RU2043354C1 - Esters of 10-(1-hydroxyethyl)- 11-oxo-1 -azatricyclo- [7,2,0,03,8]-undec- 2-ene-2- carboxylic acid and a method of their synthesis - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: products: esters of 10-(1-hydroxyethyl)- 11-oxo-1-azatricyclo- [7,2,0,0^3,8]-undec-2-ene- 2-carboxylic acid of the formula (I)

where R₁ CH(R₄)-O-C(O)-(O)_p-R₅ where R₄- H, C₁-C₄-alkyl; p 0 or 1; R₅-C₁-C₆-alkyl, C₅-C₈-cycloalkyl, phenyl; R₂ methoxy-group. Reagent 1: compound of the formula (II)

where R₂ methoxy-group, Ra H or hydroxyl-protecting group. Reagent 2: esterifying agent used for removal of R₁-group. Reaction condition: in the medium of organic solvent. Synthesized compounds were used in medicine. EFFECT: improved method of synthesis. 9 cl

Description

 The invention relates to heterocyclic derivatives having antibacterial activity, to methods for their preparation, to compositions containing them and to their use in medicine.

в которой R₁ представляет собой группу

O

(O)_pR₅ где R₄ является атомом водорода или С₁-С₄ алкильной группой; p= 0 или 1; R₅ представляет собой группу, выбранную из С₁-С₆ алкила, С₅-С₈циклоалкила, необязательно замещенного С₁-С₃ алкильной группой, фенила или С₁-С₄ алкила, замещенного С₁-С₃ алкоксигруппой; R₂ является группой OR₃, в которой R₃ представляет собой С₁-С₅ алкильную группу.Thus, the present invention provides compounds of general formula I

in which R ₁ represents a group

O

(O) _p R ₅ where R ₄ is a hydrogen atom or a C ₁ -C ₄ alkyl group; p is 0 or 1; R ₅ represents a group selected from C ₁ -C ₆ alkyl, C ₅ -C ₈ cycloalkyl optionally substituted with a C ₁ -C ₃ alkyl group, phenyl or C ₁ -C ₄ alkyl substituted with a C ₁ -C ₃ alkoxy group; R ₂ is an OR ₃ group in which R ₃ is a C ₁ -C ₅ alkyl group.

In addition, as defined in formula I in terms of stereochemical arrangement, the molecule contains two different asymmetric carbon atoms at positions 4 and 8. The group R ₁ also contains at least one asymmetric carbon atom when R ₄ has a value other than hydrogen. It is obvious that all stereoisomers, including mixtures thereof, resulting from such additional asymmetric centers, are encompassed by formula I.

 General formula I includes at least 4 stereoisomers and mixtures thereof, and these compounds can be represented by formulas 1a, 1b, 1c and 1d.

CH

Связь, обозначенная в форме клина

обозначает, что связь располагается выше плоскости рисунка. Связь, изображенная прерывисто обозначает связь, располагающуюся ниже плоскости рисунка.

CH

Wedge-shaped relationship

indicates that the bond is located above the plane of the picture. The bond depicted intermittently indicates a bond located below the plane of the picture.

 The configuration depicted for the carbon atom in position 8 in formulas 1a and 1b is a configuration that further refers to the β-configuration, and in formulas 1c and 1d to the d-configuration.

 The configuration depicted for the carbon atom in position 4 in formulas 1b and 1d is a configuration that further refers to the α-configuration, and in formulas 1a and 1c to the β-configuration.

 In general, in the individual compounds mentioned below, the β-configuration at position 8 corresponds to the S-isomer, and the β-configuration at position 4-R-isomer. The α-configuration at position 8 corresponds to the R-isomer, the α-configuration at position 4 corresponds to the S-isomer. The location of the R or S configuration in positions 4 and 8 is in accordance with the Cahn rules. Ingold and PrelogExperienta, 1956, 12, 81.

The term alkyl used in this work refers to a straight or branched chain alkyl group. When R ₄ is a C ₁ -C ₄ alkyl group, it may be, for example, methyl, ethyl, propyl, isopropyl or butyl.

When R ₅ is an alkyl group, it usually represents a C ₁ -C ₄ alkyl group such as methyl, ethyl, isopropyl or t-butyl.

In the case where R ₅ is a C ₁ -C ₄ alkyl group substituted with a C ₁ -C ₃ alkoxy, it may be, for example, methyl, ethyl, propyl or isobutyl substituted with a methoxy group.

In the case where R ₅ is cycloalkyl optionally substituted with C ₁ -C ₃ alkyl, it may be, for example, a cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group substituted with a methyl or ethyl group.

 A preferred class of compounds of formula I are compounds having a β configuration at position 8. Within this class, compounds having an α configuration at position 4 are particularly preferred.

Another preferred class of compounds of formula I are compounds in which R ₄ is hydrogen, methyl, propyl or isopropyl, in particular hydrogen or methyl.

Another preferred class of compounds of formula I are those compounds in which R ₅ represents a C ₁ -C ₄ alkyl group such as methyl, ethyl, isopropyl or t-butyl; A C ₁ -C ₄ alkyl group substituted with methoxy, such as 1-methoxy-1-methylethyl; phenyl; or a C ₅ -C ₆ cycloalkyl group, such as cyclopentyl or cyclohexyl, optionally substituted with a methyl or ethyl group, such as ethylcyclohexyl.

Another preferred class of compounds of the invention are also compounds of formula I in which R ₂ is an ethoxy or methoxy group.

A particularly preferred group of esters according to the invention are those in which R ₄ is a hydrogen atom or a methyl group, p = 0 or 1, and R ₅ is methyl, ethyl, isopropyl, t-butyl, 1-methoxy-1- methylethyl, phenyl, cyclohexyl or 4-ethylcyclohexyl group.

A particularly preferred group of compounds of the invention are those in which the carbon atom at position 8 is characterized by a β-configuration and the carbon atom at position 4 is an α-configuration; R ₄ is a hydrogen atom or a methyl group; R ₅ is C ₁ -C ₄ alkyl, C ₅ -C ₆ cycloalkyl optionally substituted with a C ₁ -C ₂ alkyl group, phenyl or C ₁ -C ₄ alkyl substituted with methoxy; p is 0 or 1, and R ₂ is methoxyl.

 Particular preferred compounds are esters of (4S, 8S, 9R, 10S, 12R) -4-methoxy-10- (1-hydroxyethyl) -11-oxo-1-azatricyclo [7.2.0.03.8] undec-2-ene -2-carboxylic acids such as pivaloyloxymethyl, 1-pivaloyloxyethyl, acetoxymethyl, 1-acetoxyethyl, 1-methoxy-1-methylethylcarbonyloxymethyl, 1- (1-methoxymethylethylcarbonyloxyethyl, 1-benzoyloxyethyl-1-isoxypropyloxy-1-methoxy-methoxy-methoxy, - (4-ethyl-cyclohexyloxycarbonyloxy) ethyl or more preferably 1-cyclohexyloxycarbonyl xylethyl ether.

 The compounds according to the invention, when administered orally, show a high level of antibacterial activity in relation to a wide variety of pathogenic microorganisms and have a very high resistance to all β-lactamases. The compounds of the invention are also relatively stable against renal dehydropeptidase.

 It was found that the compounds of the invention show a significant level of activity against the strains of Staphylococcus aureus, Streptococcus faecalis, Streptococcus pneumonial, Escherichia coli, Klebsiella pneumonial, Proteus mirabiles Citrobacter freundii, Preudomonas aeruginosa, Cloctridium perfingens morganio genus Mobacteribilis and Bactergan motganio.

 The compounds of the invention can thus be used to treat a number of diseases caused by pathogenic bacteria existing in humans and animals.

 Therefore, in accordance with another aspect of the present invention, we provide a compound of formula I for use in the treatment or prevention of common bacterial infections in humans or animals.

 In accordance with another aspect of the invention, we present the use of a compound of formula I for the manufacture of therapeutic agents for the treatment of common bacterial infections existing in humans and animals.

 In accordance with another aspect of the invention, we present a method of treating humans or non-human animals, including the fight against bacterial infections, which consists in taking an effective amount of a compound of formula I.

 For a person skilled in the art it is clear that the references to exposure that apply to this apply to prevention, as well as the treatment of established infections and symptoms.

 It is essential that the amount of the compound of the invention required for use in the treatment will vary depending on the exposure conditions, the age and conditions of the patient and, ultimately, will be separately selected by the appropriate physician or veterinarian. Typically used doses for treating an adult are in the range of 200-2000 mg per day, for example, 1000 mg per day.

 The required dose is usually taken as a single dose or as divided doses taken at appropriate intervals, for example, as two, three, four or more sub-doses per day.

 Although it is possible to take a compound of the invention as an unprocessed chemical preparation for use in therapy, it is preferable to take the active ingredient in the form of a pharmaceutical composition.

 The invention, therefore, further provides an oral pharmaceutical composition comprising a compound of Formula I together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and / or prophylactic ingredients. Carriers should be “acceptable” in terms of their compatibility with other ingredients of the composition and not harmful to those who take them.

 According to the invention, the pharmaceutical compositions may, for example, be in the form of tablets or capsules prepared by standard methods with pharmaceutically acceptable excipients, such as binding agents (e.g. pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose), excipients (e.g. starch, lactose , microcrystalline cellulose or calcium phosphate), lubricants (e.g. magnesium stearate, hydrogenated vegetable oil, talc, cream dioxide Ia, polyethylene glycols), dizintegranty (e.g. potato starch or sodium starch glycollate) or wetting agents (e.g. sodium lauryl sulphate). If necessary, flow aids, such as silicon dioxide, may also be used. Tablets can be prepared coated using methods well known in the art.

 Liquid compositions for oral administration can be prepared, for example, in the form of solutions, syrups or suspensions, or they can be prepared as a dry product or for reconstitution with water or another suitable diluent before use for administration, or as a liquid for direct administration and subsequent rinsing water or other suitable liquid. Such liquid formulations can be prepared using standard methods using acceptable additives, such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats and oils, such as castor oil), emulsifying or thickening agents (e.g. lecithin, aluminum stearate or acacia), non-aqueous solvents (e.g. almond oil, coconut oil, synthetic ester oils or ethyl alcohol), preservatives (e.g. methyl or butyl p-hydroxy enzoaty or sorbic acid) and suitable flavoring and sweetening agents.

в которой R_а является водородом или гидроксил-защищающей группой, а R₂имеет значение, определенное для формулы I, или соли, или химически активной производной этого соединения и, если требуется или желательно, превращение получающегося предшествующего соединения последующее или разделение его на стереохимические изомеры, удаление любой защищающей группы R_а. В том случае, когда R_а представляет собой гидроксильную защищающую группу, она, например, может быть гидроксикарбилсилильной группой, такой как триалкилсилил, например, триметилсилил или т-бутилдиметилсилил.Compounds of formula I can be prepared by esterification of carboxylic acid II

in which R _a is hydrogen or a hydroxyl protecting group, and R ₂ has the meaning defined for formula I, or a salt, or a chemically active derivative of this compound and, if required or desired, the conversion of the resulting preceding compound to subsequent or separation of it into stereochemical isomers , the removal of any protecting group R _a . In the case where R _a represents a hydroxyl protecting group, it, for example, may be a hydroxycarbylsilyl group, such as a trialkylsilyl, for example trimethylsilyl or t-butyldimethylsilyl.

The esterification of a compound of formula II or a salt thereof can be carried out by reacting with a compound R ₁ X, in which R ₁ is as defined in formula I, and X is a leaving group, such as a halogen atom, for example chlorine, bromine or iodine, or alkyl or aryl sulfonate, such as mesylate or tosylate, in the presence of a base. The reaction is preferably carried out in the presence of a solvent, the nature of which is not critical, provided that it does not have a reverse effect on the reaction. Suitable solvents include dimethylformamide, dimethylacetamide or dimethyl sulfoxide.

 In one embodiment of this method, the reaction is usually carried out using a salt, such as an alkali metal salt, for example, a potassium or sodium salt of a carboxylic acid (II) in the presence of a corresponding quaternary ammonium salt such as triethylbenzylammonium chloride or tetrabutylammonium bromide, and preferably in the presence of a polar an aprotic solvent such as dimethylformamide, dimethylacetamide or N-methylpyrrolidone.

The esterification reaction is usually carried out using a compound of formula II in which R _a represents a hydrogen atom. If the esterification reaction is carried out on a compound of formula II in which R _a is a hydroxyl protecting group, then this group can be removed using standard techniques. For example, when R _a is a tert-butyldimethylsilyl group, it can be removed by the action of tetrabutylammonium fluoride and acetic acid.

 The compounds of formula II can be obtained by known methods.

в которой группы R₁ и R₂ имеют значения, определенные для формулы (I), R_а является гидроксил-защищающей группой, а У является кислородным атомом или фосфиновой группой, и если требуется или желательно, превращение получающегося предшествующего соединения или в последующие для разделения на его стехиометрические изомеры с удалением защищающей группы R_a.Compounds of formula I can also be prepared by cyclization of a compound of formula III

in which the groups R ₁ and R ₂ have the meanings given for the formula (I), R _a is a hydroxyl protecting group, and Y is an oxygen atom or a phosphine group, and if required or desired, the conversion of the resulting preceding compound or subsequent ones for separation on its stoichiometric isomers with the removal of the protecting group R _a .

The cyclization of the compounds of formula III, in which Y is oxygen, is usually carried out by heating in the presence of organic phosphite. The reaction is preferably carried out in the range of 60-120 ° ^C. Suitable solvents include hydrocarbons with an appropriate boiling point, for example aromatic hydrocarbons such as toluene or xylene.

 Suitable organic phosphites include acyclic and cyclic trialkyl phosphites, triaryl phosphites and mixed alkylaryl phosphites. Particularly suitable organic phosphites are trialkyl phosphites, for example triethyl phosphites or trimethyl phosphites.

Cyclization of a compound of formula III, wherein Y is a phosphonic group is preferably carried out in a solvent at a temperature in the range 40-200 ° ^C. Suitable solvents include hydrocarbons such as aromatic hydrocarbons, e.g., xylene or toluene, aliphatic hydrocarbons and halogenated hydrocarbons, such like dichloromethane, chloroform and trichloroethane. Examples of suitable phosphine groups are triarylphosphines, for example triphenylphosphine or trialkylphosphines, for example tri-t-butylphosphine.

The hydroxyl protecting group can be removed by well-known standard methods, such as described in "Protective Groups in Organic Chemistry, pp. 46-119, edited by IFW McOmil (Printed Works of the Plenum, 1973). For example, when R _a is tertiary butyldimethylsilyl group, it can be removed by the action of tetrabutylammonium fluoride and acetic acid.This process is usually carried out in a solvent such as tetrahydrofuran.

Similarly, when R _a is a trichloroethoxycarbonyl group, it can be removed by zinc and acetic acid.

 Compounds of formula III can be prepared using known methods for the preparation of structurally related compounds.

 In order to be able to more deeply understand the invention, the following examples are given only as an illustration.

In preparations and examples, unless otherwise indicated: so pl. defined on a Gallenkamp melting point instrument and are not corrected. All temperatures are expressed in ^° C

Infrared spectra were determined in chloroform-dl solutions on an FT-IK instrument. Proton magnetic resonance spectra ( ¹ H-NMR) were recorded at 300 MHz in the form of solutions in chloroform -d ₁ . Chemical displacements are expressed in parts per million (δ) relative to tetramethylsilane used as the internal standard, and are indicated as singlet (s), doublet (d), double doublet (dd) or multiplets (m).

 Chromatography was performed through silica gel (Merk AG, Darmstadt, Germany).

The solutions were dried over anhydrous sodium sulfate. “Gasoline” means petroleum ether, b.p. 40-60 ^about C.

 Methylene chloride was twice distilled over calcium hydride; tetrahydrofuran was twice distilled over sodium; ethyl ether was twice distilled over sodium; xylene was twice distilled over phosphorus pentoxide and ethyl acetate was dried over activated molecular sieves.

 The intermediate compound 1.

 2-Methoxy-2-methyl) propionic acid vinyl ester.

Mercury (II) acetate (0.162 g), palladium acetate (0.0285 g), potassium hydroxide (0.067 g) and vinyl acetate (1.2) were added to 2-methoxy-2-methylpropionic acid (1.5 g) in a nitrogen atmosphere. d). The resulting solution was heated for 4 hours at 50 ° ^C. Then the reaction mixture was added an additional vinyl acetate (2.4g) and the mixture was heated for 16 hours at 50 ° ^C.

After cooling to 20 ° ^C was added ethyl ether (15 ml) and the mixture was filtered through a tampon and then extracted with diethyl ether (2x70 mL). The organic phase was washed with a solution of calcium chloride (150 ml) and dried over anhydrous sodium sulfate to form the crude title compound as a pale yellow oil (0.7 g); TLC cyclohexane / ethyl acetate 8: 2R _f = 0.7; IR (CDCl ₃ ) ν _max (cm ^-1 ): 1749 (C = O ether) 1640 (C = C; ¹ H-NMR (300 MHz; CDCl ₃ ) (ppm) 7.30 (m), 4.983 (dd), 3.297 (s), 1.464 (s).

 Intermediate 2.

 (2-Methoxy-2methyl) propionic acid 1-chloroethyl ester.

In a solution of Intermediate I (2,7 g) in ethyl acetate (50 ml) for one hour at 0 ° ^C was bubbled anhydrous hydrogen chloride, then, for 10 minutes, nitrogen purged. The solvent was evaporated, and the residue was purified by distillation (90 ^° C / 15 mm Hg) to give the entitled compound as a colorless oil (2.1 g) TLC cyclohexane / ethyl acetate 9: 1. R _f 0.9; IR (CDCl ₃ ) ν _max (cm ^-1 ): 1755 (C = 0 ether); ¹ H-NMR (CDCl ₃ ; 300 MHz) (ppm) 6.58 (q) 3.296 (s), 1.837 (d), 1.442 (s).

 Intermediate 3.

 (1-Chloro-2-methyl) propylmethyl carbonate.

A solution of 1-chloro-2-methylpropyl chloroformate (1.71 g) in dry dichloromethane (5 ml) was added dropwise to a solution of methanol (0.83 ml) in dry dichloromethane (5 ml) at ⁰ ° C under a nitrogen atmosphere, stirring.

Then the solution was added pyridine (0.80 ml) in dry dichloromethane (10 ml) and the reaction mixture was stirred for 18 hours at 20 ° ^C.

The mixture was diluted with dichloromethane (950 ml), washed with a solution of calcium chloride (3x40 ml), dried over anhydrous sodium sulfate and concentrated in a stream of nitrogen at low temperature, forming the title compound as a colorless oil in quantitative yield. H-NMR (300 MHz, CDCl ₃ ): 6.18 (d), 3.86 (s), 2.28-2.12 (m), 1.08 (d), 1.06 (d) mil .d.

 Intermediate 4.

 1-Chloroethyl-4-ethylcyclohexyl carbonate.

A solution of 1-chloroethyl chloroformate (5.46 g) in dry dichloromethane (20 ml) at ⁰ ° C under nitrogen was added dropwise to a stirred solution of 4-etiltsiklogeksanola (5 g) in dry dichloromethane (20 ml) in presence of 3A molecular sieves . To the reaction mixture was added dropwise pyridine solution (3 g) in dry dichloromethane (20 ml) for 20 min at ⁰ ° C after which the reaction mixture was heated to 20 ° ^C, stirred for 20 hours, washed with a solution of calcium chloride (2x50 ml) and dried. The solvent was removed in vacuo, and the residue was purified to give the entitled compound as a colorless oil (7.9 g; bp 130 ^o / mbar; t.s. cyclohexane / ethyl acetate 9 / 1R _f = 0.88; IR (CDCl ₃ ), ν _max (cm ^-1 ): 1757 (С = 0); ¹ H-NMR (300 MHz, CDCl ₃ ): 6.43 (q), 6.42 (q), 4.93 (br. s), 4.59 (T.T.), 2.00-1.88 (br.s), 1.88-1.78 (m), 1.83 (d), 1.82 (d) , 1.60-1.50 (m), 1.50-1.32 (m), 1.30-1.15 (m), 1.28-1.18 (m), 1.05-0 95 (m), 0.95-0.85 (m).

 Intermediate 5.

 1-Chloro-2-methylpropyl-2,2-dimethylpropionate.

2-methylpropionaldehyde (5.98 g) was added dropwise over 10 minutes to a stirred mixture of zinc chloride (0.11 g) and pivaloyl chloride (10 g) in a nitrogen atmosphere at -20 ^o C. Then, the reaction mixture was heated to 23 ^o C and further stirred for 2 hours, the solid was separated by centrifugation and the oily residue was subjected to distillation to form the title compound as a colorless oil (11.55 g. b.p. 70 ° ^C / mbar. IR (CDCl _3), ν _max (cm ^-1 ): 1749 (C = 0); ¹ H-NMR (300 MHz, CDCl ₃ ): 6.28 (d), 2.16 (m), 1.22 (s), 1.05 (e) mil.d.).

 Intermediate 6.

 Cyclohexyl chloromethyl carbonate.

A stream of chlorine was slowly passed into cold (-10 / + 5 ^° C) methyl chloroformate (6 ml) in ambient light. The reaction was monitored by 1-H-NMR spectra and stopped when the concentration of dichloromethyl chloroformate> 5 molar was reached. Nitrogen was passed through the solution until it became transparent, and the residue was distilled to obtain two main functions containing the required intermediate chloromethyl chloroformate; fraction a (2.48 g; molar ratios: methyl chloroformate / chloromethyl chloroformate / dichloromethyl chloroformate 19/77/4), fraction b (1.76 g; molar ratios: methyl chloroformate / chloromethyl chloroformate / dichloromethyl chloroformate 4/90/6) . To an ice-cooled solution of cyclohexanol (1.37 ml) in dry dichloromethane (5 ml) in the presence of 3A molecular sieves and a solution (fraction a) (1.7 g) was added under nitrogen atmosphere over 5 minutes. Then, the reaction mixture was stirred for 30 min at ⁰ ° C is added a solution of pyridine (1.06 ml) in dry dichloromethane (5 ml) and the mixture was slowly heated to 20-25 ° ^C. After 5 h the solution was filtered, diluted with dichloromethane ( 30 ml), washed with water (20 ml), brine (3x30 ml) and dried. The solvent was distilled off, and the residue was purified by column chromatography using silica gel and a 9: 1 cyclohexane / ethyl acetate / eluent mixture to give the title compound as white wax (1.98 g; t.c. cyclohexane / ethyl acetate 9 / 1R _f = 0.44; IR (CDCl ₃ ) ν _max (cm ^-1 ): 1759 (C = 0); ¹ H-NMR (3000 MHz, CDCl ₃ ): 5.73 (s), 4.78 -4.66 (m), 2.00-1.90 (m), 1.80-1.70 (m), 1.60-1.20 (m) ppm

EXAMPLE 1. 1- (Cyclohexyloxycarbonyloxy) ethyl (4S, 8S, 9R, 10S, 12R) -4-methoxy-10- (1'-hydroxyethyl) -11-oxo-1-azatricyclo- [ 7.2.7.0 ^3.8 ] undec-2-ene-carboxylate.

To a solution of potassium (4S, 8S, 9R, 10S, 12R) -4-methoxy-10- (1-hydroxyethyl) -11-oxo-1-aza-tricyclo [7.2.0.0 ^3.8 ] undec 2-en-2-carboxylate (hereinafter referred to as “Intermediate A”) (0.5 g) in dimethylformamide (8 ml) was added tetrabutylammonium bromide (0.5 g) and (1-chloroethyl) cyclohexyl carbonate ( 0.65 g) at 22 ^C. The resulting mixture was stirred for 15 h at 22 ^C then poured into diethyl ether (60 mL), washed with 10% aqueous HCl (40 mL), 5% aqueous sodium NaHCO ₃ (2x50 ml) and brine (2x50 ml), dried and concentrated. The residue (1 g) was dissolved in diethyl ether (2 ml) and petroleum ether (20 ml) was added with vigorous stirring. The precipitate (0.1 g) was filtered off, and the mother liquors were concentrated, forming a residue, which was dissolved in diethyl ether (1 ml) and petroleum ether (20 ml), added with thorough stirring to obtain a larger precipitate (0.14 g). The precipitates were combined (0.24 g) and subjected to further purification by dissolving in diethyl ether (3 ml) and precipitating from petroleum ether (30 ml) with thorough stirring to form the entitled compound as a white powder (0.160 g; t.s. diethyl ether Rf 0.44, bp 90-100 ^о С.

IR (CDCl ₃ ) ν _max (cm ^-1 ) 1771, 1632; ¹ H-NMR (3000 MHz, CDCl ₃ ) 6.93-6.85 (q + q), 4.92 (t), 4.64 (m), 4.25-4.05 (m), 3 , 30-3.15 (m), 3.25 (s), 3.24 (s), 2.08 (m), 2.0-1.2 (m), 1.61 (d), 1 59 (d), 1.31 (d), 1.30 (d).

 In accordance with the experimental methods described in example 1, the following esters were obtained from intermediate compound A.

Example 2. 1- (Ethyloxycarbonyloxy) ethyl (4S, 8S, 9R, 10S, 12R) -4-methoxy-10- (1'-hydroxyethyl) -11-oxo-1-azatricyclo- [7, 2.7.0 ^3.8 ] undec-2-ene-carboxylate were obtained as an oil (t.h. diethyl ether R _f 0.42).

IR (CDCl ₃ ) ν _max (cm ^-1 ) 1765, 1738, 1600; ¹ H-NMR (300 MHz, CDCl ₃ ) 6.93-6.87 (q + q), 4.933 (m), 4.3-1.8 (m), 3.26-3.24 (s + s), 3.32-3.20 (m), 2.08 (m), 1.94-1.3 (m), 1.62 (d), 1.60 (d), 1.36- 1.28 (m) from intermediate A and (1-chloroethyl) ethyl carbonate.

Example 3 1- (Isopropyloxycarbonyloxy) ethyl (4S, 8S, 9R, 10S, 12R) -4-methoxy-10- (1'-hydroxyethyl) -11-oxo-1-azatricyclo- [ 7.2.0.0 ^3.8 ] undec-2-ene-carboxylate. IR (CDCl ₃ ) ν _max (cm ^-1 ) 3614, 1767, 1632, 1H-NMR (300 MHz, CDCl ₃ ) 6.90 (q), 6.89 (q), 4.95-4.83 ( m), 4.3-4.2 (m), 4.19 (dd), 3.35-3.20 (m), 3.257 (s), 3.243 (s), 2.07 (m), 1 , 93-17.5 (m), 1.7-1.3 (m), 1.613 (d), 1.33-1.29 (d + d + d), t.s. cyclohexane, ethyl acetate 4: 6R _f 0.4 was obtained from intermediate A and (1-chloroethyl) -isopropyl carbonate.

Example 4. 1- (Acetoxy) ethyl (4S, 8S, 9R, 10S, 12R) -4-methoxy-10- (1'-hydroxyethyl) -11-oxo-1-azatricyclo- [ 7.2.0.0 ^3.8 ] undec-2-en-2-carboxylate.

Was obtained as an oil (0.160 g; cyclohexane, ethyl acetate 4: 6R _f 0.4. IR (CDCl ₃ ) ν _max (cm ^-1 ) 3605, 1769, 1700, ¹ H-NMR (300 MHz, CDCl ₃ 6, 99 (q), 6.98 (q), 4.93 (t), 4.25 (m), 4.19 (dd), 3.3-3.2 (m), 3.25 (s) , 3.24 (s), 2.10 (s), 2.07 (s), 2.08 (m), 1.95-1.3 (m), 1.56 (d), 1.55 (d), 1.31 (d), 1.30 (d) from intermediate A and (1-chloroethyl) acetate.

Example 5. 1- (Cyclohexylcarbonyloxy) ethyl (4S, 8S, 9R, 10S, 12R) -4-methoxy-10- (1'-hydroxyethyl) -11-oxo-1-azatri cyclo- [7 2.0.0 ^3.8 ] undec-2-ene-carboxylate.

IR (CDCl ₃ ) ν _max (cm ^-1 ) 1774, 1750, 1630; 1 H-NMR (300 MHz, CDCl ₃ ) 6.997 (q), 6.977 (q), 4.931 (t), 4.913 (t), 4.24 (m), 4.193 (dd), 3.3-3.2 ( m), 3.25 (s), 3.245 (s), 2.38-2.24 (m), 2.05 (m), 1.95-1.2 (m), 1.65 (dd) 1,566 (d), 1,326 (d), 1,314 (d) was obtained from intermediate A and (1-chloroethyl) cyclohexanecarboxylate.

PRI me R 6. 1- (Benzoyloxy) ethyl (4S, 8S, 9R, 10S, 12R) -4-methoxy-10- (1'-hydroxyethyl) -11-oxo-1-azatricyclo [7 , 2.0.03.0] undec-2-en-2-carboxylate was obtained as an oil (0.045 g; t.s.h. cyclohexane, ethyl acetate 1: R _f 0.25).

IR (CDCl ₃ ) ν _max (cm ^-1 ) 1776, 1738, 1640, 1603, 1H-NMR (300 MHz, CDCl ₃ ) 8.1-8.02 (m), 7.58 (tt), 7, 48-7.4 (m), 7.27 (m), 4.948 (t), 4.914 (t), 4.3-4.2 (m), 4.20 (dd), 3.3-3, 2 (m), 3.23 (s), 3.21 (s), 2.05 (m), 1.9-1.3 (m), 1.725 (d), 1.326 (d), 1.302 (d ), from intermediate A and (1-chloroethyl) benzoate.

PRI me R 7. 1 - [(1,1-Dimethylethyl) carbonyloxy] ethyl (4S, 8S, 9R, 10S, 12R) -4-methoxy-10- (1'-hydroxyxyl) -11-oxo- 1-azatri-cyclo- [7,2,0,0 ^3,8 ] undec-2-ene-carboxylate was obtained in the form of an oil (0.160 g; t.c. cyclohexane, ethyl acetate 4: 6 R _f 0, 37); IR (CDCl ₃ ) ν _max (cm ^-1 ) 3666, 1776, 1744, 1632; 1 H-NMR (300 MHz, CDCl ₃ ) 6.982 (q), 6.941 (q), 4.94-4.88 (m), 4.3-4.16 (m), 3.3-3.18 ( m), 3.238 (s), 3.20 (s), 2.05 (m), 1.9-1.2 (m), 1.565 (d), 1.554 (d), 1.317 (d), 1.306 ( d), 1.207 (s), 1.179 (s) from intermediate A and 1 - [(1,1-dimethylethyl) carbonyloxy ethyl] chloride.

Example 8. 1- [2-Methoxy-2-methyl-propanoyloxy)] ethyl (4S, 8S, 9R, 10S, 12R) -4-methoxy-10- (1'-hydroxyethyl) -11- oxo-1-aza-tricyclo [7.2.0.0 ^3.8 [-undec-2-en-2-carboxylate) was obtained as an oil (0.130 g; t.c.diethyl ether R _f 0.35);
IR (CDCl ₃ ) V _max (cm ^-1 ) 1772, 1603, 1H-NMR (300 MHz, CDCl ₃ ) 7.028 (q), 6.984 (q,), 4.914 (m), 4.3-4.2 ( m), 4.190 (dd), 3.3-3.2 (m), 3.260 (s), 3.248 (s), 3.290 (s), 3.226 (s), 2.06 (m), 1.9- 1.35 (m), 1.604 (m), 1.447 (s), 1.429 (s), 1.403 (s) 1.400 (s), 1.315 (d) from intermediate A and 2-methoxy-2-methiolpropanoic acid ester .

PRI me R 9. Acetoxymethyl (4S, 8S, 9R, 10S, 12R) -4-methoxy-10- (1'-hydroxyethyl) -11-oxo-1-azatricyclo [7.2.0.0 ^{3 , 8} ] undec-2-en-2-carboxylate was obtained as an oil (0.240 g; t.s.h. cyclohexane, ethyl acetate 4: 6 R _f 0.24);
IR (CDCl ₃ ) ν _max (cm ^-1 ) 1769, 1730, 1640; 1 H-NMR (300 MHz, CDCl ₃ ) 4.996 (t), 4.802 (s), 4.3-4.2 (m), 4.23 (dd), 3.774 (s), 3.36-3.24 (m + dd), 3.28 (s), 2.1 (m), 1.94-1.30 (m), 1.769 (d), 1.327 (d) from intermediate A and chloromethyl acetate.

PRI me R 10. [1,1-Dimethyl-ethyl) carbonyloxy] methyl (4S, 8S, 9R, 10S, 12R) -4-methoxy-10- (1'-hydroxyethyl-11-oxo-1- aza-tricyclo [7.2.0.0 ^3.8 ] undec-2-en-2-carboxylate was obtained as an oil (0.260 g; t.s.c. cyclohexane, ethyl acetate 1: 1 R _f 0 , 26;
IR (CDCl ₃ ) ν _max (cm ^-1 ) 3568, 1772, 1751, 1600; 1 H-NMR (300 MHz, CDCl ₃ ) 5.95 (d), 5.85 (d), 4.88 (t), 4.24 (m), 4.20 (dd), 3.27 (m ), 3.25 (dd), 3.23 (s), 2.1 (m), 2.0 (broad s), 1.95-1.6 (m), 1.5-1.20 (m), 1.31 (d), 1.21 (s), from intermediate A and [(1,1-dimethylethyl) carbonyloxy] methyl iodide.

PRI me R 11. 1- (2-Methoxy-2-methyl-propanoyloxy) methyl (4S, 8S, 9R, 10S, 12R) -4-methoxy-10- (1'-hydroxyethyl) -11-oxo -1-aza-tricyclo [7.2.0.0 ^3.8 ] undec-2-en-2-carboxylate was obtained as an oil (0.110 g; t.c. diethyl ether R _f 0, 33;
IR (CDCl ₃ ) V _max (cm ^-1 ); 3600, 1742, 1740, 1640; 1-H-NMR (300 MHz, CDCl ₃ ) 5.964 (d + d), 4.904 (m), 4.242 (m), 4.203 (dd), 3.984 (dd), 3.33-3.22 (m + dd ), 3.292 (s), 3.240 (s), 2.1 (m), 1.95-1.2 (m), 1.441 (s), 1.429 (s), 1.315 (s) from intermediate A and chloromethyl (2-methoxy-2-methyl) propionic acid ester.

PRI me R 12. 1- (Methyloxycarbonyloxy) -2-methylopropyl (4S, 8S, 9R, 10S, 12R) -4-methoxy-10- (1'-hydroxyethyl) -11-oxo-1-aza tricyclo [7.2.0.0 ^3.8 ] undec-2-en-2-carboxylate was obtained as an oil (0.040 g); t.s.kh. cyclohexane, ethyl acetate 4: 6 Rf 0.36;
IR (CDCl ₃ ) ν _max (cm ^-1 ) 1767, 1734, 1680, 1H-NMR (300 MHz, CDCl ₃ ), 6.661 (d), 60636 (d), 4.974 (m), 4.936 (m), 4 , 3-4.15 (m), 3.824 (s), 3.805 (s), 3.262 (s), 3.242 (s), 3.32-3.18 (m), 1.327 (d), 1.306 (d) 1.15-0.95 (m), 2.4-1.2 (m), from intermediate A and (1-chloro-2-methyl) propyl methyl carbonate.

PRI me R 13. 1- (Acetyloxy) butyl- (4S, 8S, 9R, 10S, 12R) -4-methoxy-10- (1'-hydroxyethyl) -11-oxo-1-azatricyclo [ 7.2.0.0 ^3.8 ] undec-2-ene-carboxylate was obtained as an oil (0.050 g; t.s.h. cyclohexane, ethyl acetate 1: 1 R _f 0.33);
IR (CDCl ₃ ) ν _max (cm ^-1 ) 1769, 1732, 1632, 1H-NMR, (300 MHz, CDCl ₃ ) 6.925 (q), 4.948 (m), 4.28-4.16 (m), 3.3-3.2 (m), 3.251 (s), 3.243 (s) 2.105 (s), 2.069 (s), 2.12-2.04 (m), 1.94-1.74 (m ), 1.74-1.58 (m), 1.54-1.349 (m), 1.318 (d), 1.307 (d), 0.962 (t), 0.957 (t) from intermediate A and 1-bromobutyl acetate .

PRI me R 14. 1 - [(4-Ethylcyclohexyloxy) carbonyloxy] ethyl (4S, 8S, 9R, 10S, 12CR) -4-methoxy-10- (1'-hydroethyl) -11-oxo-1- azatricyclo [7.2.0.0 ^3.8 ] undec-2-en-2-carboxylate.

To a solution of intermediate A (0.3 g) in N, N-dimethylformamide (5 ml) were added tetra-n-butylammonium bromide (0.3 g) and intermediate 4 (0.47 g) under nitrogen, and stirring It was continued at 22 ^{° C} for 16 hours. The reaction mixture was diluted with diethyl ether (15 mL), washed with saturated ammonium chloride (2x10 ml), brine (2.times.20 ml), dried and evaporated in vacuo. The oily residue was chromatographed through silica gel using a 7/3 cyclohexane / ethyl acetate mixture as eluent to give the title compound as a foam (0.169 g; t.h. cyclohexane / ethyl acetate 1 / 1R _f = 0.41; IR (CDCl ₃ ), ν _max (cm ^-1 ): 3640 (OH), 1761 (C = 0), 1634, (C = C); 1H-NMR (300 MHz, CDCl ₃ ): 6.88 (m), 4, 92 (m), 4.91 (m), 4.95-4.85 (m), 4.54 (m), 4.28-4.18 (m), 4.18 (dd), 3, 30-3.20 (m), 3.24 (s), 3.23 (s), 2.05 (m), 2.00-1.75 (m), 1.70-1.50 (m ), 1.50-1.09 (m), 1.31 (d), 1.29 (d), 1.25-1.15 (m), 0.86 (m), mil.

PRI me R 15. (Cyclohexyloxycarbonyloxy) methyl (4S, 8S, 9R, 10S, 12R) -4-methoxy-10- (1'-hydroxyethyl) -11-oxo-1-azatricyclo [7.2.0 , 0 ^3.8 ] undec-2-en-2-carboxylate.

To a solution of intermediate A (0.22 g) in N, N-dimethylformamide (6.5 ml), tetra-n-butylammonium bromide (0.222 g) and intermediate 6 (0.191 g) were added in the presence of 3A molecular sieves. The resulting mixture was stirred for 5 hours at ²² ° C, diluted with diethyl ether and ammonium chloride (2.times.30 ml), 5% aqueous sodium gidrokapbonata (30 ml), brine (2.times.30 mL), water (30 ml), and dried out. The solvent was removed in vacuo, and the residue was chromatographed over silica gel using cyclohexane / ethyl acetate 100/0 to 65/35 to give the title compound as a white foam (0.1 g; t.c. cyclohexane / ethyl acetate 1 / 1R _f = 0.18; IR (CDCl ₃ ) ν _max (cm ^-1 ): 3614 (OH), 1772 (C = 0 β-lactam), (C = 0 ether), 1640 (C = C); 1H-NMR (300 MHz, CDCl3): 5.90 (dd), 4.93 (t), 4.67 (m), 4.30-4.20 (m), 4.20 (dd), 3.35- 3.25 (m), 3.25 (s), 2.08 (m), 2.00-1.8 (m), 1.80-1.30 (m), 1.32 (d, mil .d.).

PRI me R 16. 1 - [(1,1-dimethylethyl) carbonyloxy] -2-methylpropyl (4S, 8S, 9R, 10S, 12R) -4-methoxy-10- (1'-hydroxyethyl) -11 - hydroxy-1-azatricyclo [7.2.0.0 ^3.8 ] undec-2-en-2-carboxylate.

To a solution of intermediate A (0.3 g) in N, N-dimethylformamide (5 ml) was added tetra-n-butylammonium bromide (0.3 g) and intermediate 5 (0.398 g) under nitrogen and stirring was continued at 22 ^about 16 hours. The reaction mixture was diluted with diethyl ether (15 ml), washed with saturated ammonium chloride (2x30 ml), brine (2x30 ml), dried and evaporated in vacuo. The oily residue was chromatographed over silica gel using 7/3 cyclohexane / ethyl acetate as eluent to give the title compound as a colorless oil (0.057 g, t.c. cyclohexane / ethyl acetate 1 / 1Rf = 0.45; IR (CDCl ₃ ), ν _max (cm ^-1 ): 3611 (NH), 1774 (С = 0 β-lactam), 1747 (С = 0 ether, 1632 (С = С), 1Н-NMR (300 MHz, CDCl ₃ ) : 6.76 (d), 4.95 (t), 4.92 (t), 4.30-4.16 (m), 3.32-3.19 (m), 3.24 (s) 3.23 (s), 2.10 (m), 2.06 (m), 1.94-1.80 (m), 1.75-1.60 (m), 1.50-1, 20 (m), 1.32 (m), 1.22 (s), 1.19 (s), 1.06-0.98 (d) ppm

Example 17. 1- (Cyclohexyloxycarbonyloxy) ethyl (4S, 8S, 9R, 10S, 12S) -4-methoxy-10- (1'-hydroxyethyl) -11-oxo-1-azatricyclo [7 2.0.0 ^3.8 ] undec-2-en-2-carboxylate.

To a solution of sodium (4S, 8S, 9R, 10S, 12R) -4-methoxy-10- (1'-hydroxyethyl) -11- oxo-1-azatricyclo [7.2.0.0 ^3.8 ] undec-2 en-2-carb-oxylate (194 mg) in dimethylformamide (8 ml) was added at room temperature triethylbenzylammonium chloride (146 mg) im (1-chloroethyl) -cyclohexylcarbonate (0.142 ml). The resulting mixture was stirred at ⁶⁰ ° C for 97 min, diluted with diethyl ether (30 mL) and washed with cold water (60 mL). The aqueous solution was re-extracted with diethyl ether (30 ml), and the combined organic extracts were washed with brine (30 ml) and dried over sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting white foam (288 mg) was recrystallized from diethyl ether / petroleum ether to give the entitled compound (220 mg) as a white solid.

 Pharmaceutical Examples

Tablets
PRI me R And mg / tab. The compound of example 1 320 Lactose 150 Ethyl cellulose 20 Sodium lauryl sulfate 7 Magnesium stearate 3 Tablet weight 500 mg
The active ingredient and lactose are mixed together and then granulated using water as a granulating liquid. The dried granules are mixed with ethyl cellulose, sodium lauryl sulfate and magnesium stearate and the tablet mass is formed using an appropriate die. The tablets can then be coated using standard techniques and coatings. PRI me R In mg / table Compound of example 1 320 Compressed sugar 170 Sodium lauryl sulfate 7 Magnesium stearate 3 Tablet weight 500 mg
The active ingredient and excipients are mixed together and then pressed using a suitable die. If necessary, tablets thus formed can be coated using standard methods.

Granules PRI me R C mg / standard. dose Compound of example 1 320 Starch 100 Cellulose 40 Polymethacrylate 30 Sodium lauryl sulfate 7 Magnesium stearate 3 Aromatic agent How much is needed Example D mg / standard. Dose. Compound of Example 1 320 Ethyl cellulose 140 Polymethacrylate 30 Sodium lauryl sulfate 7 Magnesium stearate 3 Flavoring agent How much is needed EXAMPLE E. mg / standard. dose Compound of example 1 320 Compressed sugar 140 Polymethacrylate 30 Sodium lauryl sulfate 7 Magnesium stearate 3 Flavoring agent How many
need
A solution of the active ingredient in ethanol is sprayed onto an appropriate liquid base of a granulator mixed with basic excipients. The granules thus formed are dried and sieved. If desired, the granules can then be enteric coated and dried. The dried granules are then mixed with the remaining excipients, including a flavoring agent, and coated, for example, with an enteric coating. The granules thus obtained can be made into capsules and the like. for a single dose of administration or placed in vessels for the manufacture of appropriate preparations intended for repeated oral administration in the form of liquid doses.

 Activity data.

 Conducted under standard test conditions, using mice, revealed a very high activity of the compounds of the invention when administered orally in protection against pathogenic bacteria, as illustrated in the following table, in which these compounds are compared with the known broad-spectrum antibiotic Cefuroxime axetil, taken orally . The data are given in the table.

 The compounds of the invention are also non-toxic at the dose levels used in therapeutic treatment. For example, no adverse effects were observed with the oral administration by mice of the compound of Example 1 at doses reaching 1000 mg / kg.

Claims (8)

1. Esters of 10 (1-hydroxyethyl) - 11-oxo-1-azatricyclo (7.2.0.0 ^{3 , 8} ) undec-2-en-2-carboxylic acids of the general formula I

where R ₁ group

where R _{4 is} hydrogen or a C ₁ C ₄ alkyl group;
p 0 or 1;
R _{5 a} group selected from C ₁ C ₆ alkyl, C ₅ to C ₈ cycloalkyl optionally substituted with a C ₁ C ₃ alkyl group, phenyl or a C ₁ C ₄ alkyl substituted with C ₁
C ₃ alkoxy;
R ₂ methoxy. 2. The compound according to claim 1, where R _{4 is} hydrogen or a methyl group. 3. Compounds according to any one of claims 1 and 2, where R _{5 is} methyl, ethyl, isopropyl, tert-butyl, 1-methoxy-1-methylethyl, phenyl, cyclohexyl or 4-ethylcyclohexyl. 4. The compounds according to claim 1, where R _{4 is} hydrogen or methyl; R ₅ is a group selected from C ₁ C ₄ alkyl, C ₅ - C ₆ cycloalkyl optionally substituted with a C ₁ C ₂ alkyl group, phenyl or a C ₁ C ₄ alkyl substituted with a methoxy group. 5. Pivaloyloxymethyl, 1-pivaloyloxyethyl, acetoxymethyl, 1-acetoxyethyl, 1-methoxy -1-methylethylcarbonyloxymethyl, 1- (1-methoxy-1-methylethylcarbonyloxy) ethyl, 1-benzoyloxyethyl, 1-isopropoxycarbonyloxyethyl-4-ethyl ethylcyclohexyloxy carbonyloxy) ethyl esters (4S, 8S, 9R, 10S, 12R) -4-methoxy-10 (1-hydroxyethyl) - 11-oxo-1-azatricyclo (7.2.0.0 ^{3 , 8} ) -undec 2-en-2-carboxylic acid. 6. 1-Cyclohexyloxycarbonyloxyethyl (4S, 8S, 9R, 10S, 12R) -4-methoxy-10 (1-hydroxyethyl) -11-oxo-1-azatricyclo (7.2.0.0 ^{3 , 8} ) -undec- 2-en-2-carboxylate. 7. A method of obtaining compounds of General formula I, as described in paragraph 1, characterized in that it comprises reacting a compound of general formula II

where R _{2 is} methoxy;
R _{a is} hydrogen or a hydroxyl protecting group,
or a salt thereof, or a reactive derivative thereof with an esterifying agent serving to introduce the group R _1, the value of which is defined in p.I when necessary replacement of the product obtained hydroxyl-protecting group R _as hydrogen and / or isolation of the desired isomer of the compound of the general formula I mixtures of one or more other isomers of this compound.  8. Compounds according to any one of claim 1 to 6 of general formula I, having antibacterial activity.

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