-methylceph-3-em-4-carboxylic acid,

7- [4- (4-cyano) phenyl-2-imidazolin-2-yl] amino-3-methylcef-3-em-4-carboxylic acid,

7- [4- (4-dimethylamino) phenyl-2-imidazolin-2-yl] amino-3-methyl-3-em-4-carboxylic acid,

7- (2,4-diazabicyclo 3,1.0 hex-2-en-3-yl) amino-3-methylceph-3-em-4-carboxylic acid,

7- (2,4-diazabicyclo-3,1,0-hex-2-en-3-yl) amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethylcef-3-em -4-carboxylic acid a

7- (2,4-diazabicyclo-3,1,0-hex-2-en-3-yl) amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethylcef-3-em-4-carboxylic acid as well as pharmaceutically acceptable acid or base addition salts of these compounds.

Suitable acid addition salts of cephalosporin derivatives according to the invention are, for example, salts with hydrochloric, hydrobromic, phosphoric, sulfuric, citric or maleic acids. Suitable base addition salts of cephalosporin derivatives according to the invention are, for example, alkali metal salts (such as sodium or potassium salts), alkaline earth metal salts (such as calcium or magnesium salts), or salts and primary, secondary or tertiary organic amines (such as triethylamine, procaine, dibenzylamine and N, N ¹ -dibenzylethylenediamine, and with other amines used for preparation with cephalosporins).

As mentioned above, the cephalosporin derivatives produced by the process of the invention have antibacterial properties. Thus, the disclosed compounds are useful antibacterial agents, many of which have a broad spectrum of in vitro activity against standard laboratory microorganisms (both gram negative and gram positive) that are used to determine activity against pathogenic bacteria. The antibacterial spectrum and the potency of the respective compound can be determined by a standard assay. The results of such in vitro assays illustrating the biological activity of the three chemical subgroups of the compounds of the invention (imidazoles, benzimidazoles, and 2-imidazolines) are shown in the following table, the antibacterial activity being reported as Minimum Inhibition Concentration (MIC) values use inoculum of about .05 bacteria.

The test compounds correspond to the general formula

Table

Organism Designation MIC jug / ml R ¹ fi ¹ A <R ¹ A <Z H CH ₂ OCOCH _{3 2} ch ₂ eyes ₃ CH ₀ I ² CH _O - ch ₃

Strep .. pyogenes AI 16 2 256 Staph. aureus A6 32 2 > 256 E. ooli A8 0.12 2 8 K. aerogenes AI 0 0.5 4 8 Ent. cloacae AI 3 4 > 64 8 Serratia maresoens AI 6 1 64 32 Proteus mirabilis A18 32 4 256 Ps. aeruginosa A21 > 256 > 64 > 256 Antibacterial Properties compounds produced according to the invention is possible

than normal mouse tests.

Mice are dosed subcutaneously in two individual doses within one day with the compounds listed below. Each of the above dosages represents at least 10 times the maximum effective dose, protecting them 50% of the mice against bacterial infection (ΡΒ ^ θ).

7- (2-imidazolyl) amino-3- (1H-1-methyltetrazol-5-yl) thiomethylceph-3-em-4-carboxylic acid (dose 100 mg / kg);

3-acetoxymethyl-7- (2-imidazolyl) aminoceph-3-em-4-carboxylic acid (dose 100 mg / kg);

3-acetoxymethyl-7- (4-hydroxybenzimidazol-2-yl) aminocef-3-em-4-carboxylic acid (200 mg / kg dose);

3-acetoxymethyl-7- [4- (4-dimethylamino) phenylimidazol-2-yl] amino-alpha-3-em-4-carboxylic acid (dose 100 mg / kg);

There were no clear signs of toxicity or side effects.

Similarly, and to mice, both orally and subcutaneously, at a single dose of 2 g / kg, 7- (2-imidazolyl) amino-3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethylceph-3-em- 4-carboxylic acid. Again, no clear signs of toxicity or side effects were observed.

The cephalosporin derivatives obtainable by the process of the invention may be used in the form of pharmaceutical compositions comprising the cephalosporin derivatives in combination with a non-toxic, pharmaceutically acceptable diluent or carrier.

For example, the pharmaceutical compositions may be in a form suitable for oral, rectal or parenteral administration. For this purpose, they may be formulated in known manner, for example, into tablets, capsules, aqueous or oily solutions or suspensions, emulsions, dispersible powders, suppositories and sterile injectable aqueous or oily solutions or suspensions.

In addition to the cephalosporin derivative of formula (I), the pharmaceutical composition may also contain, or may be administered together with one or more known drugs selected from other clinically used antibacterial agents (such as other beta-lactam derivatives or aminoglycosides), beta-lactamase inhibitors (such as clavulanic acid), renal tubular blockers (such as probenicide), and metabolizing enzyme inhibitors (such as peptidases, such as Z-2-acylamino-3-substituted propenoates).

A preferred pharmaceutical composition is a composition suitable for intravenous, subcutaneous or intramuscular injection, for example a sterile injectable composition comprising between 1 and 10% w / w cephalosporin derivative, or a composition suitable for oral administration in unit dosage form, for example a tablet or capsule containing between 100 mg and 1 g cephalosporin derivative.

The pharmaceutical compositions are normally administered to humans to combat infections caused by bacteria in the same general manner as cephalotin, cefoxitin, cefradine and other known clinically used cephalosporin derivatives, bearing in mind the effectiveness of the cephalosporin derivative produced by the method of the invention in relation to the efficacy of known clinically used cephalosporins. , for appropriate dose determination. Each patient will receive a daily dose of from 0.5 to 50 g, preferably from 0.5 to 10 g of cephalosporin derivative intravenously, subcutaneously or intramuscularly, the active agent being administered one to four times daily. Intravenous, subcutaneous and intramuscular administration is by large injection. Alternatively, intravenous administration may be by continuous infusion over a period of time. Alternatively, each patient may be given a daily oral dose that is approximately equivalent to a daily parenteral dose. Thus, a preferred daily oral dose of the cephalosporin derivative is 0.5 to 10 g, with the respective active agent being administered one to four times daily.

The invention is illustrated by the following non-limiting examples. Spectrum Rates are given in S values relative to tetremethylsilane (<5 = 0) as an internal standard, with signal shapes being denoted by common abbreviations (s = singlet, d = doublet, t = triplet, m = multiplet, w = broad signal ). Temperatures are given in degrees Celsius. The boiling point of petroleum ether used is 47 to 61 ° C unless otherwise stated. Ether means diethyl ether.

In the examples, the cephalosporin derivatives are isolated in the form of salts, either internal salts (zwitterion) or salts with acids such as hydrobromic acid or trifluoroacetic acid. The nature of the isolated salt depends on a number of factors, such as the basicity of the product, the reaction, the reaction conditions, the reaction product treatment and purification conditions, and the nature of the starting material (salt or free base).

He did

This example describes the preparation of a compound of the formula

To a solution of 3 g of p-valoyloxymethyl-3-methyl-7-aminoceph-3-em-4-carboxylate-p-toluenesulfonate in 100 ml of water is added excess sodium bicarbonate, extracted three times with ethyl acetate, the combined extracts are washed with brine and concentrated se. The residue (2 g) is dissolved in 75 ml of acetonitrile and 0.86 g of 2-chloro-2-imidazoline hydrochloride is added. The mixture was stirred at 40 ° C for 5 hours, then filtered and the filtrate was concentrated. After recrystallization of the residue from a mixture of isopropanol and ether, 0.99 g of pivaloyloxymethyl-3-methyl-7- (2-imidazolin-2-yl) aminocef-3-em-4-carboxylate hydrochloride is obtained, the NMR spectrum of which contains perdeuteromethanol. the following signals: 1.2 (s, 9H), 2.15 (s, 3H), 3.55 (dd, 2H), 3.8 (s, 4H), 5.15 (d, 1H), 5, Δ (d, 1H), 5.85 (dd, 2H).

Example 2

To a suspension of pivaloyloxymethyl 7-amino-3-methylceph-3-em-4-carboxylate p-toluenesulfonate in ethyl acetate was added an aqueous solution of 0.336 g sodium bicarbonate with stirring. The organic layer was separated, dried over magnesium sulfate and treated with 1 equivalent of ethereal hydrogen chloride. The mixture is evaporated to dryness and 3 ml of dimethylformamide and 1.218 g of 2-chlorobenzimidazole are added to the residue. The reaction mixture was stirred at 70 ° C for 24 h, then evaporated to dryness, the residue was dissolved in dichloromethane, washed with water, the organic layer was dried and concentrated. The product was purified by chromatography on silica gel using dichloromethane / methanol / acetic acid (98.5: 1: 0.5 v / v / v) as eluent. The resulting oily product is further purified by precipitation from a dichloromethane solution with diisopropyl ether. Pivaloyloxymethyl 7- (2-benzimidazolyl) amino-3-methylceph-3-em-4-carboxylate hydrochloride is obtained in 14% yield as the NMR spectrum contains the following signals (perdeuterodimethylsulfoxide): 1.1 (s, 9H), 2 .05 (s, 3H), 3.65 (quartet, 2H), 4.25-4.8 (quartet, 2H), 4.75 (quartet, 2H), 6.9 to 7.4 (m, 2H ).

The above procedure was repeated except that an equivalent amount of 2-chloro-5-nitrobenzimidazole was used in place of 2-chlorobenzimidazole and the reaction was carried out at 50 ° C. The product was purified by chromatography on silica gel at low temperature using a mixture of dichloromethane and ethyl acetate (70:30 v / v) as eluent, dissolving in dichloromethane, filtering and further chromatography on silica gel at low temperature using a mixture of dichloromethane, ether and methanol. (69: 30: 1 v / v / v) as eluent.

Pivaloyloxymethyl 7- (5-nitrobenzimidazol-2-yl) -3-methylcef-3-em-4-carboxylate was obtained in 25% yield, whose NMR spectrum (perdeuterodimethylsulfoxide) contains the following signals: 1.15 (s, 9H, 2.05 (s, 3H), 3.5 (quartet, 2H), 5.25 to 5.8 (quartet, 2H), 5.8 (m, 2H), 7.35 to 8.0 (m, 3H), 8.5 (m, 1H).

Example 3

Η

NH «

N-CH ₃

COOCH ₂ OC _oc X

HCl

A solution of 0.28 g of acetoxymethyl-7-amino-3- (2-methyl-1,3,4-thiβ-diazol-5-yl) thiomethylleef-3-em-4-carboxylate and 0.1 g of 2-fluoroimidazole hydrochloride in 1 ml of dry dimethylformamide was heated at 60 ° C for 2 hours. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel using dichloromethane / methanol (95: 5 v / v) as eluent. The purified compound was then treated with 1 equivalent of hydrogen chloride in methanol. The hydrochloride is then precipitated by introducing the resulting solution into dry ether. The product, acetoxymethyl 7- (2-imidazolyl) amino-3- (2-methyl-1,3,4-thiadlazol-5-yl) thiomethylcef-3-em-4-carboxylate hydrochloride, has the following IR spectrum ( KBr, cm ^- '): 1780 (br), 1740 (shoulder), 1655 (sharp band), and the following NMR spectrum (deuterated DMSO + TFA): 2.15 (s, 3H) , 2.7 (a, 3H), 3.8 (bs, 2H), 5.3 and 5.8 (quartet, 2H), 7.1 (s, 2H), the other signals being covered by the solvent or misjudge.

The starting ester used in the above process can be prepared as follows:

To a solution of 3 g of sodium iodide in 6 ml of acetone was added 2.17 g of chloromethyl acetate. The mixture was stirred at room temperature for 1 hour and then added to a solution of 4.7 g of sodium 3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-7- (1H-tetrazole-1-). yl) ethylaminocef-3-em-4-carboxylate in 6 mL of dimethylsulfoxide. The mixture was heated at 50 ° C for 5 hours, the acetone was evaporated and the residue was poured into 200 ml of water. A triturate is obtained after trituration, which is filtered off and washed with ether. The crude product was purified by silica gel chromatography eluting with dichloromethane / methanol (95: 5 v / v). The NMR spectrum of the resulting acetoxymethyl ester contains the following signals (perdeuterodimethylsulfoxide + perdeuteromethanol): 2.1 (s, 3H), 2.7 (s, 3H), 3.8 (m, 2H), 4.2 and 4.7 (quartet, 2H), 5.2 (d, 1H), 5.45 (s, 2H), 5.80 (d, 1H), 5.9 (m, 2H), 9.3 (s, 1H).

To a solution of 2.08 g of phosphorus pentachloride in 12 ml of dry dichloromethane was added 1.93 g of ohinoline. The resulting suspension was cooled to -15 ° C and 2.63 g of the above-prepared acetoxymethyl ester was added portionwise. The resulting black mixture was allowed to warm to room temperature and after stirring for 1 hour, the resulting solution was added under nitrogen to a solution of 3 g of 1,3-butanediol in 5 ml of dichloromethane cooled to -15 ° C. After stirring at room temperature for 2 hours, 100 ml of dichloromethane are added and the precipitate is filtered off. 1.8 g of acetoxymethyl-7-amino-3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethylcef-3-em-4-carboxylate hydrochloride are obtained, followed by a partial NMR spectrum (perdeuterodimethylsulfoxide +). deuterated acetic acid): 2.1 (s, 3H), 2.7 (s, 3H), 5.2 (bs, 1H), 5.7 (bs, 1H).

The free base is obtained by adding triethylamine to a suspension of this hydrochloride in a mixture of water and dichloromethane up to pH 8. The organic phase is then separated and evaporated.

Example

To a solution of 54 mg of p-toluenesulfonic acid hydrate in 1 ml of dry dimethylformamide was added 110 mg of 2-fluoro-1-triphenylmethyl imidazole and the solution was heated to 80 ° C in a preheated bath. After 5 minutes, during which 2-fluorimidazole is completely formed in situ,

1

2,110,60 7 mg of 7-emino-3- (1,3,4-thiadiazol-2-yl) thiomethylceph-3-em-4-carboxylic acid are added, heating is continued for 2.5 hours, an additional 50 mg of fluorimidezole, heated for a further 30 minutes, cooled and evaporated at room temperature. 10 ml of water and 25 ml of ethyl acetate were added to the residue, the mixture was filtered and the phases were separated. The aqueous layer was concentrated to 4 mL, filtered and subjected to high pressure liquid chromatography on a Partisil 10 adsorbent (Whatman), using a mixture of water, methanol, and acetic acid (80: 20: 1 v / v / v) as eluent. . Upon addition of acetone, the product crystallized which, after washing with acetone and ether, gave 15 mg of 7- (2-imidazolyl) amino-3- (1,3,4-thiadiazol-2-yl) thiomethylcef-3-em-4-carboxylic acid, whose NMR spectrum contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 3.52 (d, 1H), 3.79 (d, 1H), 4.33 (d, 1H), 4.6 (d, 1H), 5.12 (d, 1H), 5.58 (d, 1H), 6.83 (s, 2H), 9.49 (s, 1H).

The above procedure was repeated using 4-carboxy-2-fluoro-1-triphenylmethylimidazole, 4-ethoxycarbonyl-2-fluoro-1-triphenylmethylimidazole and 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid as starting materials. The following compounds are obtained:

CH ₂ OCOCH ₃ COOH

R Note cooc ₂ h ₅ 1, 2 COOH 3, 4

Comment:

1. The product was purified by high pressure liquid chromatography using a mixture of water, methanol and acetic acid (74: 25: 1 v / v / v) as eluent.

2. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide): 1.22 (t, 3K), 2.03 (s, 3H), 3.32 to 3.61 (quartet, 2H), 4.17 (quartet, 2H) 4.56-4.93 (quartet, 2H), 5.14 (d, 1H), 5.67 (quartet, 1H), 7.01 (d, 1H), 7.28 (s, 1H) ).

3. The product is purified by high pressure liquid chromatography using a water mixture. methanol and acetic acid (76.5: 12.5: 1 v / v / v) as eluent.

4. NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide + + deuterated acetic acid): 2.03 (s, 3H), 3.43-3.6 (quartet, 2H), 4.72-5.0 (quartet, 2H) 5.16 (d, 1H), 5.71 (d, 1H), 7.24 (s, 1H).

The starting imidazole derivative can be prepared as follows:

To a solution of 4.45 g of 2-fluorimidazole in 100 ml of dichloromethane and 7.93 ml of trimethylamine was added 14.4 g of triphenylmethyl chloride, stirred for 2.5 hours, the resulting solution was washed with water and brine, dried over magnesium sulfate, Clarified with activated carbon and evaporated after filtration. The solid residue was triturated with ether and then with methanol to give 13.6 g of 2-fluoro-1-triphenylmethylimidazole, m.p. 182-185 ° C.

To a solution of 3.28 g of 2-fluoro-1-triphenylmethylimidazole in 33 mL of dry tetrahydrofuran under argon at -75 ° C was added 2 equivalents of t-butyllithium (10 mL of a 1.9314 solution in pentane). After stirring at -75 ° C for three hours, 1.5 ml of dimethylformamide was added, the reaction mixture was cooled to -75 ° C for an additional hour, then allowed to warm slowly to room temperature. The reaction mixture was diluted with ether, washed first with 2N hydrochloric acid and then brine, and the ether layer was concentrated under argon to give 2.2 g of 4-formyl-2-fluoro-1-triphenylmethylimidazole melting at 177-179 °. C.

To a solution of 356 mg of 4-formyl-2-fluoro-1-triphenylmethylimidazole in 5 ml of ethanol and 3 ml of dichloromethane is first added a solution of 0.37 g of silver nitrate in 0.5 ml of water and then 5 ml of potassium hydroxide solution is added dropwise. (5 ml of a solution of 2.1 g of potassium hydroxide in 35 ml of water). The mixture was stirred at room temperature for 2 hours, then filtered and the filtrate was extracted with ether. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with chloroform. The organic layer was dried (MgSO4), filtered and evaporated. 261 mg of 4-carboxy-2-fluoro-1-triphenylmethylimidazole are obtained, the NMR spectrum of which contains the following signals (perdeuterodimethylsulfoxide): 7.0 to 7.68 (m, 16H), 11.5 to 12.5 (broad signal, 1H).

To a solution of 280 mg of 4-carboxy-2-fluoro-1-triphenylmethylimidazole in 0.75 ml of tetrahydrofuran, under argon, was first added 0.112 ml of 1,5-diazabicyclo [5.4.0] undec-5-ene and then 0.069 ml of ethyl iodide. . After stirring at room temperature for 2 hours, water was added and the mixture was extracted with ether. The ethereal extract was dried over magnesium sulphate and evaporated to give 4-ethoxycarbonyl-2-fluoro-1-triphenylmethylimidazole as a yellow foam. Yield: 185 mg, NMR (CDCl3): 1.38 (t, 3H), 4.36 (quartet, 2H), 7.0-7.5 (m, 16H).

Example 5

A suspension of 0.74 g of anhydrous p-toluenesulfonic acid and 1.17 g of 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid in 17.5 ml of dry dimethylformamide was stirred at room temperature for 15 minutes, resulting in partial dissolution of solids. 0.74 g of 2-fluorimidazole are added in one portion, the mixture is stirred at 90 ° C for 2 hours, the solvent is evaporated at room temperature, 20 ml of 2% (v / v) aqueous acetic acid are added to the residue, extract with 20 ml of ethyl acetate. The aqueous layer was concentrated to a volume of 15 ml, filtered, and the filtrate was purified by preparative high pressure liquid chromatography on a Partisil 10 adsorbent (Whatman), eluting with water, methanol and acetic acid (80: 20: 1 v / v) as eluent. reagents. The product is then further purified by trituration with acetone and washing with acetone and ether. 0.42 g of 3-acetoxymethyl-7- (2-imidazolyl) aminoceph-3-em-4-carboxylic acid is obtained in the form of a mixture of the hydrates of the salts with acetic acid and p-toluenesulfonic acid, melting with decomposition above 160 ° C. The NMR spectrum of the product contains the following signals (deuterium oxide): 2.28 (s, 3H), 3.58 (d, 1H), 3.89 (d, 1H), 4.92 (d, 1H), 5.13 ( d, 1H), 5.42 (d, 1H), 5.70 (d, 1H), 7.08 (s, 2H).

The above procedure was repeated using the appropriate 7-aminocephalosporin derivative as starting material. The following compounds are obtained in this way:

COOH

_R 1 Note N- N ₂ -s- / N 1, 2, 3 ch ₃ 0 II li N - N / ^X i ^N - CH ₂ COOH 4, 5 N - N ch ₂ -s-7 1, 6, 7 I ch ₂ Sat ₃ hr

Comment:

1. The reaction is carried out at 85 ° C for 3 hours.

2. The product is purified by removing the residue from the reaction mixture by distilled water, filtering and extracting the filtrate with ethyl acetate. The aqueous layer is clarified with activated carbon, the pH is adjusted to 6 with aqueous sodium hydroxide solution and the volume is reduced to 2 ml. The product is then crystallized from the concentrate.

3. The product melts with decomposition at 203-220 ° C.

4. The product was purified by preparative high pressure liquid chromatography on a Partisil 10 adsorbent (Whatman), eluting with a mixture of water, methanol and acetic acid (70: 40: 1 v / v / v).

5. The NMR spectrum of the product, which is in the form of the hydrate, contains the following signals (deuterium oxide + trifluoroacetic acid): 3.3 (d, 1H), 3.64 (d, 1H), 3.92 (d, 1H), 4.26 (d, 1H), 4.59 (s, 2H), 4.93 (d, 1H), 5.20 (d, 1H), 6.56 (s, 2H), 6.75 (d) 1 H, 7.25 (d, 1 H).

6. The product was purified by preparative high pressure liquid chromatography on a Partisil 10 adsorbent (Whatman), eluting with a mixture of water, methanol and acetic acid (90: 10: 1 v / v / v). The product crystallizes after acetone treatment

7. The NMR spectrum of the p-toluenesulfonic acid salt contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 2.32 (s, 3H) 3.64 (d, 1H), 3.9 (d, 1H), 4.19 (d, 1H), 4.46 (d, 1H), 5.05 (s, 2H), 5.17 (d, 1H), 5.57 (d, 1H), 7, 06 (s, 2H); 7.14 (d, 2H); 7.54 (d, 2H).

Example 6

A solution of 0.18 g of pivaloyloxymethyl 3-methyl-7-aminoceph-3-em-4-carboxylate and 0.14 g of 2-fluoro-imidazole hydrochloride in 1 ml of cimethylformamide and 1 ml of acetone-tril was heated at 50 ° C for 7 hours. After evaporation of the reaction mixture, the residue is chromatographed on silica gel using dichloromethane / methanol (95: 5 v / v) as eluent. The oily product was treated with 1 equivalent of hydrogen chloride in methanol. The solution was evaporated, the residue was triturated with ether and the product was filtered off. Plvoyloxymethyl-7- (2-imidazolyl) amino-3-methylcef-3-em-4-carboxylate hydrochloride is obtained whose NMR spectrum contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): f, 2 (s, 911), 2 1 (s, 3H), 3.6 (m, 2H), 5.25 (d, 1H), 5.7 (d, 1H), 5.85 (m, 2H), 7.05 (s) , 2H).

Example 7

The procedure described in Example 4 was repeated using the appropriate starting materials. The following compounds are obtained:

HO-ICH ₂ ) i.e

Η H

COOH

R ¹ Note CHgOCOCH ^ ! N - N ch _{2 -} s - n ^{X X Z Z} 2, 3 ch ₃ N — N || N — N H 2, 4 -

Comment:

1. The NMR spectrum of the product resulting from a mixture of aols with p-toluenesulfonic acid and acetic acid contains the following signals (perdeuterodimethylsulfoxide):

1.6-1.9 (m, 2H), 2.05 (s, 3H), 2.5 (t, 2H), 3.3-3.7 (m, 4H), 4.9 (quartet) 2H, 5.17 (d, 1H), 5.63 (quartet, 1H), 6.61 (s, 1H), 7.28 (quartet, 2H), 8.8 (s, 1H).

2. A high pressure liquid chromatography solvent is a mixture of water, methanol and acetic acid (70: 30: 1 v / v / v).

, 5

3. The NMR spectrum of the product resulting from the mixture of salts with p-toluenesulfonic acid and acetic acid contains the following signals (perdeuterodimethylsulfoxide):

1.6-1.9 (m, 2H), 2.5 (t, 2H), 3.3-3.7 (m, 4H), 3.95 (s, 3H >, 4.34 (s, 2H), 5.08 (d, 1H), 5.70 (quartet, 1H), 6.58 (s, 1H), 8.65 (s, 1H).

4. The NMR spectrum of the product resulting from the mixture of salts with p-toluenesulfonic acid and acetic acid contains the following signals (perdeuterodimethylsulfoxide):

1.6-1.9 (m, 2H); 2.44 (t, 2H); 3.42 (t, 2H); 3.59 (d, 2H); 4.04 (s, 2H); 10.08 (d, 1H); 5.50 (d, 1H); 6.57 (s, 1H); 7.84 (s, 1H).

The 2-fluoro-1-triphenylmethyl-4- (3-hydroxy) propylimidazole used as starting material can be prepared as follows:

To a solution of 1.31 g of 2-fluoro-1-triphenylmethylimidazole in 22 mL of tetrahydrofuran at -70 ° C under argon was added tert-butyllithium (4 mL of a 2M solution in pentane). The red colored solution was stirred at -70 ° C for 2 hours, then 0.78 g of copper (I) iodide was added. The resulting dark red solution was stirred at -70 ° C for 1 hour, then 1.8 ml of allyl bromide was added, the mixture was allowed to warm to room temperature over 18 hours and then poured into 150 ml of ether. The resulting mixture was washed with saturated aqueous ammonium chloride (6 x 50 mL) and brine (50 mL), clarified with charcoal and dried (MgSO4). Evaporation of the solution gave 4-allyl-2-fluoro-1-triphenylmethylimidazole as a pale yellow solid melting at 136-138 ° C.

To a solution of 3.68 g of this allyl derivative in tetrahydrofuran was added diborane (40 mL of a 1M solution in tetrahydrofuran) under stirring at 5 ° C under argon. The mixture was stirred for 15 minutes at 5 ° C and then for 16 hours at room temperature, 20 ml of water was added to the resulting solution, and after 15 minutes 20 ml of 2N aqueous sodium hydroxide solution and 6 ml of 30% w / w aqueous hydrogen peroxide solution. The reaction mixture was heated to 50 ° C with vigorous stirring for 2 hours, then cooled, saturated with sodium chloride, and the layers separated. The aqueous layer was extracted three times with 75 ml of ether each time, the combined extracts were washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel using dichloromethane / methanol (40: 1 v / v) as eluent. 2-Fluoro-1-triphenylmethyl-4- (3-hydroxy) propylimidazole is obtained as a crystalline solid, the NMR spectrum of which contains the following signals (perdeuteromethanol): 1.5 to 1.9 (m, 2H), 2.47 (t, 2H), 3.54 (t, 2H), 6.37 (s, 1H), 7.0-7.5 (s, 15H).

♦

Example

The procedure described in Example 4 was repeated using 7-amino-3- (1,2,3-thiadiazol-5-yl) thiomethylceph-3-em-4-carboxylic acid as the starting material. The product was purified by high pressure liquid chromatography using a mixture of water, methanol and acetic acid (70: 30: 1 v / v / v) as eluent. 7- (2-imidazolyl) amino-3- (1,2,3-thiadiazol-5-yl) thiomethylceph-3-em-4-carboxylic acid is obtained, the NMR spectrum of which contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid). 3.47 (d, 1H); 3.71 (d, 1H); 4.36 (s, 2H); 5.13 (d, 1H); 5.58 (d, 1H); 6.81 (d, 1H); s, 2H), 8.88 (s, 1H).

Example 9

By repeating the procedure described in Example 1, the following compounds can be obtained using the appropriate starting materials:

R ¹ R ⁴ R ⁸ R ⁹ Note ch ₃ H H H H 1 ch ₃ H ch ₃ H H 2 CH ₃ H ^CH 3 ch ₃ H 3 ch ₃ H Ph H H 4 ch ₃ coch ₃ H H H 5 ch ₃ ch ₃ H H H 6 CH ₂ OCOCH ₃ H H H H 7 CH ₃ H H cis- (CH _{2) 4} 8 CH ₂ OCOH ₃ H Ph H H 9 ch ₃ , H Ph-OCHg H H 10 CH ₃ H ^{, Ph,} 2 ^CH 2 == H H 11 CZ) ^{-0CH 2} CH ₂ OCOCH ₃ H <ΟΗ ₃ > 2Ν-θ- H H 1 2 CH ₃ H COOH H H 13 ch ₃ H (CHjljN-θ- H H 14 y ^CH 3 N— / CHjS—? H H H H 1 5 N = / ch ₃ • N — N ch ₂ s- # In _ch H H H H 1 6 ^X S ^{X 3}

, 7 continued table

Note

CH,

CH ₂ OCOCH ₃ eis-CH, ois- (CH ₂ ) 4 ch ₂ s ch ₂ s - ( ^z

N — N

Z ||

N — N

CH-1 ch ₂ s ch ₂ s ₂₃

N N

AND

Ph

CH ₂ S -

COOH

CH ₂ OCOCH ₃

OH

CH,

R (R)

CH,

CH,

NC continuation table

Note

CH,

Cl

CH,

Cl

CH,

CH,

CH,

CH,

CH,

CH,

CH,

CH,

CH,

H

H

H

H

H

H

H

HIM

HIM

HIM

CH ₃ (CH ₂ ) ₅ HOCH, h ₂ nco cis-CO ₂ CH ₃ cis-Ph

N-N (/ II

CH 3 COOH <M N — N ™ II JI

CH ₃ CH ₂

CHj

CH,

CH,

HIM

CH,

CH ₂ NH ₂ cis- (CH ₂ ) ₂ cis-CH ₂ CH = CHeis-CO ₂ CH ₃ cis-Pheis-CH, cis-CH,

Comment:

1. The zwitterion NMR spectrum contains the following signals: 2.38 (s, 3H), 3.70 (d, 1H), 4.11 (d, 1H), 4.22 (s, 4H), 60 (d, 1H); 5.80 (d, 1H);

2. The hydrobromide melts at 160-164 ° C and its NMR spectrum (perdeuteromethanol) contains the following signals: 1.35 (d, 3H), 2.13 (s, 3H), 3.28 (d, 1H), 59 (d, 1H), 4.2 (broad signal, 3H), 5.12 (d, 1H), 5.3 (d, 1H).

3. NMR spectrum of hydrated trifluoroacetic acid salt (perdeuterodimethylsulfoxide): 1.35 (s, 6H), 2.02 (s, 3H), 3.35 (s, 2H), 3.7 (broad signal, 2H); 5.05 (d, 1H); 5.38 (a, 1H); 8.50 to 9.40 (m, 2H).

4. The trifluoroacetic acid salt dihydrate melts at 175-177 ° C and its NMR spectrum (perdeuterodimethylsulfoxide) contains the following signals: 2.07 (s, 3H), 3.30 (m, 2H), 3.50 (m) 1 H, 4.15 (m, 1 H), 5.15 (d, 1 H), 5.21 (t, 1 H), 5.51 (d, 1 H), 7.40 (s, 5 H), 9 , 0 (broad signal, 1H, replaceable).

5. The trifluoroacetic acid salt melts at 110-115 ° C. Nuclear Magnetic Resonance Spectrum (Perdeuterodimethylsulfoxide): 2.03 (s, 3H), 2.26 (s, 3H), 3.30 (d, 1H), 3.62 (d, 1H), 3.73 (m, 2H) 4.13 (m, 2H); 5.16 (d, 1H); 5.51 (d, 1H); 7.22 (m, 1H).

6. The hydrobromide melts at 153-156 ° C. Nuclear Magnetic Resonance Spectrum (Perdeuterodimethylsulfoxide): 2.06 (s, 3H), 2.97 (s, 3H), 3.49 (s, 2H), 3.64 (s, 4H), 5.1 (d, 1H) 5.44 (d, 1 H).

7. NMR spectrum of the salt with trifluoroacetic acid (perdeuteromethanol / deuterated trifluoroacetic acid): 2.10 (s, 3H), 3.44 (d, 1H), 3.81 (d, 1H), 3.81 (s, 4H) 4.86 (d, 1H), 5.19 (d, 1H), 5.20 (d, 1H), 5.51 (d, 1H).

8. The hydrobromide melts at 167-170 ° C. NMR Spectrum (CDCl 3): 1.52 (broad signal, 8H), 2.08 (s, 3H), 3.38 (d, 1H), 3.65 (d, 1H), 3.92 (s, 2H) 5.12 (d, 1 H), 5.45 (d, 1 H).

9. NMR spectrum of the trifluoroacetic acid salt (perdeuterodimethylsulfoxide): 2.0 (s,

3H), 4.75 (d, 1H), 5.0 (d, 1H), 5.1 (d, 1H), 5.55 (m, 1H), 5.2 (m, 1H), a variety of signals is covered by a wide replaceable proton signal.

10. The product melts with decomposition at 137-145 ° C and its NMR spectrum (perdeuterodimethylsulfoxide) reaches the following signals: 2.02 (s, 3H), 3.2 to 4.5 (m, 9H), 5.1 ( 2d, 1H), 4.45 (m, 1H), 6.8-7.5 (m, 5H).

The product melts with decomposition at 172-180 ° C and its NMR spectrum (perdeuterodimethylsulfoxide) contains the following signals: 1.95 (s, 3H), 2.7 to 4.5 (m, 7H), 5.0 (m (1H),

5.5 (m, 1H); 7.1 (m, 14H).

12. NMR spectrum of the product (perdeuterodimethylsulfoxide): 2.0 (s, 3H), 2.9 (s, 6H), 3.0 to 3.8 (broad signal, replaceable), 4.6 to 5.1 (broad) signal, 3H), 5.2 (s, 1H), 5.4-8

5.6 (quartet, 1 H), 6.7 (d, 2 H), 7.2 (d, 2 H).

13. NMR spectrum of the salt with trifluoroacetic acid (perdeuterodimethylsulfoxide / trifluoroacetic acid): 2.05 (s, 3H), 3.45 (quartet, 2H), 3.6-4.0 (m, 2H), 4.55 (m, 1H), 5.05 (d, 1H), 5.4 (dd, 1H), 9.55 (d, 1H).

14. The product melts above 180 ° C and its NMR spectrum (perdeuterodimethylsulfoxide) contains the following signals: 2.05 (s, 3H), 2.85 (s, 6H), 3.25-3.6 (m, 3H), 4.05 (t, 1H), 4.95 (s, 1H), 5.12 (d, 1H), 5.4 to 5.55 (quartet, 1H), 6.7 (d, 2H), 7 2 (d, 2H), 8.4-8.8 (m, 1H), 9.2 (m, 1H), 9.75 (d, 1H).

15. NMR (MSD): 2.35 (s, 6H), 3.65 (m, 6H), 4.3 (dd, 2H), 5.1 (d, 1H), 5.45 (d) 1 H, 6.95 (s, 1 H).

16. NMR spectrum of the product (perdeuterodimethylsulfoxide): 2.65 (s, 3H), 3.65 (s, 4H), 3.75 (dd, 2H), 4.4 (dd, 2H), 5.1 (d) 1 H, 5.5 (dd, 1 H), 9.5 (d, 1 H).

17. The product melts with decomposition at 120-150 ° C and its NMR spectrum (deuterated acetic acid) contains the following signals: 0.3 (m, 1H), 0.9 (m, 1H), 2.08 (s, 3H) 3.1, 3.9 (m, 4H), 5.0 (d, 1H), 5.34 (d, 1H). with

18. The IR spectrum of the product (KBr-technique) comprises the following bands: 1775 cm ^-1 (CO-NH);

730 cm ^-1 (COOH), 1650 cm ^-1 (guanidinium).

19. NMR (CDCl3): 5.10 (d, 1H), 5.55 (d, 1H),

3.0 to 4.6 (m, 12H).

20. NMR spectrum of the product (perdeuterodimethylsulfoxide + deuterated acetic acid): 3.7 (a, 4H), 3.85 (dd, 2H), 4.55 (dd, 2H), 5.2 (d, 1H), 5 55 (d, 1H); 7.2-7.7 (m, 4H).

21. The NMR spectrum of the product (perdeuterodimethanol) contains the following signals: 3.8 (s, 6H), 4.0 (β, 3H), 4.36 (s, 2H), 5.15 (d, 1H), 4 (d, 1 H).

22. NMR (DMSO): 3.65 (s, 4H), 3.6-4.0 (m, 2H);

4.55 (dd, 2H), 5.1 (d, 1H), 5.5 (d, 1H), 7.3-8.0 (m, 4H).

23. NMR spectrum of the product (perdeuterodimethylsulfoxide + deuterated acetic acid): 3.6 to 3.8 (m, 2H), 3.7 (s, 4H), 4.5 (dd, 2H), 5.15 (s, 1H), 5.55 (b, 1H), 7.7 (s, 5H).

24. The product melts at 169-172 ° C and its NMR spectrum (perdeuteromethanol / deuterium oxide / perdeuterodimethylsulfoxide) contains the following signals: 3.5 (dd, 2H), 3.75 (s, 4H), 3.95 (d, 1H), 4.4 (1H), 5.05 (d, 1H), 5.30 (d, 1H), 7.35-8.0 (m, 4H).

25. The product melts at 230 DEG C. with decomposition and its NMR spectrum (perdeuterodimethylsulfoxide / deuterated trifluoroacetic acid) contains the following signals: 2.0 (s, 3H), 3.6 (m, 6H), 4.7 (d, 1H), 5.0 (d, 1H), 5.1 (d, 1H), 5.5 (d, 1H).

26. The product, which is the salt with hydrochloric acid, melts with decomposition at 171 ° C and its NMR spectrum (perdeuterodimethylsulfoxide / deuterated acetic acid) contains the following signals: 2.1 (β, 3H), 3.54 (quartet, 2H) 3.2 to 3.8 (m, 3H), 4.1 (t, 1H), 5.15 (d, 1H), 5.2 (t, 1H), 5.6 (d, 1H), 7.4 (s, 5H).

27. The product, which is a mixture of hydrobromic acid and trifluoroacetic acid salt, melts at 172-175 ° C with decomposition and its NMR spectrum (perdeutarodimethylaulfoxide / deuterated acetic acid) contains the following signals: 2.05 (s, 3H), 3.35 (quartet, 2H), 3.1-3.8 (m, 1H), 4.2 (m, 1H), 5.1 (d, 1H), 5.2 (m, 1H), 5.9 ( d, 1H), 7.38-7.8 (m, 9H).

28. The product, the trifluoroacetic acid salt, melts at 178-185 ° C with decomposition and its NMR spectrum (perdeuterodimethylsulfoxide / perdeuteromethanol) contains the following signals: 2.15 (s, 3H), 3.3 to 3.8 ( m, 3H), 4.0 to 4.4 (m, 1H), 5.0 to 5.7 (m, 3H),

7.8 to 8.0 (m, 4H).

29. The product, a mixture of hydrobromic acid and trifluoroacetic acid salts, melts at 172-176 ° C with decomposition and its NMR spectrum (perdeuterodimethylsulfoxide / deuterated acetic acid) contains the following signals: 2.05 (s, 3H), 3.4 (m, 3H), 3.4 (quartet, 2H), 4.12 (m, 1H), 5.1 (d, 1H), 5.15 (m, 1H), 5.5 (d, 1H) 7.45 (m, 4H).

30. The product, a mixture of β salts of hydrobromic acid and trifluoroacetic acid, melts with decomposition at 178-185 ° C and its MMR spectrum (perdeuterodimethylsulfoxide / deuterated acetic acid) contains the following signals: 2.05 (s, 3H), 3.47 (quartet, 2H), 3.2 to 3.7 (m, 1H), 4.2 (t, 1H), 5.08 and 5.1 (2d, 1H), 5.25 to 5.6 (· 2 H, 5.4 (m, 4H).

31. The product, which is the salt with fluoroacetic acid, has the following NMR spectrum (perdeuterodimethylsulfoxide): 1.9 (s) and 2.05 (s), (total 3H), 3.2 to 3.6 (m, 3H) 4.1 (t, 1H), 5.0 (m, 1H), 5.1 (d, 1H), 5.45 (d, 1H), 6.7-7.4 (m, 4H).

32. The product, which is the trifluoroacetic acid salt, has the following NMR spectrum (perdeuterodimethylsulfoxide / deuterated acetic acid): 2.3 (s, 3H), 3.4 to 3.85 (m, 3H)

4.2 (t, 1H), 5.05 to 5.20 (m, 1H), 5.30 (d, 1H), 5.7 (d, 1H), 6.7 to 7.1 (m, 3H).

33. The product in the form of a mixture of hydrated salts of 8 with hydrobromic acid and trifluoroacetic acid melts at 110 DEG C. with decomposition and its NMR spectrum (deuterated acetic acid) contains the following signals: 0.88 (m, 3H), 1.34 (m, 10H) ), 2.12 (s, 3H), 3.2 to 3.8 (quartet, 2H), 5.22 (d, 1H), 5.55 (d, 1H).

34. The product in the form of the trifluoroacetic acid salt melts at 145-147 ° C and its NMR spectrum (deuterochloroform / perdeuteromethanol) contains the following signals: 2.25 (s, 3H), 3.4 to 3.55 (m, 2H) 3.55-4.0 (m, 5H), 5.15 (d, 1H), 5.4 (d, 1H).

35. The product, a mixture of salts with hydrobromic acid and trifluoroacetic acid, melts at 180 DEG C. with decomposition and its NMR spectrum (deuterium oxide) contains the following signals: 2.0 (s, 3H), 3.15-3.65 ( quartet, 2H), 3.75 (dd, 1H), 4.05 (dd, 1H), 5.15 (d, 1H), 5.35 (d, 1H).

36. The product in the form of a mixture of salt and hydrobromic acid and trifluoroacetic acid melts at 160 DEG C. with decomposition at 160 DEG C. and its NMR spectrum (perdeuterodimethylsulfoxide) contains the following signals: 2.1 (s, 3H), 2.0 to 2.4 (m, 4H), 3.25-3.72 (quartet, 2H),

4 * 2 to 4.6 (m, 2H), 5.15 (d, 1H), 5.3 (d, 1H).

37. The product, which is a mixture of salts with hydrobromic acid and trifluoroacetic acid, melts at 170 DEG C. with decomposition at 170 DEG C. and its NMR spectrum (perdeuterodimethylsulfoxide / deuterium oxide) contains the following signals: 2.1 (s, 3H), 2.6 (m, 2H), 3.15-3.85 (quartet, 2H), 4.5-5.1 (m, 2H), 5.15 (d, 1H), 5.35 (d, 1H), 5.8 (dd, 1H), 6.05 (Sd, 1H).

38. The product, a mixture of salts with hydrobromic acid and trifluoroacetic acid, melts at 155 DEG C. with decomposition and its NMR spectrum (deuterated acetic acid) contains the following signals: 2.27 (s, 3H), 3.5 (broad signal) 2 H, 3.8 (β, 6H), 5.15 (s, 2H), 5.27 (d, 1H), 5.62 (d, 1H).

39. The product in the form of a mixture of salts with hydrobromic acid and trifluoroacetic acid melts at 196-199 ° C and its NMR spectrum (deuterated acetic acid) contains the following signals: 2.11 (s, 3H), 3.42-3.7 (quartet, 2H), 5.19 (d, 1H),

5.56 (d, 1H); 7.05 (m, 10H).

40. The product is a mixture of trifluoroacetic acid salt and zwitterion. The NMR spectrum of the product (perdeuteromethanol / deuterium oxide / deuterium chloride) contains the following signals: 3.80 (m, 6H), 4.3 (d, 1H), 4.5 (d, 1H), 5.2 (d, 1H), 5.3 (s, 2H).

5.5 (d, 1 H).

The NMR spectrum of the product consisting of a mixture of salts with hydrobromic acid and trifluoroacetic acid contains the following signals (perdeuterodimethylsulfoxide / deuterated acetic acid / trifluoroacetic acid): 0.25 (m, 1H), 0.80 (m, 1H), 2, 65 (s. 3H),

3.2 to 3.8 (m, 4H), 4.25 and 4.5 (quartet, 2H), 5.1 (d, 1H), 5.4 (d, 1H).

42. The product, consisting of a mixture of salts with hydrobromic acid and trifluoroacetic acid, melts at 165 DEG C. with decomposition and its NMR spectrum (perdeuterodimethylsulfoxide / deuterated acetic acid) contains the following signals: 0.25 (m, 1H), 0.8 (ra). 1 H, 3.6 (m, 4H), 3.9 (β, 3H), 4.25 (broad signal, 2H), 5.05 (d, 1H), 5.4 (d, 1H).

43 · Trifluoroacetic acid salt product has the following NMR spectrum (perdeuterodimethylsulfoxide * deuterated acetic acid): 2.05 (β, 3H), 3.2 to 3.8 (m, 3H), 4.0 (t, 1H ), 4.9-5.1 (m, 3H), 5.45 (broad signal, 1H), 6.8 (d, 2H), 7.2 (d, 2H).

44. The NMR spectrum of the product, which is a 2 mol trifluoroacetic acid salt, contains the following signals (deuterium oxide): 2.0 (s, 3H), 3.2 to 4.4 (m, 6H), 4.4 to 4, 7 (m, 1 H),

5.15 (d, 1H), 5.4 (d, 1H).

Ph = phenyl.

Example 10

By repeating the procedure described in Example 2, the following compounds are obtained:

COOH

R ¹ H ² r3 (benzimidazole ring numbering) Note ch ₂ eyes ₃ H H 1 CH ₂ OCOCH ₃ H _5-CH3 2 CO ₂ OCOCH ₃ H _4-CH3 3 CH ₂ OCOCH ₃ H 5,6-diCH ₃ 4 CH ₂ OCOCH ₃ H _4-NH2 5 CH ₂ OCOCH ₃ H 4-NHCOCH ₃ 6 CH ₂ OCOCH ₃ H 5-HO ₂ 7 ch ₂ eyes ₃ H 4-COOH 8 ch ₃ H H 9 CU ₃ H 5,6-diCH ₃ 10 ^ch 3 H 5-OCH ₃ 11 CH, H 5,6-diCl 12

continued table

R ¹ R ² R ^ (benzimidazole ring numbering) Note ch ₃ H _4-NH2 13 ch ₃ H 4-NHCOCH ₃ 14 ch ₃ H see footnote 15 15, 16 ch ₃ H see footnote 17 17, 18 NN CH ₂ S- <'| l Nk CH ₃ H H 19 Dec NN AA ch ₂ s ch ₃ H H 20 May CH ₃ CH ₃ H 21 CHgOCOCHj ch ₃ H 22nd ch ₂ eyes ₃ H 5-OH 23 CH ₂ OCOCH ₃ ^C H ₂ - ^ ~ ^ ~ ^OCH3 H 24 CH ₂ OCOCH ₃ H 4-OH 25 CH ₂ OCOCH ₃ H 5-CH ₂ NH ₂ 26 N — N ch ₂ s— (II N — N I AT 5-OH 27 Mar: l ch ₃ CH ₂ OCOCH ₃ H 5'-CO ₂ H 28 CH ₂ OCOCH ₃ H 5-F 29 CH ₂ OCOCH ₃ H 5-CF ₃ 30 CH ₂ OCOCH ₃ H 5-CH 3 OH 31 CH ₃ H _5-NH2 32 CH ₂ OCOCH ₃ H _5-NH2 33 CH ₂ OCOCH ₃ H 5-CH ₂ OCOCH ₃ 34 CH ₂ OCOCH ₃ H 5-CH ₂ NH ₂ 35 CH ₂ OCOCH ₃ H 5-CH ₂ N ₃ 36 CH ₂ OCOCH ₃ H 5-CH ₂ NHCOCH ₃ 37

continued table

R ¹ B ² R ^ (benzimidazole ring numbering) Note CHgOCOCHj H 5 -CH ₂ NH COCH ₃ NH ₂ ) -X 2 38 ch ₂ eyes ₃ H 5 ch ₂ nhcoch ₂ nh ₂ 39 ch ₂ eyes ₃ H 5-CH ₂ CN 40 CH ₂ OCOCH ₃ H 5-CH ₂ CONH 2 41 CH ₂ OCOCH ₃ H 5 - CH ₂ N «CH-NX 42 čh ₃ och ₃ H 43

Comment:

. t

The product in the form of a salt and trifluoroacetic acid melts at 210-230 ° C and its HUS spectrum (perdeuterodimethylsulfoxide) contains the following signals: 2.04 (a, 3H), 3.82 (m, HgO), 4.76 (d, 1H), 5.07 (d, 1H), 5.28 (d, 1H), 5.84 (d, 1H), 6.8-7.7 (m, 4H).

2. mR spectrum (perdeuterodimethylsulfoxide / perdeuteromethanol): 2.02 (β, 3H), 2.43 (s,

3H), 3.40-4.0 (m, 2H), 4.0-6.0 (Ss, 4H), 6.70-7.70 (m, 3H).

3 · ms spectrum (CDC): 2.05 (s, 3H), 2.47 (s, 3H), 3.48, 3.72 (2d, 2H), 4.75, 5.05 (2d, 2H) 5.32, 5.96 (2d, 2H), 7.05 (m, 2H).

4. ms spectrum (perdeuterodimethylsulfoxide / perdeuteromethanol): 2.04 (s, 3H), 2.35 (s,

6H), 3.43, 3.73 (2d, 2H), 4.85, 5.15 (2d, 2H), 5.30 (d, 1H), 5.72 (d, 1H), 7.23 (s, 2H).

5. ms spectrum (CDCl 3): 2.12 (s, 3H), 3.7 (broad signal, 2H), 4.77, 5.13 (2d, 2H), 5.37 (d, 1H), 5 9 (broad signal, 1H), 6.60 (d, 1H), 6.73 (d, 1H),

7.05 (t, 1H), 6.90 to 7.80 (broad signal, exchangeable), 10.15 (broad signal, 1H, exchangeable).

6. NMR Spectrum (DMSO): 2.02 (s, 3H), 2.10 (β, 3H), 3.7 (broad signal, 2H), 4.7, 5.05 (2d, 2H), 5 25 (d, 1H), 5.90 (broad signal, 1H), 6.90 to 7.35 (m, 3H), 8.35 to 8.80 (m, 1H), 9.97 (broad signal) , 1H).

7. mR spectrum (CDCl 3): 2.05 (β, 3H), 3.57 (d, 2H), 4.73, 5.05 (2d, 2H), 5.27 (d, 1H), Δ (m, 1H), 7.6 (m, 3H).

8. mR spectrum (CDCl 3): 2.05 (s, 3H), 3.39, 3.74 (2d, 2H), 4.72,

5.07 (2d, 2H), 5.29 (d, 1H), 5.95 (m, 1H), 7.36 (m, 3H).

9. The melting point of the salt and trifluoroacetic acid is 185-187 ° C (decomposition). Nuclear Magnetic Resonance Spectrum (Deuterium Oxide / Perdeuteromethanol / Trifluoroacetic Acid): 2.3 (s, 3H), 3.24,

3.60 (2d, 2H); 7.4 (m, 4H). The signals of the other protons are hidden behind the signals of the solvent system.

10. NMR spectrum of the trifluoroacetic acid salt (perdeuterodimethylsulfoxide): 2.04 (s,

3H), 3.9 (m, 2H, exchangeable protons Η, Ο), 5.75, 5.16 (2d, 2H), 7.03 (s, 2H); mp 198-208 ° C.

11. The melting point of the salt and trifluoroacetic acid is 180-185 ° C. NMR Spectrum (CDCl3): 2.04 (s, 3H), 3.40, 3.04 (2d, 2H), 3.80 (s, 3H), 3.14 (d, 1H), 5, 44 (d, 1H), 6.6-7.0 (m, 2H), 7.27 (d, 1H).

12. NMR spectrum of trifluoroacetic acid salt (perdeuteromethanol): 2.18 (s, 3H), 3.43,

3.56 (2d, 2H), 5.20, 5.65 (2d, 2H), 7.42 (s, 2H).

13. NMR spectrum of the trifluoroacetic acid salt (perdeuterodimethylsulfoxide): 2.08 (s, 3H), 3.42-3.66 (2d, 2H), 5.27 (d, 1H), 5.74 (d, 1H) 6.52 (d, 1H), 6.65 (d, 1H), 6.97 (t, 1H).

14. The melting point with trifluoroacetic acid is 200 ° C (decomposition). Nuclear Magnetic Resonance Spectrum (DMSO): 2.10 (s, 3H), 2.18 (s, 3H), 3.38, 3.67 (2d, 2H), 5.23 (d, 1H), 5.80 ( d, 1H), 7.13 (m, 3H), 9.15 (broad signal, 1H, exchangeable), 10.2 (s, 1H, exchangeable).

15. The rest of the substituted benzimidazole corresponds to the formula

16. NMR spectrum of the trifluoroacetic acid salt (perdeuterodimethylsulfoxide): 2.08 (s, 3H), 3.35 (d, 1H), 3.68 (d, 1H), 5.25 (d, 1H), 5, 85 (d, 1H), 7.20-8.15 (m, 6H).

17. The rest of the substituted benzimidazole corresponds to the formula

18. NMR spectrum of the trifluoroacetic acid salt (perdeuterodimethylsulfoxide): 2.03 (s, 3H), 3.32 (s, 4H), 3.30 (d, 1H), 3.60 (d, 1H), 5, 22 (d, 1H), 5.80 (d, 1H), 4.30-6.70 (m, exchangeable), 7.15 (d, 1H), 7.30 (s, 1H), 7.44 (t, 1H), 7.87 (d, 1H), 8.57 (broad signal, exchangeable).

19. NMR spectrum of the trifluoroacetic acid salt (perdeuterodimethylsulfoxide): 3.6 (d, 1H), 3.9 (d, 1H), 3.95 (s, 3H), 4.34 (m, 2H), 5, 25 (d, 1H), 5.81 (d, 1H), 6.90-7.50 (m, 4H).

20. NMR spectrum of the trifluoroacetic acid salt (perdeuterodimethylsulfoxide): 2.69 (s, 3H), 3.59 (d, 1H), 3.84 (d, 1H), 4.23 (d, 1H), 4, 59 (d, 1H), 5.25 (d, 1H), 5.82 (d, 1H), 7.1-7.5 (broad signal, 4H).

21. The hydrobromic acid salt melts with decomposition at 181-182 ° C and its NMR spectrum (perdeuterodimethylsulfoxide) contains the following signals: 2.05 (s, 3H), 3.5 (m, 2H),

3.7 (s, 3H), 5.2 (d, 1H), 5.7 (d, 1H), 7.2-7.7 (m, 4H).

22. The NMR spectrum of the product (perdeuterodimethylsulfoxide) contains the following signals: 2.0 (s, 3H), 3.58 (s + m, 3H + 2H), 4.67 (d, 1H), 4.95 (d, 1H) 5.25 (d, 1H), 5.76 (d, 1H), 6.95-7.42 (m, 4H).

The product melts with decomposition at 180 ° C and its NMR spectrum (perdeuterodimethylsulfoxide) contains the following signals: 2.05 (β, 3H), 3.42 (d, 1H), 3.68 (d, 1H), 70 (d, 1H), 5.05 (d, 1H), 5.18 (d, 1H), 5.78 (d, 1H), 6.4-7.1 (m, 4H).

24. The product melts at 160 ° C and its NMR spectrum (perdeuteromethanol containing 2 drops of perdeuterodimethylsulfoxide) contains the following signals: 2.00 (s, 3H), 3.70 (s, 3H),

3.5 (d, 1H), 3.75 (d, 1H), 4.8 (m, 2H), 5.15 (d, 1H), 5.67 (d, 1H), 5.31 (d, 1H); s, 2H),

6.66 to 7.66 (m, 8H).

25. The product melts with decomposition at 190 ° C and its NMR spectrum (perdeuteromethanol / perdeuterodimethylsulfoxide) contains the following signals: 2.05 (s, 3H), 3.52 (d, 1H), 3.80 (d, 1H) 1.87 (d, 1H), 5.16 (d, 1H), 5.28 (d, 1H), 5.74 (d, 1H), 6.6-7.3 (m, 3H) .

26. NMR (DMSO): 2.01 (s, 3H), 3.55 (m, 3H), 4.04 (m, 2H), 4.68 (β, 1H), 5.01 (s) 1 H, 5.22 (s, 1H), 5.85 (s, 1H), 7 to 7.4 (m, 3H).

27. The NMR spectrum of the trifluoroacetic acid salt product contains the following signals (perdeuterodimethylsulfoxide): 3.7 (m, 2H), 3.9 (s, 3H), 4.3 (s, 2H), 5.2 (d). 1H, 5.75 (d, 1H), 6.5-7.3 (m, 3H), 7.85 (d, 1H).

28. The NMR spectrum of the trifluoroacetic acid salt product contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 2.05 (d, 3H), 3.3 to 3.8 (quartet, 2H), 4.6 to 5, Δ (quartet, 2H), 5.24 (d, 1H), 5.84 (d, 1H), 7.3 (d, 1H), 7.8 (m, 2H).

29. The NMR spectrum of the product as the trifluoroacetic acid salt contains the following signals (perdeuterodimethylsulfoxide): 2.04 (s, 3H), 3.6 (m, 2H), 4.72-5.1 (quartet, 2H); 28-5.82 (quartet, 2H), 6.7-7.5 (m, 3H), 9.05 (m, 1H).

30. The NMR spectrum of the trifluoroacetic acid salt product contains the following signals (perdeuterodimethylsulfoxide): 2.1 (s, 3H), 3.7 (quartet, 2H), 4.80 to 5.12 (quartet, 2U), 5; 34 to 5.90 (quartet, 2H), 7.4 to 7.8 (m, 3H).

31. The NMR spectrum of the hydrobromic acid salt product contains the following signals (perdeuterodimethylsulfoxide): 2.04 (a, 3H), 3.38 (quartet, 2H), 4.52 (s, 2H), 4.71-5. 03 (quartet, 2H), 5.25-5.80 (quartet, 2H), 6.9-7.25 (m, 3H).

32. The NMR spectrum of the trifluoroacetic acid disodium product contains the following signals (perdeuterodimethylsulfoxide): 2.06 (a, 3H), 5.5-5 * 60 (quartet, 2H), 6.6-6.

7.2 (m, 2H), (two proton signals covered with solvent).

33. The NMR spectrum of the trifluoroacetic acid disodium product contains the following signals (perdeuterodimethylsulfoxide): 2.02 (s, 3H), 3.6 (quartet, 2H), 4.75 to 5.05 (quartet, 2H); 25 to 5.78 (quartet, 2H), 6.5 to 7.3 (m, 3H).

34. The NMR spectrum of the trifluoroacetic acid disodium product contains the following signals (perdeuterodimethylsulfoxide): 2.1 (s, 6H), 3.4 (m, 2U), 4.76 to 5.08 (quartet, 2H); 27 to 5.90 (quartet, 2H), 7.16 (β, 2H), 7.74 (s, 1H), 9.84 (s, 1H).

35. The NUK spectrum of the trifluoroacetic acid salt product contains the following signals (perdeuterodimethylsulfoxide): 2.01 (s, 3H), 3.55 (m, 3H), 4.04 (a, 2H), 4.68 and 5. 0.01 (quartet, 2H), 5.22 and 5.85 (quartet, 2H), 7.4-7.7 (m, 3H).

36. The NMR spectrum of the trifluoroacetic acid salt product contains the following signals (perdeuterodimethylsulfoxide): 2.1 (s, 3H), 3.66 (m, 2H), 4.55 (s, 2H), 4.8 and 5. 11 (quartet, 2H), 5.33 and 5.87 (quartet, 2H), 7.0-7.5 (m, 3H).

37. The NMR spectrum of the product in the form of a β trifluoroacetic acid salt contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 1.88 (s, 38), 2.0 (s, 3H), 3.48 and 3.6 (quartet, 2H), 4.3 (s, 2H), 4.7 and 5.05 (quartet, 2H), 5.23 (d, 1H), 5.76 (d, 1H), 6.90 to 7.4 (m, 3 H).

38. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide): 2.02 (s, 38), 3.54 (m, 2H), 4.17-4.4 (m, 2H), 4.7 and 5.05 (quartet, 2H), 4.90 (s, 1H), 5.18 (d, 1H), 5.82 (d, 1H), 6.7-7.6 (m, 8H), 8.65 ( m, 1H).

39. The NMR spectrum of the trifluoroacetic acid salt contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 2.05 (s, 3H), 3.0 to 4.0 (m, 4H), 3.6 (m, 4H), 4.37 (s, 2H), 4.7 and 5.0 (quartet, 2H), 5.2 (d, 1H),

5.78 (d, 18), 6.8-7.3 (m, 3H).

40. The NMR spectrum of the product as the trifluoroacetic acid salt contains the following signals (perdeuterodimethylsulfoxide): 2.03 (s, 3H), 3.42 and 3.67 (quartet, 28), 4.01 (s, 2H), 4. 71 and 5.01 (quartet, 2H), 5.22 (d, 1H), 5.80 (d, 1H), 6.90-7.45 (m, 3H).

41. The NMR spectrum of the product as the trifluoroacetic acid salt contains the following signals (perdeuterodimethylsulfoxide): 2.07 (s, 3H), 3.39 (β, 2H), 3.0 to 4.0 (m, 2H),

4.7 (d, 1H), 5.15 (d, 1H), 5.24 (d, 1H), 5.86 (m, 1H), 6.65-7.45 (m, 7H).

42. The NMR spectrum of the product as a mixture of hydrobromide and trifluoroacetate contains the following signals (perdeuterodimethylsulfoxide): 1.72 (s, 8H), 2.09 (s, 3H), 3.18-4.0 (broad signal, 6H), 4.7 to 5.1 (broad signal, 4H), 5.2 (d, 1H), 5.9 (d, 1H), 6.9 to 5.1

7.5 (broad signal, 3H), 8.5 (broad signal, 1H).

43. The NMR spectrum of the product as the trifluoroacetic acid salt contains the following signals (perdeuterodimethylsulfoxide): 2.10 (s, 3H), 3.40 (d, 1H), 3.60 (d, 1H), 3.72 (s 3H), 5.23 (d, 18), 5.67 (d, 1H), 7.18-7.58 (m, 4H).

Example 11

By repeating the procedure described in Example 3, the following compounds were obtained:

C ₃ H OH H 1

CH- H CN CN Continuation of Table “1

R ²

R ^ r4 Note

CH, ch ₂ eyes ₃

CH,

CH,

OH

H

H

H ^ch2 ~ C1

AND

CHj

N - N ch ₂ s - _{s s} A-ch ₃

COOH \

ch ₂ s-0

CH ₂ S— (

N-N

N N

CH3COOH

CH,

N-N

AA

CH ₂ S _C n ₃

H

N - N ^CH 2 ^with -C 1-4

CH,

CH,

CH, ch ₂ eyes ₃

H

H

H

H

CH ₃ H 3 OH H 4 H H 5 ch ₃ H 6 H H 7 H H 8 H H 9 H H 10 H H 11 ch ₃ H 12 ch ₃ H 13 ch ₃ H 14 ch ₃ ch ₃ 15 Dec ch ₃ 16 ch ₃ H 17 ch ₂ oh H 18

continued table

R ¹ R ² r3 R ⁴ Note CH ₂ OCOCH ₃ H CH ₃ H 19 Dec CH ₂ OCOCH ₃ H <ch ₂ ) ₄ 20 May CH ₂ OCOCH ₃ OH H 21 N — N ch ₂ s ^ || N — N H ch ₃ CH ₃ 22nd ch ₃ CH ₂ OCOCH ₃ H H 23 zN-N ch ₂ s —- ζ ί! H H H 24 1 H ₃ CF ₃ N — N ch ₂ s — f II N — N H H H 25 CHICH ₃ ) ₂ N — N CH ₂ S — II NN H H H 26 1 ch ₂ cf ₃ NN ^ch 2s— (j | N — N H H H 27 Mar: CH ₂ CH ₂ SCH ₃

Comment:

The product melts at 217-218 ° C and its NMR spectrum (perdeuterodimethylsulfoxide) contains the following signals: 2.00 (s, 3H), 3.30 (d, 1H), 3.60 (d, 1H), 3 60 (d, 2H); 4.95 (d, 1H); 5.55 (dd, 1H); 6.40 (t, 1H); 6.95-7.30 (m, 2H).

2. The NMR spectrum of the product (perdeuteromethanol) contains the following signals; 2.15 (a, 3H), 3.25-3.55 (m, 2H), 5.10 (d, 1H), 5.55 (d, 1H).

3. The product melts with decomposition above 220 ° C and its NMH spectrum (perdeuterodimethylsulfoxide) contains the following signals: 2.04 (s, 6H), 3.44 (s, 2H), 5.04 (d, 1H), 48 (d, 1 H), 6.42 (s, 1 H).

4. The product melts with decomposition above 220 ° C and its NMR spectrum (perdeuterodimethylsulfoxide) contains the following signals: 2.0 (s, 3H), 4.65 (d, 1H), 5.0 (d, 1H), Δ (d, 1H), 5.65 (d - d, 1H), 6.35 (t, 1H), 7.05 (d, 1H), 6.95 (bs, 1H).

5. NMR spectrum of the trifluoroacetic acid salt (perdeuterodimethylsulfoxide) contains the following signals: 2.075 (s, 3H), 3.48 (quartet, 2H), 5.13 (d, 1H), 5.5 (quartet, 1H) 7.07 (s, 2H), 9.45 (d, 1H).

6. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide): 2.08 (s, 3H), 2.10 (s, 3H), 3.44 (d-d, 2H), 6.10 (d, 1H), 6.48 (d, 1H), 6.55 (bs, 1H).

7. The NMR spectrum of the product contains the following signals (deuterium oxide): 3.10 (s, 6H), 3.6-4.0 (m, 4H), 4.2 (m, 2H), 4.9 (m, 2H) 5.3 to 5.5 (2d, 2H), 6.9 (s, 2H).

8. The product melts at 140-145 ° C and its NMR spectrum (perdeuterodimethylsulfoxide) contains the following signals: 2.6 (s, 3H), 3.4 (d, 1H), 3.8 (d, 1H), 2 (d, 1 H), 4.5 (d, 1 H), 5.1 (δ, 1 H), 5.5 (dd, 1 H), 6.9 (s, 2 H), 9.2 (s, 1 H) ).

9. The product melts at 145-150 ° C and its NMR (Perdeuterodimethylsulfoxide) spectrum contains the following signals: 3.5 (d, 1H), 3.8 (d, 1H), 4.0 (m, 2H), 1 (d, 1H), 5.5 (dd, 1H), 7.05 (s, 2H), 7.2 (m, 1H), 7.9 (s, 1H), 9.3 (d, 1H) ).

10. The product melts at 75-180 ° C and its NMR spectrum contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 3.5 (d, 1H), 3.8 (d, 1H), 4.0 (d, 1H, m.p. 1K), 4.3 (d, 1H), 5.2 (d, 1H), 5.6 (d, 1H), 7.0 (s, 2H), 7.2-8.0 (m, 3H) ).

11. The NMR spectrum of the product contains the following signals (perdeuteromethanol + deuterium oxide): 3.65 (d, 1H), 3.9 (d, 1H), 4.3 (d, 1H), 4.5 (d, 1H), 5.25 (d, 1 H), 5.25 (s,

2H), 5.5 (dd, 1H), 7.0 (s, 2H).

, 2. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide): 2.1 (s, 3H), 2.15 (s, 3H), 3.3 (d, 1H), 3.6 (d, 1H), 5.1 ( d, 1H), 5.5 (m, 1H), 6.7 (s,

1H), 9.1 (m, 1H).

13. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide): 2.1 (s, 3H), 2.7 (β, 3H), 3.6 (d, 1H), 3.8 (d, 1H), 4, 2 (d, 1H), 4.5 (d, 1H), 5.2 (d, 1H),

5.5 (dd, 1 H), 6.7 (s, 1 H), 9.2 (d, 1 H).

14. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 2.0 (s, 3H), 3.4 to 3.7 (m, 2H), 3.7 to 4.1 (m, 2H) 5.2 (d, 1H); 5.6 (d, 1H); 6.7 (s, 1H); 7.9 (s, 1H).

15. The NMR spectrum of the trifluoroacetic acid salt (perdeuterodimethylsulfoxide) contains the following signals: 2.05 and 2.1 (2s, 9H), 3.40-3.60 (2d, 2H);

5.1 (d, 1H); 5.4 (d, 1H);

16. The NMR spectrum of the product as a β trifluoroacetic acid salt (perdeuterodimethylsulfoxide) contains the following signals: 2.06 (s, 3H), 2.28 (s, 3H), 3.35 to 3.60 (2d, 2H), 5 18 (d, 1H); 5.65 (d, 1H); 7.2-7.6 (m, 5H); 8.2 (m, 1H).

17. The NMR spectrum of the product as a mixture of salts with hydrobromic acid and trifluoroacetic acid (perdeuterodimethyleulfoxide) contains the following signals: 2.08 (s, 3H), 2.10 (s, 3H), 3.30-3.60 (2d, 2H), 5.10 (d, 1H), 5.48 (d, 1H), 6.55 (s, 1H).

18. The NMR spectrum of the product in the form of hemitrifluoroacetate contains the following signals (perdeuterodimethylsulfoxide): 2.0 (s, 3H), 3.4 and 3.65 (2d, 2H), 4.3 (s, 2H), 4.75 and 5.05 (2d, 2H), 5.15 (d, 1H), 5.7 (m, 1H), 6.8 (s, 1H).

19. The NMR spectrum of the product as the trifluoroacetic acid salt contains the following signals (perdeuterodimethylsulfoxide): 2.1 (s, 3H), 2.2 (s, 3H), 3.7 (s, 2H), 4.9 (d) 1 H, 5.2 (d, 1H), 5.3 (d, 1H), 5.7 (m, 1H), 6.8 (s, 1H).

20. The NMR spectrum of the trifluoroacetic acid salt product contains the following signals (perdeuterodimethylsulfoxide): 1.7 (m, 4H), 2.0 (s, 3H), 2.4 (m, 4H), 3.4-

3.5 (m, 2H), 4.7 (d, 1H), 5.05 (d, 1H), 5.1 (d, 1H), 5.5 (d, 1H).

21. The NMR spectrum of the trifluoroacetic acid salt contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 2.0 (s, 3H), 3.5 to 3.6 (m, 2H), 4.7 (d, 1H), 5.0 (d, 1H), 5.2 (d, 1H), 5.7 (d, 1H), 7.0 (s, 1H), 7.1-7.7 (m, 5H).

22. The NMR spectrum of the trifluoroacetic acid salt contains the following signals (perdeuterodimethylsulfoxide): 2.04 (s, 6H), 2.67 (s, 3H), 3.68 (2d, 2H), 4.26-4. 56 (2d, 2H), 5.16-5.48 (2a, 2H).

23. The NMR spectrum of the trifluoroacetic acid salt product contains the following signals (perdeuterodimethylsulfoxide): 2.0 (s, 3H), 3.5 to 3.6 (quartet, 2H), 4.7 (d, III), 0 (d, 1H), 5.2 (d, 1H), 5.8 (d, 1H), 7.3 (s, 1H), 7.2-7.8 (m, 5H), 4 to

8.7 (m, IH).

24. The product melts at 244 ° C and its NMR spectrum contains signals (deuterium oxide + trifluoroacetic acid): 3.03 (d, 1H), 3.32 (d, 1H), 3.58 (d, 1H), 78 (d, 1H), 4.95 (d, 1H), 6.32 (s, 2H) (one proton of the beta-lactam moiety is obscured by a water signal at 4.6 to 4.8).

25. The product as a hydrate melts at 219-220 ° C with decomposition and its NMR spectrum (deuterium oxide + trifluoroacetic acid) contains the following signals: 1.50 (d, 6H), 3.6 (d, 1H), 3.83 (d, 1H), 4.2 (s, 2H), 4.6-5.1 (m, 1H), 5.48 (d, 1H), 6.82 (s, 2H), (one proton beta -lactam group covered by a water signal).

26. The NMR spectrum of the product contains the following signals (deuterium oxide + trifluoroacetic acid): 3.35 (d, 1H), 3.60 (d, 1H), 4.14 (s, 2H), 4.98 (d, 1H) 5.0 (quartet, 2H), 5.26 (d, 1H), 6.64 (s, 2H).

27. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 2.05 (s, 3H), 2.97 (t, 2H), 3.52 (d, 1H), 3.78 (d, 1H) ), 4.36 (bs, 2H), 4.51 (t, 2H), 5.09 (d, 1H), 5.52 (d, 1H), 6.82 (s, 2H).

Example 12

By repeating the procedure described in Example 1, the following compounds were obtained using the appropriate starting materials:

Η H

COOH

R ⁶ R ^{7 *} R ⁶ R ⁹ Note H H H 1 -O H H H 2 cis-CH3 H cis-CH ₃ H 3 trans-CH3 H _Tran-CH3 H 4 trana-CH3 H trans-CH3 AT 5 ch ₃ ch ₃ ch ₃ ch ₃ 6

Comment:

1. The trifluoroacetic acid salt product has the following NMR spectrum (perdeuterodimethylsulfoxide + deuterated acetic acid): 2.1 (s, 3H), 3.25-3.7 (m, 3H), 4.1 (t, 1H) 5.0 to 5.3 (m, 1H), 5.1 (d, 1H), 5.45 (d, 1H), 7.1 to 7.5 (m, 4H).

2. The NMR spectrum of the trifluoroacetic acid salt contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 2.1 (s, 3H), 3.3 to 3.75 (m, 3H), 4.1 (t, 1H), 5.1-5.5 (m, 3H), 6.9-7.3 (m, 4H).

3. The product resulting in a mixture of salts with hydrobromic acid and trifluoroacetic acid melts at 190 DEG C. and its NMR spectrum contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 1.1 (d, 6H), 2.08 (s). 3H), 3.32 (d, 1H), 3.58 (d, 1H), 4.1 (m, 2H), 5.08 (d, 1H), 5.4 (d, 1H).

4. The product in the form of a mixture of salts with hydrobromic acid and trifluoroacetic acid, containing 20% of the cis-isomer, has the stereochemistry corresponding to 1-threo-2,3-diaminobutane, melts with decomposition at 165 ° C and its NMR spectrum (perdeuterodimethylsulfoxide + deuterated acid) acetic) contains the following signals: 1.2 (d, 6H), 2.02 (s, 3H), 3.2 to

3.8 (m, 4H), 5.05 (d, 1H), 5.36 (d, 1H).

5. The product in the form of a mixture of salts with hydrobromic acid and trifluoroacetic acid has the stereochemistry corresponding to d-threo-2,3-diaminobutane, melts with decomposition at 165 ° C and its NMR spectrum (perdeuterodimethylsulfoxide + deuterated acetic acid) contains the following signals: 2 (d, 6H), 2.02 (s, 3H), 3.2-3.8 (m, 4H), 5.05 (d, 1H),

5.35 (d, IH).

6. The NMR spectrum of the product in the form of a mixture of salts with hydrobromic acid and trifluoroacetic acid contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 1.22 (s, 12H), 2.1 (s, 3H), 3.35 (d, 1H), 3.63 (d, 1H), 5.1 (d, 1H),

5.35 (d, IH).

Example 13

By repeating the procedure described in Example 3, the following compounds were obtained using the appropriate starting materials:

\

COOH

R ²

Note

N-N

CH-5-OH

H.

CH,

CH ₂ OCH ₃ ch ₂ oco

N - N CH ₂ S - LgA

SCH,

NN ch ₂ s — L _s A.

Sh

CH ₂ N ₃

CH,

H 5

H 4

H 6

H 7

CH ₂ NH ₂ 8 ch ₂ nh ₂

CH ₂ NHCOCH ₃

CH ₂ OCOCH ₃

H 9

H 10

CH ₂ NH ₂

CH,

N-Ti

CH, S — ζ V-OH continued table

R ¹ R ² Note S N-CH ₂ S- <II _N-CH3 H 13 H 14 ^cb ^ OO H 15 Dec NN ^CH 2 ⁸ AA ch ₂ Sat ₃ h H 16 CH ₂ OH H 17 CHgOCOCHj ch ₂ ch ₂ ch ₂ nh ₂ 18

Comment:

1. The NMR spectrum of the product contains the following: signals (DMSO): 3.3 (s, 3H), 3.5 (d, 1H), 3.8 (d, 1H), 1H), 6.9 (s, 2H).

2. NMR spectrum of the product in the form of salt signals (perdeuterodimethylsulfoxide) 1H), 5.5 (d, 1H), 6.9 (d, 2H).

3. NMR Bp spectrum of the product in the form of salt signals (perdeuterodimethylsulfoxide (m, 1H), 5.0 (d, 1H), 5.3 (d, 1H), (m, 5H).

4. NMR spectrum of the product in the form of salt signals (perdeuterodimethylsulfoxide · (d, 1H), 5.7 (d, 1H), 6.55 (t, 1H);

5. NMR spectrum of the product in the form of salt signals (perdeuterodimethylsulfoxide (d, 1H), 3.8 (d, 1H), 4.3 (d, 1H);

1.9 (d, 1H), 4.3 (d, 1H), 5.2 (d, 1H), 5.7 (m, with trifluoroacetic acid contains the following 3.2 (s, 3H), 3, Δ (m, 2H), 4.2 (s, 2K), 5.2 (d, with trifluoroacetic acid contains the following deuterated acetic acid): 3.6 (m, 1H), 3.9, 4 (d, 1H), 5.7 (d, 1H), 7.0 (d, 2H), 7.4-8.1 with trifluoroacetic acid contains the following deuterated acetic acid): 3.65 (s, 2H), 5.1

7.0 (s, 2 H).

trifluoroacetic acid contains the following deuterated acetic acid): 2.8 (s, 3H), 3.7, 5 (d, 1H), 5.2 (d, 1H), 5.6 (d, 1 Η), 7.0 (s, 2H).

6. The NMR spectrum of the product as the trifluoroacetic acid salt contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 3.5 (d, 1H), 3.6 (d, 1H), 4.1 (d, 1H), 4.2 (d, 1H), 5.05 (d, 1H), 5.6 (d, 1H), 6.8 (s, 2H).

7. NMR spectrum of the product as a trifluoroacetic acid salt containing 20%

Δ-isomer, contains the following signals (perdeuterodimethylsulfoxide * deuterated acetic acid): 3.55 (d, 1H), 3.75 (d, 1H), 4.0 (d, 1H), 4.5 (d, 1H) 5.25 (d, 1H); 5.75 (d, 1H); 7.0 (s, 2H).

8. The NMR spectrum of the p-toluenesulfonic acid salt product contains the following signals (perdeuterodimethylsulfoxide): 2.22 (s, 3H), 3.4 to 4.2 (m, 6H), 5.08 (d,

1H), 5.52 (d, 1H), 6.83 (a, 1H), 7.0 (d, 2H), 7.5 (d, 2H), 7.85 (s, 1H).

9. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 3.2 to 3.8 (m, 4H), 5.05 (d, 1H), 5.55 (d, 1H), 6.9 (s, 2H).

10. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 1.9 (s, 3H), 3.3 (d, 1H), 3.55 (d, 1H), 3.9 (d, 1H) ), 4.2 (d, 1H), 5.05 (d, 1H), 5.5 (d, 1H), 6.8 (s, 2H), 8.2 (s, 3H).

11. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide): 2.05 (s, 3H), 3.58 (q, 2H), 3.85 (s, 2H), 4.7 (d, 1H), 1 (d, 1H), 5.17 (d, 1H), 5.68 (d, 1H), 6.76 (s, 1H).

12. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide + trifluoroacetic acid): 3.2 (d, 1H), 3.6 (d, 1H), 3.7 (s, 3H), 3.7 (d, 1H) 4.1 (d, 1H); 5.25 (d, 1H); 5.51 (d, 1H); 7.05 (s, 2H).

The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide + trifluoroacetic acid): 2.65 (s, 3H), 3.45-4.0 (m, 2H), 4.5 (s, 2H), 5.25 ( d, 1H),

5.6 (d, 1 H).

14. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide): 3.6 (s, 2H), 3.8 to 4.1 (m, 2H), 5.05 (d, 1H), 5.45 (d, 1H) 6.8 (s, 2H), 6.8-8.1 (m, 3H).

15. The NMR spectrum of the product contains the following signals (deuterium oxide + trifluoroacetic acid): 3.95 (d, 1H), 4.22 (d, 1H), 5.0 (broad signal, 2H), 5.52 (d, 1H) 5.80 (d, 1H), 7.2 (s, 2H), 9.0-9.3 (m, 2H).

16. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide / acetic acid): 3.35 to 3.85 (m, 2H), 3.65 to 4.15 (m, 2H), 4.0 (s, 2H), 5.2 (d, 1H), 5.35 (broad signal, 1H), 7.0 (s, 2H).

17. The NMR spectrum of the product contains the following signals (deuterium oxide + pyridine): 3.34 (d, 1H), 3.6 (d, 1H), 4.25 (d, 1H), 4.5 (d, 1H), 5.26 (d, 1 H), 5.55 (d, 1 H), 6.65 (d, 2 H).

18. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 2.05 (m, 2H), 2.07 (s, 3H), 2.55 (t, 2H), 2.82 (t, 2H) ), 3.58 (q, 2H), 4.89 (q, 2H), 5.28 (d, 1H), 5.9 (d, 1H), 6.78 (s, 1H).

Example 14

The procedure described in Example 3 was repeated except that the corresponding 7-amino-ephthalosporin derivative was used as the starting material. The following compounds are obtained:

R ¹ R ² Note N N ch ₂ 8-IL ₈ J L-ch ₃ <Q 1, 2 0 N — N CH3S — JJ — CH3 CH ₂ OCOOC ₂ H ₅ 1, 3, 4 Cl H 5, 6 N — N ch ₂ s ~ jL _n her H H 7, 5, 8 N — N ch ₂ s-1 _s > -ch ₃ ch ₂ coch ₃ 1, 3, 9 N — N CH ₂ S ——ch ₃ CH ₂ OCOC ₄ Hg 10, 3, 11

Comment:

1 · Reaction as carried out in a sweep of methanol and chloroform.

2. The NMR spectrum of the hydrochloride contains the following signals (perdeuterodimethylsulfoxide + + deuterated acetic acid): 2.65 (s, 3H), 3.75 (d, 2H), 4.4 (q, 2H), 5.25 (d, 1H),

5.7 (d, 1H), 7.0 (s, 2H), 7.6 (β, 1H), 7.75 (s, 4H).

3. The reaction is carried out in the presence of potassium carbonate.

O

4. The NMR spectrum of the p-toluenesulfonic acid salt containing 30% of the obsahuje-isomer contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 1.25 (t, 3H), 2.3 (s, 3H), 2.7 ( s, 3H), 3.75 (m, 2H), 4.2 (m, 2H), 4.25 (d, 1H), 4.55 (d, 1H), 5.3 (m, 1H), 5.55 (m, 1H), 5.8 (s, 2H), 7.0 (s, 2H), 7.1 (d, 1H), 7.5 (d, 1H).

5. The product is purified by high pressure liquid chromatography.

6. The NMR spectrum of the hydrochloride in trifluoroacetic acid contains the following signals:

3.6 (d, 1H), 3.9 (d, 1H), 5.4 (s, 1H), 5.6 (s, 1H), 6.85 (s, 2H).

7. The reaction is carried out in a mixture of dimethylformamide and acetonitrile.

8. The hydrochloride Ni spectrum contains the following signals (perdeuterodimethylsulfoxide):

3.8 (s, 2H), 4.35 (q, 2H), 5.15 (q, 2H), 7.08 (s, 2H), 9.11 (s, 1H).

9. NMR salts of p-toluenesulfonic acid contain the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 2.15 (s, 3H), 2.3 (s, 3H), 2.75 (β, 3H), 3.75 (broad signal, 2H), 4.95 (s, 2H), 5.3 (broad signal, 1H), 5.65 (broad signal, 1H), 6.85 (s, 1H).

10. The reaction is carried out in aqueous dimethylformamide.

11. The product after purification by chromatography on silica at -20 ° C, was obtained as a mixture of Δ - and -isomers and ^J, which comprises the following NMR signals (DMSO-deuterated acetic acid): 1.2 (s, 9H), 2 75 (3H), 7.97 (2H).

The starting materials used in the above process can be prepared as follows:

Reaction of 7-triphenylmethylamino-3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethylceph-3-em-4-carboxylic acid with 3-iodophthalide (prepared from 3-bromophthalide) in dimethylsulfoxide in the presence of carbonate Potassium ester gave the corresponding ester which was purified by silica gel chromatography. This ester is treated with p-toluenesulfonic acid in acetonitrile phthalidyl-7-amino-3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethylceph-3-em-4-carboxylate.

Reaction of 7-triphenylmethylamino-3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethylcef-3-em-4-carboxylic acid with chloromethyl ethyl carbonate in dimethylsulfoxide in the presence of potassium carbonate affords the corresponding ethoxycarbonyloxymethyl ester, which was purified by silica gel chromatography. This ester is treated with p-toluenesulfonic acid in acetonitrile to give ethoxycarbonyloxymethyl-7-amino-3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethylcef-3-em-4-carboxylate whose NMR The spectrum measured in perdeuterodimethylsulfoxide contains the following signals: 1.25 (t, 3H), 2.35 (s, 3H), 2.75 (s, 3H), 4.25 (broad signal, 4H),

5.9 (s, 2 H).

Reaction of 3-chloro-7- (2-amino-2-phenyl) acetylaminoceph-3-em-4-carboxylic acid (cefachlor) with p-toluenesulfonyl chloride in aqueous tetrahydrofuran at 0 ° C affords 2 3 of the corresponding p-toluenesulfonamide in in the form of a mixture of Δ - and Δ-isomers. Reaction of this mixture of acids with diphenyldiazomethane in a mixture of acetonitrile and hexane gives the corresponding diphenylmethyl ester as a mixture of the Λ - and Δ-isomers. This mixture was treated with 3-chloroperbenzoic acid in dichloromethane to give the corresponding 1-oxide which was isolated as the pure isisomer. This isomer is reduced by treatment with phosphorus trichloride in dimethylformamide. The product obtained is treated in dichloromethane with phosphorus pentachloride in pyridine and then 1,3-dihydroxybutane to give 3-chloro-7-aminoceph-3-em-4-carboxylic acid, the NMR spectrum of which contains the following signals (trifluoroacetic acid + perdeuteromethanol). ): 3.85 (s, 2H), 5.30 (d, 1H), 5.45 (d, 1H).

Reaction of 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid with 1H-1,2,4-triazole-3-thiol in aqueous acetone in the presence of sodium bicarbonate affords 7-amino-3- (1H-1). 2,4-triazol-2-yl) thiomethylcef-3-em-4-carboxylic acid.

Reaction of 3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-7-triphenylmethylaminoceph-3-em-4-carboxylic acid 8 with chloroacetone in dimethylformamide in the presence of potassium carbonate affords the corresponding acetyl methyl ester. This compound is treated with acetylmethyl-7-amino-3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethylcef-3-em-4-carboxylate-p-toluenesulfonate in acetonitrile in p-toluenesulfonic acid.

Reaction of 3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-7-triphenylmethyl &apos; -ceino-3-em-4-carboxylic acid with iodomethyl pivalate in dimethylformamide in the presence of potassium carbonate affords the corresponding ester. This compound provides pivaloyloxymethyl-7-amino-3- (2-methyl-1,3,4-thiadiazol-5-yl) thionethylceph-3-em-4-carboxylate-p-toluenesulfonate by treatment with p-toluenesulfonic acid in acetone.

Example 15

A mixture of 500 mg of ethoxycarbonyloxymethyl-7-amino-3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethylceph-3-em-4-carboxylate-p-toluenesulfonate and 500 mg of 2-fluoro-4- methyl 1-triphenylmethylimidazole in a 2 ml mixture of chloroform and ethanol (4: 1 v / v) was heated at 60 ° C for 2 hours. The solvent was evaporated and the residue was purified by silica gel chromatography at -15 ° C using dichloromethane. methanol and acetic acid (96: 3.5: 0.5 v / v / v) as eluent. There was obtained ethoxycarbonyloxymethyl-7- (4-methylimidazol-2-yl) amino-3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethylcef-3-em-4-carboxylate, the NMR spectrum of which contained the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 1.2 (t, 3H), 2.1 (s, 3H), 2.25 (s, 3H), 2.75 (s, 3H), 4.2 ( m, 4H), 5.3 (m, 1H), 5.4 (m, 1H), 5.8 (s,

2H), 6.7 (d, 1H), 7.1 (d, 1H), 7.5 (d, 1H).

Example 16

The procedure described in Example 4 was repeated using the respective 2-fluoro-1-triphenylmethylimidazole and the 7-aminocephalosporin derivative as starting materials. The following compounds are obtained:

COOH ch ₂ oconh ₂

N-CH3

Note

1, 2

3. 4 continued table

R ¹ R ² Note N — N CjsTJÍ CH ₃ CHOHCH ₂ 5 6 7 I CH ₃ N-1-CH 3, ^CH 2 ^{S -} Γ 5 -> - ( ^CH ₃ ) ₃ COOH H 8, 9, 10 N - N ^CH 2 ^S -A _n ) * I ^CH 3 CH ₃ (CH ₂ ) ₃ 11, 12, 13 CH3S '^ ® o © H 14 N - N ch ₂ s - L _{s NHCOCH 3} H 3, 15, 16

Comment:

1. The high pressure liquid chromatography eluent is a 90: 10: 1 (v / v / v) mixture of water, methanol and acetic acid.

2. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 3.56 (q, 2H), 4.8 (q, 2H), 5.18 (d, 1H), 5.58 (d, 1H) 6.96 (s, 1H).

3. The high pressure liquid chromatography eluent is a 70: 30: 1 (v / v / v) mixture of water, methanol and acetic acid.

4. NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 3.46 (d, 1H), 3.74 (d, 1H), 3.86 (d, 1H), 4.09 (s, 3H) 4.17 (d, 1H), 5.08 (d, 1H), 5.5 (d, 1H), 6.84 (s, 2H), 8.69 (s, 1H).

5. The high pressure liquid chromatography eluent is a 75: 25: 1 (v / v / v) mixture of water, methanol and acetic acid.

6. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 1.07 (d, 3H), 2.46 (m, 2H), 3.66 (q, 2H), 3.93 (s, 3H) ), 4.32 (broad singlet, 2H), 5.1 (d, 1H), 5.54 (d, 1H), 6.64 (s, 1H).

7. The starting fluorimidazole can be prepared as follows. For the preparation of 2-fluoro-4- (3-hydroxypropyl) -1-triphenylmethylimidazole on a larger scale, chromatography on silica gel, using mixtures of petroleum ether (b.p. 60-80 ° C) and ether in volume ratios from 50:50 to 0: 100, isolates the 2-hydroxypropyl derivative as a byproduct. The NMR spectrum of this product contains the following signals (deuterochloroform): 1.18 (d, 3H), 2.47 (m, 2H), 3.3 (broad singlet, 1H), 4.0 (m, 1H), 6, 27 (s, 1H), 7.0-7.5 (m, 15H).

8. The high pressure liquid chromatography eluent is a 60: 40: 1 (v / v / v) mixture of water, methanol and acetic acid.

9. NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 1.71 (m, 2H), 2.18 (t, 2H), 2.24 (s, 3H), 2.7 (t, 3H) )

3.44 (d, 1 H), 3.73 (d, 1 H), 4.07 (d, 1 H), 4.47 (d, 1 H), 5.06 (d, 1 H), 5.54 (d, 1 H) )

6.8 (a, 2 H).

10. The starting material can be prepared as follows. Reaction of 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid with 5- (3-carboxypropyl) -4-methylthiazole-2-thiol in a pH 6.4 buffer in the presence of sodium bicarbonate affords 7-amino- 3- [5- (3-Carboxypropyl) -4-methylthiazol-2-yl] thiomethylceph-3-em-4-carboxylic acid. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 1.71 (m, 2H), 2.17 (t, 2H), 2.23 (s, 3H), 2.68 (t, 2H), 3.43 (d, 1H), 3.74 (d, 1H), 3.98 (d, 1H), 4.44 (d, 1H), 4.73 (d, 1H), 4.93 (d) , 1H).

11. The high pressure liquid chromatography eluent is a 55: 45: 1 (v / v / v) mixture of water, methanol and acetic acid.

12. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide * deuterated acetic acid): 0.9 (t, 3H), 1.1 to 1.8 (m, 4H), 2.3 to 2.5 (obscured by H 2 O) O, 2H), 3.52 (d, 1H), 3.78 (d, 1H), 4.34 (broad singlet, 2H), 5.08 (d, 1H), 5.56 (d, 1H);

1H), 6.58 (b, 1H).

13. The starting material can be prepared as follows: reaction of 4-formyl-2-fluoro-1-triphenylmethylimidazole with allyltriphenylphosphonium bromide in dichloromethane in the presence of aqueous sodium hydroxide affords 4-0,4-butadienyl) -2-fluoro-1-triphenylmethylimidazole. This dione is hydrogenated in ethyl acetate in the presence of palladium on carbon at atmospheric pressure to give 4-butyl-2-fluoro-1-triphenylmethylimidazole whose NMR spectrum contains the following signals (deuterochloroform): 0.9 (t, 3H), 1 , 1 to

1.8 (m, 4H), 2.42 (t, 2H), 6.2 (β, 1H), 7.0-7.4 (m, 15H).

14. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 3.46 (d, 1H), 3.73 (d, 1H), 4.17 (s, 2H), 5.16 (d, 1H) 5.55 (d, 1H), 6.8 (s, 2H), 8.28 (dd, 1H), 7.05 to 7.69 (3H).

15. The NMR spectrum of the product contains the following signals (perdeuterodimethylsulfoxide + deuterated acetic acid): 2.13 (s, 3H), 3.41 (d, 1H), 3.73 (d, 1H), 4.19 (d, 1H) )

4.44 (d, 1 H), 5.06 (d, 1 H), 5.64 (d, 1 H), 6.71 (s, 2 H).

16. The starting material can be prepared as follows. Reaction of 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid with β 2 -acetylamino-1,3,4-thiadiazole-5-thiol in a mixture of acetone and buffer pH 6.4 in the presence of sodium bicarbonate gives 7 amino-3- (2-acetylamino-1,3,4-thiadiazol-5-yl) thiomethyl-3-em-4-carboxylic acid41

Whose NMR spectrum contains the following signals (perdeuterodimethylsulfoxide + + deuterated acetic acid): 2.14 (s, 3H), 3.43 (d, 1H), 3.73 (dd, 1H), 4.06 (d, 1H) ), 4.4 (d, 1H), 4.7 (d, 1H), 4.91 (d, 1H).

Claims (3)

Process for the preparation of cephalosporin derivatives of the general formula I R ³ N AND N Η H in which ii 'represents a hydrogen or chlorine atom, a methyl group, an acetoxymethyl group, 1-methyl-1H-tetrazol-5-ylthiomethyl, 1-carboxymethyl-1H-tetrazol-5-ylthiomethyl, 1- (2-dimethylamino) ethyl-1H-tetrazol-5-ylthiomethyl, 1 -sulfomethyl-1H-tetrazol-5-ylthiomethyl, 1-isopropyl-1H-tetrazol-5-ylthiomethyl, 1- (2,2,2-trifluoro) ethyl-1H-tetrazol-5-ylthiomethyl, 1-phenyl -1H-tetrazol-5-ylthiomethyl, 1- (2-methylthio) ethyl-1H-tetrazol-5-ylthiomethyl, 1,3,4-thiadiazol-2-ylthiomethyl, 5-methyl-1,3,4 -thladiazol-2-ylthiomethyl group, 1,2,3-thiadiazol-5-ylthiomethyl, 1H-1,2,3-trlazol-4-ylthiomethyl, 5-trifluoromethyl-1H-1,2,4-triazol-3-ylthiomethyl, 4,6 -dimethylpyrimid-2-ylthiomethyl, 2-thiazolin-2-ylthiomethyl, benzoxazol-2-ylthiomethyl, benzthiazol-2-ylthiomethyl, 2-carboxyphenylthiomethyl, (6-carboxymethyl-7-hydroxypyrrolo [1,2-b] thiomethyl) ] pyridazin-2-yl) thiomethyl, methoxymethyl, hydroxymethyl, azidomethyl, aminomethyl, benzoyloxymethyl, acetylaminomethyl, carbamoyloxymethyl, 2-methylthio-1,3,4-thiadiazol-5-ylthiomethyl, 2- mercapto-1,3,4-thiadiazol-5-ylthiomethyl, 2-acetylamino-1,3,4-thiadiazol-5-ylthiomethyl, 5-methyl-1,2,4-thiadiazol-2-ylthiomethyl, 2 -sulfomethyl-1,2,4-oxadiazol-5-ylthiomethyl, 4-methyl-5- (3-carboxypropyl) thiazol-2-ylthiomethyl, 2H-2-methyl-1,2,3-triazole-4- ylthiomethyl group; 1H-1,2,4-triazol-2-ylthiomethyl, 4,5-dihydro-6-hydroxy-4-methyl-5-oxo-1,2,4-triazin-3-ylthiomethyl, 2, 5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-2-ylthiomethyl, 1-oxidopyrid-2-ylthiomethyl, imidazo [4,5-b] pyrid-2- ylthiomethyl or imidazole [4,5-d] pyrimidin-2-ylthiomethyl, R represents a carboxyl radical or a radical of formula Cooch ₂ OCOR 'wherein ^{0 0} R ¹ denotes methyl, ethyl or t-butyl, or R is a radical of formula COOCH ₂ COCH ₃ or coo r 3 represents a hydrogen atom, a hydroxyl group, a methyl group, a methoxy group, an acetyl group or a 4-methoxybenzyl group and A is a radical of formula (IX) or (III) R ⁶ (II) (III) in which: Each of R and R, which may be the same or different, each represents a hydrogen atom, a cyano group, a hydroxyl group, a carboxyl group, a methyl group, a hydroxymethyl group, a 3-hydroxypropyl group, an ethoxycarbonyl group, a phenyl group, an aminomethyl group; a hydroxypropyl, propyl, butyl or 3-aminopropyl group, or 4 5 R and R are taken together and together with the carbon atoms to which they are attached to form a cyclohexene, benzene, naphthalene or dihydroacenaphthalene ring, wherein the benzene ring is optionally substituted with one or two substituents selected from the group consisting of fluorine and chlorine atoms, hydroxyl, amino , carboxyl, nitro, methyl, methoxy, trifluoromethyl, hydroxymethyl, aminomethyl, acetylamino, azidomethyl, acetylaminomethyl, cyanomethyl and carbamoylmethyl, and residues of formulas IV, V and VI ch ₂ - ch ₂ ) ₆ (ch ₂ - ch ₂ ) ₆ ( IV) CH 2 HCOGHgNHg (V) CH ₂ NHCOCH (Ph) NH ₂ (VI) wherein Ph is phenyl, and each of R 8, R 7, R 8 and R 6, which may be the same or different, is hydrogen, hydroxymethyl, aminomethyl, carbamoyl, methoxycarbonyl, methyl, n- hexyl, phenoxymethyl, optionally substituted with diphenylmethyl, or phenyl, optionally substituted with one or two substituents selected from the group consisting of fluorine and chlorine atoms, cyano, hydroxyl, phenyl, and dimethylamino, or 1 fi R and R, when cis to one another, are linked together and together with the carbon atoms to which they are attached form a cyclopropane, cyclobutane, cyclopentene or cyclohexane ring, or 6 7 8 9 R 0 represents a carboxyl group and R 3a represents hydrogen atoms, and pharmaceutically acceptable acid or base addition salts of those compounds of formula (I) which contain free basic or acidic groups, characterized in that the compound of formula (VII) Η H (VII) in which 1 2 R and R are as defined above, reacted with a compound of formula VIII (VIII) R ³ wherein a is as defined above and a R ^J is halogen, then optionally the obtained compound of formula I having free acid groups, by reaction with a base affording a pharmaceutically acceptable cation is converted to its acid addition salt with a base or a resulting compound of formula I containing free basic groups, optionally converted by reaction with an acid providing a pharmaceutically acceptable anion to its acid addition salt. 2. The process according to item 1, for the preparation of the compounds of the above general formula I, wherein R, R and R are as defined in item 1 and R @ 2 is the radical of the above formula (II) or (III) in which each of R @ 1 and R @ 2 which may be the same or different represents a hydrogen atom, a cyano group, a hydroxyl group, a carboxyl group, a methyl group, a hydroxymethyl group. , 3-hydroxypropyl, ethoxycarbonyl, or phenyl; R and R are taken together and together with the carbon atoms to which they are attached to form a cyclohexene, benzene, naphthalene or dihydroacenaphthalene ring, wherein the benzene ring is optionally substituted with one or two substituents selected from the group consisting of fluorine and chlorine atoms, hydroxyl, amino , carboxyl, nitro, methyl, methoxy, trifluoroethyl, hydroxyethyl, aminomethyl, acetylamino, cyanomethyl and carbamoylmethyl, and the radicals of the above formulas IV, V and VI, wherein Ph is phenyl and each of R ^ is R ^; , R,, R® and R ⁹ , which may be the same or different, each represent a hydrogen atom, a hydroxymethyl group, a methyl group, an n-hexyl group, a phenoxymethyl group, or a phenyl group optionally substituted by one or two substituents selected from the group consisting of chlorine atoms, kya a hydroxyl group, a phenyl group, and a dimethylamino group, or 7 8 R 1 and R 2, when cis to each other, are taken together and together with the carbon atoms to which they are attached to form a cyclopropane, cyclobutane, cyclopentene or cyclohexane ring, or bP represents a carboxyl group and R 7, R 8 and R 8 Are hydrogen atoms, and pharmaceutically acceptable acid or base addition salts of the compounds of formula (I) which contain free basic and / or free base salts, respectively. acidic group, characterized in that the compound of the above formula (VII), wherein R 1 and R ² are as defined in (1), is reacted with a compound of the above formula (VIII), in which a r 1 is as defined in and optionally having a free acid group thereof, reacted with a base providing a pharmaceutically acceptable cation to a base addition salt thereof, or a compound of formula I containing a compound of formula I containing a free acid group. the free base group, optionally converted by treatment with an acid giving a pharmaceutically acceptable anion to its acid addition salt. 3. Process according to claim 1, characterized ee that is used as starting material elouče3 15 Nina formula VIII in which R A and ^J are as defined in claim 1 and R is fluorine or chlorine, and the reaction is carried out in the presence of at least one acid equivalent.