CS273195B2 - Method of pharmacologically active carboxyl acids' new ester production - Google Patents

Description

The present invention relates to a process for the preparation of novel pharmacologically active carboxylic acid esters from the beta-1 '

Η H

WITH.

wherein R is a hydrogen atom or a group of formula

OHb řf

Sa

CO wherein R a is an optionally substituted 5-membered heteroaromatic group with a sulfur or oxygen atom and optionally with one or two nitrogen atoms as ring heteroatoms and

R b represents a hydrogen atom or an alkyl group having 1 to 7 carbon atoms or an alkanoyl group having up to 7 carbon atoms,

Rc denotes an alkyl group having 1 to 7 carbon atoms or a group -CHg-Rd, wherein Rd is an alkanoyloxy group having up to 7 carbon atoms, a carbamoyloxy group, an azido group or a 5-membered nitrogen atom containing a heteroaromatic group having up to 4 nitrogen atoms as heteroatoms a ring optionally substituted with a C 1 -C 7 alkyl group or a carbamoyl group,

R ^ represents a hydrogen atom or an alkyl group having 1 to 7 carbon atoms,

R is hydrogen, alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms, alkenyl of 2 to 7 carbon atoms or alkoxycarbonyl of 1 to 7 carbon atoms in the alkoxy moiety or together with R ¹ forms an alkylene group having from 1 to 7 carbon atoms,

R represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms or an alkoxycarbonyl group having 1 to 7 carbon atoms in the alkoxy moiety,

R ⁴ represents -COOR ^5, - COR ^6, -SOg-R ^6, -CONR ⁷ R ⁸ or -POCOR ⁹⁾ _2, wherein R ⁵ denotes a saturated or unsaturated hydrocarbon group having up to 12 carbon atoms, which are optionally substituted up to two methylene groups replaced by oxygen atoms, R ⁸ is C 1 -C 7 alkyl, R and R are hydrogen or C 1 -C 7 alkyl, or together form an C 1 -C 7 alkylene group in which one methylene optionally substituted with oxygen or sulfur, or imino or C 1 -C 7 alkylimino, and R ⁹ is C 1 -C 7 alkyl, and, where a basic substituent is present, also their addition salts with acids which are pharmaceutically acceptable.

The above esters are novel compounds and possess valuable pharmacological properties. These compounds cleave under physiological conditions into free, pharmacologically active carboxylic acids, which exert their therapeutic effects. They can therefore be used for the prevention or treatment of diseases as medicaments and are suitable for enteral administration, in particular for oral administration.

The term C 1 -C 7 alkyl refers to straight or branched, saturated C 1 -C 7 hydrocarbon groups, preferably C 1 -C 4, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl butyl group, sec. butyl and 2-ethylhexyl.

The term haloalkyl of 1 to 7 carbon atoms refers to an alkyl group of 1 to 7 carbon atoms, preferably of 1 to 4 carbon atoms, which is mono-, di- or trisubstituted by halogen, such as chloromethyl, trichloromethyl and trifluoromethyl.

The term C 1 -C 7 alkoxy refers to an alkyl group of 1 to 7 carbon atoms, preferably of 1 to 4 carbon atoms, which is bonded via an oxygen atom.

The term C 1 -C 7 alkylene denotes straight or branched saturated C 1 -C 7 hydrocarbon radicals, preferably C 1 -C 4, with two free valences such as dimethylene, trimethylene and tetramethylene.

The term C 2 -C 7 alkenyl refers to straight or branched hydrocarbon radicals having 2 to 7 carbon atoms, preferably 2 to 4 carbon atoms, containing at least one olefinic double bond, such as vinyl, 1-propenyl and 2- propenyl.

The term saturated or unsaturated hydrocarbon group having up to 12 carbon atoms in which up to two methylene groups can be replaced by oxygen atoms refers to open chain and cyclic groups and combinations thereof. Examples of open-chain groups that may have a straight or branched chain include: alkyl groups of 1 to 7 carbon atoms, alkenyl groups of 2 to 7 carbon atoms, and alkoxyalkyl groups with a total of up to 12 carbon atoms as defined above and alkoxyalkoxyalkyl groups as well as dialkoxyalkyl groups having up to 12 carbon atoms in total, such as 2,3-dimethoxypropyl. Examples of cyclic groups and combinations of cyclic and open-chain groups include: optionally substituted cycloalkyl groups and cycloalkylaalkyl groups in which the cyclic group contains up to 7 ring members and in which up to two methylene groups can be replaced by oxygen atoms such as is tetrahydro-2H-pyran-4-yl, (tetrahydro-2H-pyran-2-yl) methyl, cyclohexyl and cyclohexylmethyl.

The five-membered heteroaromatic groups R a contain, as a member of the heterocycle, an oxygen or sulfur atom and optionally one or two nitrogen atoms. Examples of such groups include: thienyl, thiazolyl, thiadiazolyl and furyl. These groups are unsubstituted or are amino-substituted. Preferably, they are unsubstituted or monosubstituted. Examples are: 3-thienyl, 2-furyl, 2-amino-4-thiazolyl, 2-bromo-5-furyl and 5-amino-1,2,4-thiadiazol-3-yl.

The term 5-membered nitrogen-containing aromatic group attached through a nitrogen atom (Rd) refers to aromatic heterocyclic groups containing up to 4 nitrogen atoms as heterocycle members. They may also contain a fused 5- or 6-membered cycloalkane ring or benzene ring. Preferably, they are unsubstituted or substituted by C 1 -C 7 alkyl or carbamoyl. An example of a nitrogen-containing heterocyclic group is 5-methyl-2-tetrazolyl.

Rb represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms or an alkanoyl group having 1 to 7 carbon atoms, in particular an alkyl group having 1 to 7 carbon atoms.

The substituent R c represents an alkyl group having 1 to 7 carbon atoms, in particular a methyl group or a -C 1 - R d group, wherein R d is preferably an azido group R 1 is preferably a hydrogen atom.

R is preferably an alkyl group having 1 to 7 carbon atoms.

R represents a preferred hydrogen atom.

5 5

R is preferably -COOR, wherein R is preferably C 1 -C 7 alkyl, C 7 -C 7 alkenyl, or C 12 -C 12 alkoxyalkyl. In a particularly preferred embodiment, R 1 is C 1 -C 7 alkyl, C 1 -C 12 alkoxyalkyl, especially isobutyl, isopropyl or 2-ethoxyethyl, with isobutyl being particularly preferred.

The following compounds are particularly preferred esters of the invention:

(E) -2- (isobutoxycarbonyl) -2-pentenyl- (6R, 7R) -7- [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3- ( azidomethyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate, (E) -2- (isobutoxycarbonyl) -2-butenyl- (6R, 7R) ) -7 - [(Z) -2- (2-Amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3- (azidomethyl) -8-oxo-5-thia-1-azabicyclo [4.2.1.0 < 2,7 > O] oct-2-ene-2-carboxylate, (E) -2 - [(2) -ethoxyethoxy) carbonyl] -2-butenyl- (6R, 7R) -7- [(Z) -2- (2-) amino-4-thiazolyl) -2- (methoxyimino) acetamido-3- (azidomethyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate, (E) - 2- (ethoxycarbonyl) -2-butenyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3- (azidomethyl) -8- oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate, (E) -2 - [[(3-methyl-2-butenyl) oxy] carbonyl] -1,2-butenyl- (6R) 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.1 < 2,7 > (E) -2- (isopropoxycarbonyl) -2-butenyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazoles), 0-ioct-2-ene-2-carboxylate l) -2- (methoxyimino) acetamido-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate, (E) -2- (isobutoxycarbonyl) - 2-Pentenyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl-8-oxo-5-thia-1- azabicyclo [4.2.0] oct-2-ene-2-carboxylate, (E) -2- (ethoxycarbonyl) -2-pentenyl- (6R, 7R) -7- [(Z) -2- (2-amino- 4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.1] oct-2-ene-2-carboxylate, (E) -2 - [(2 -ethoxyethoxy) carbonyl-2-butenyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2 (methoxyimino) acetamido] -3-methyl-8-oxo-5- thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate, (E) -2- (isobutoxycarbonyl) -2-butenyl- (6R, 7R) -7- [(Z) -2- ( 2-Amino-4-thiazolyl) -2- (methoxyimino) acetamido 3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate, ( E) -2- (t-butoxycarbonyl) -2-butenyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate and (E) -2- (ethoxycarbonyl) -2-butenyl- ( 6R, 7R) -7 - [(Z) -2- (2-Amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl-8-oxo-5-thiazabicyclo [4.2.0] Ioc-2-ene-2-carboxylate.

According to the invention, the esters of the formula I and, if they contain a basic group, also their pharmaceutically usable acid addition salts, can be prepared by esterifying the carboxylic acid corresponding to the compound of the formula I with a compound of the formula IX

(II),

Wherein X is hydroxy or a leaving group and R, R, R and R are as defined above, whereupon the ester obtained is optionally converted into an acid addition salt which is pharmaceutically acceptable.

The esterification by the process according to the invention can be carried out by methods known per se and by one of ordinary skill in the art. Thus, for example, a salt, in particular an alkali metal salt, such as sodium salt or potassium salt, of a pharmacologically active carboxylic acid can be reacted with a compound of formula II in which X is a leaving group. Suitable leaving groups are, for example, halogen atoms such as bromine and iodine, as well as alkyl and arylsulfonyloxy groups such as methylsulfonyloxy and p-toluenesulfonyloxy groups. Suitable solvents are, for example, dimethylformamide and dimethylacetamide. The reaction is preferably carried out in a temperature range of about -30 ° C to about room temperature, preferably at about 0 ° C.

However, it is also possible to react a free, pharmacologically active carboxylic acid in the presence of a condensing agent with a compound of formula II in which X is a hydroxyl group. A suitable condensing agent is, for example, a mixture of diethyl azodicarboxylate and triphenylphosphine. Suitable solvents are, for example, dimethylformamide and dimethylacetamide. The reaction is preferably carried out in a temperature range of -30 ° C to about room temperature, especially at temperatures around 0 ° C.

The preparation of acid addition salts of the esters of the invention with base-substituted acids can also be carried out by methods known to those skilled in the art. Both salts with pharmaceutically usable inorganic acids and salts with pharmaceutically usable organic acids are suitable.

Examples of acid addition salts of the esters of the invention include salts with mineral acids such as hydrohalic acids such as hydrochloric acid, hydrobromic acid and hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, salts with organic sulfonic acids, e.g. with alkyl and arylsulfonic acids such as ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid and the like, as well as salts with organic carboxylic acids such as acetic acid, tartaric acid, maleic acid, citric acid, benzoic acid, salicylic acid , ascorbic acid, and the like.

Esters of the invention may also be. hydrated. These hydrates are mostly obtained spontaneously in connection with the manufacturing process or as a result of the hygroscopic properties of the initially anhydrous product. To intentionally manufacture a hydrate, the wholly or partially anhydrous product may be exposed to a humid atmosphere.

Pharmacologically active carboxylic acids, in particular antibiotic active carboxylic acids of the beta-lactam type antibiotics, which are used as starting materials, belong to the group of substances known per se. Particularly unrepresented representatives of these groups of substances can be produced analogously to known representatives by methods known per se.

The compounds of formula II which are used as starting materials also belong to a group of substances known per se. In particular, unwritten representatives of these groups of substances can be produced analogously to known representatives by methods known per se. In this connection, reference is made to the following publications: DE-OS 2 155 113 (published May 10, 1972); Η. M. R. Hoffmann and J. Rabe, Angew. Chem. 95, 795-796 (1983); F. Ameer et al., J. Chem. Soc. Perkin Trans. I, 1983, 2293-2295; and P. Knochel and J.F. Normant, J. Organamet. Chemistry 309: 1-23 (1986).

As mentioned above, the carboxylic acids corresponding to the esters of the invention have valuable pharmacological properties. They are particularly suitable for enteral, especially oral treatment of diseases.

The antimicrobial activity of the esters of the antibiotic carboxylic acids of the invention when administered orally can be demonstrated, for example, by the following animal experiment:

White mice weighing 16 to 20 g are induced experimental septicemia by injecting a test sample of a diluted culture of the test organism, i.e. Escherichia coli 25922, which has been grown overnight (intraperitoneally). The administered sample is measured so that the dose administered is about ten to twenty times higher than the dose required to cause 50% of the untreated test animals to die within 48 hours. The bacteria are applied as a suspension in the culture medium by injection. Groups of 5 animals each were used for both control and treatment. The esters of the invention are administered orally in the form of a solution in Tween 80 (4%), the concentration being chosen such that each animal receives 500 µl. Treatment is carried out 1 and 3 hours after infection. ED _5Q is the dose which protects 50% of the animals and is calculated from the proportion of surviving animals 4 days after infection by probit method. The following table gives the values Εϋ ^ θ in mg / kg po for the representative group of substances according to the invention. The table also contains acute toxicity data of the esters of the invention when administered to mice in a single dose.

TABLE Ester according to the invention ^ED 50 in mg / kg po

^DL 50 in mg / kg po

Compound A Compound B Compound C

0.28 5,000

1.4

0.89 5,000 Compound A: (E) -2- (isobutoxycarbonyl) -2-pentenyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- ( methoxyimino) acetamido-3- (azidomethyl) -8-oxo-5-thia-1-azabicyclo [4.2.0} oct-2-ene-2-carboxylate, compound Β: (E) -2- (isobutoxycarbonyl) 2-Pentenyl- (6R, 7R) -7-E (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido-3-methyl-8-oxo-5-thia-1 -azabicyclo [4.2.0] oct-2-ene-2-carboxylate, compound C: (E) -2- (ethoxycarbonyl) -2-butenyl- (6R, 7R) -7- [(Z) -2- ( 2-amino-4-thiazolyl) -2- (methoxyimino) acetamido-3-methyl-8-oxo-5-thiaazabicyclo [4.2.0] oct-2-ene-2-carboxylate.

The compounds of the invention may be used as medicaments, for example in the form of pharmaceutical preparations for enteral administration. The compounds produced by the process of the invention may be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, or rectally, for example in the form of suppositories.

The preparation of the pharmaceutical preparations can be carried out by any person skilled in the art in conventional manner by converting the compounds obtained according to the invention, optionally in admixture with other therapeutically valuable substances, together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carriers and optionally conventional pharmaceutical auxiliaries. to a galenic dosage form.

Both inorganic and organic carriers are suitable as such carriers. For tablets, coated tablets, dragees and hard gelatine capsules, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or stearic acid salts can be used as carriers. For soft gelatine capsules, suitable carriers are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (however, depending on the state of the active substance, no carriers are required, if appropriate, in the case of soft gelatine capsules). Suitable carriers for the preparation of syrups and solutions are, for example, water, polyols, sucrose, invert sugar and glucose. Suitable suppositories for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.

Suitable pharmaceutical auxiliaries are customary preservatives, auxiliary solvents, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents and antioxidants.

The esters of the invention and their pharmaceutically usable acid addition salts and their hydrates are suitable for enteral, especially oral administration.

The pharmaceutical preparations may contain the esters of the invention, depending on the nature of the pharmacologically active carboxylic acid corresponding to the respective ester, in an amount of from about 25 to 2000 mg, preferably in an amount of from 100 to 1000 mg, per unit dosage form. For the prophylaxis and treatment of infectious diseases, daily doses of from about 0.05 g to about 4 g, in particular from about 0.5 g to about 2 g, are suitable for adult patients. The dose may be administered as a single dose or in divided doses. benefits.

The following examples serve to illustrate the invention in greater detail, but do not limit its scope in any way. All temperatures are in degrees Celsius.

Example 1

(a) 1 g of (6R, 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido-3-methyl-8-oxo-5-thia- The 1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid is dissolved in 20 ml of dimethylformamide, cooled to 0 DEG C., and 0.7 g of bromomethyl acrylic acid ethyl ester is added. After 2 hours, 80 ml of water are added to the reaction mixture, and extraction is carried out with 200 ml of ethyl acetate. The organic phase is washed three times with 50 ml of water each time, dried over magnesium sulphate and concentrated to a volume of 20 ml. Thereafter, 100 ml of ether are added for stirring, the precipitated product is filtered off with suction and dried under reduced pressure at room temperature. 2- (ethoxycarbonyl) allyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl-8-oxo- 5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a white solid (from ethyl acetate / ether).

Elemental analysis for ^C 20 ^H 23 ^N 5 ° 7 ^S 2 (509.552):

calculated: 47.14% C, 4.55% H, 13.74% N, 12.58% S;

Found: C, 46.82; H, 4.64; N, 13.50.

The following compounds are obtained in an analogous manner:

b) 2- (ethoxycarbonyl) allyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3 - [(5-methyl- 2H-Tetrazol-2-yl) methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a white solid (from ethyl acetate / ether).

7>

fe

Elemental analysis for ^C 22 ^H 25 ^N 9 ° 7 ^S 2 ^{(591 '62):} calculated 44.66% C, 4.26% H, 21.31% N, 10.84% S;

Found: C, 44.39; H, 4.45; N, 21.05; S, 10.79.

c) 2- (ethoxycarbonyl) allyl- (6R, 7R) -3-carbamoyloxy) methyl-7-L (Z) -2- (2-furyl) -2- (methoxyimino) acetamido-8-oxo-5- thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a white solid (from a mixture of ethyl acetate and isopropyl ether).

Elemental analysis for ^C 22 ^H 24 ^N 4 ° 10 ^S (536,521):

C, 49.25; H, 4.51; N, 10.44; S, 5.98;

found: C 49.46, H 4.80, N 10.24, S 5.84.

Example 2

(a) 2 g of (6R, 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido-3-methyl-8-oxo-5-thia-1 sodium salt -azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid is dissolved in ml of dimethylformamide, the solution is cooled to 0 DEG C., then 1.58 g of alpha-bromomethyl-acrylic acid tert-butyl ester is added. . After 5 hours, 200 mL of water was added to the reaction mixture and extraction was performed with 350 mL of ethyl acetate. The organic phase is washed three times with 100 ml of water each time, dried over magnesium sulphate and concentrated to a volume of 20 ml. 250 ml of isopropyl ether are then added to the residue with stirring. The precipitated product is filtered off and dried under reduced pressure at room temperature. 2- (tert-butoxycarbonyl) allyl- (6R, 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl- is obtained as a white solid. 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (from ethyl acetate / isopropyl ether).

Elemental analysis for ^C 22 ^H 27 ^N 5 ° 7 ^S 2 (537.61):

H, 5.06; N, 13.03; S, 11.93.

Found: C 48.78, H 5.14, N 13.03, S 12.15.

The following compounds are obtained in an analogous manner:

b) 2- (tert-butoxycarbonyl) allyl- (6R, 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido-3- (azidomethyl) - 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a beige solid (from a mixture of ethyl acetate and isopropyl ether).

Elemental analysis for C 22 ^H 26 ^N 8 ° 7 ^S 2 (578.63) ⁺ 0.15 mol of ethyl acetate:

calculated: 45.67%, H 4.52, N 19.36, S 11.08;

Found: C 45.87, H 4.63, N 18.93, S 10.83.

c) 2- (tert-butoxycarbonyl, allyl- (6R, 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido) -3- (5-methyl) -2H-Tetrazol-2-yl) methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a white solid (from ethyl acetate / isopropyl ether).

Elemental analysis for ^C 24 ^H 29 ^N 9 ° 7 ^S 2 (619,683):

C, 46.52; H, 4.72; N, 20.39; S, 10.35.

Found: C, 46.33; H, 4.84; N, 20.12.

d) 2- (tert-butoxycarbonyl) allyl- (6R, 7R) -3- (carbamoyloxy) methyl-7- (2-Z) -2- (2-furyl) -2- (methoxyimino) acetamido-8-oxo -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a white solid (from ethyl acetate / petroleum ether (high boiling)).

Elemental analysis for ^C 24 ^H 28 ^N 4 ^O 10 ^S (564.576) ⁺ 0.25 mol of ethyl acetate: calculated C 51.06%, H 5.00, N 9.92, S 5.68%;

Found: C, 51.19; H, 5.16; N, 9.55; S, 5.47.

Example 3

A solution of 2.5 mmol of an antibiotic-carboxylic acid salt of the beta-lactam type anitibiotics with alkali metal in 20 ml of absolute dimethylformamide is treated with a solution of 2.7 mmol of the corresponding halide II in 2 ml of absolute dimethylformamide while cooling with ice water. discarded and the resulting solution was stirred at about 0 ° C overnight. The solution is then diluted with 100 ml of ethyl acetate and the ethyl acetate solution is extracted three times with 50 ml of water each time and extracted once with 50 ml of brine. The organic phase is dried over magnesium sulphate, then filtered and evaporated. The evaporation residue is chromatographed on a short column of silica gel, eluting with ethyl acetate / hexane (8: 2), by flash chromatography. The fractions containing the desired product were combined and evaporated. A solution of the residue in 2 ml of methylene chloride was then added dropwise to 300 ml of a 1: 1 mixture of ethyl acetate and hexane. The crystals obtained are filtered off and dried under reduced pressure.

The following compounds were prepared in the same manner:

a) (E) -2- (ethoxycarbonyl) -2-butenyl- (6R, 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido-3- methyl 8-oxo-5-thiaazabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid (from a mixture of methylene chloride and ether).

Elemental analysis for ^C 21 ^H 25 ^N 5 ^O 7 ^S 2 ^{533 55} ) calculated C 48.17%, H 4.81%, N 13.38%, S 12.25%;

Found: C 47.90, H 4.97, N 13.26, S 12.23.

b) (E) -2- (tert-butoxycarbonyl) -2-butenyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamide] - 3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid.

Elemental analysis for ^C 23 ^H 29 ^N 5 ^O 7 ^S 2 calculated C 50.08%, H 5.30%, N 12.70, S 11.62%;

found: C 49.89; H 5.39; N 12.60; S 12.69.

c) (E) -2- (Isobutoxycarbonyl) -2-butenyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] - 3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid (from a mixture of ether and methylene chloride).

Mass spectrum: protonated ion of the molecule at m / e 552.

d) (E) -2 - [(2-ethoxyethoxy) carbonyl-3-butenyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino)] acetamido-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid.

Elemental analysis for C ₂ ^H 3 29 ^N 5 ^O 8 ^S 2 ^{(567 '6 °)} vypočteno'48,67 »C, 5.15% II, 12.34% N, 11.30% S; Found: C, 48.37; H, 5.41; N, 12.57; S, 13.31.

e) (E) -2 - [(RS) -2-ethylhexyloxycarbonyl] butenyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3 methyl 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a solid.

Mass spectrum: inter alia maximums at m / e 368.

f) (E) -2 - [[(RS) -2,3-dimethoxypropoxy carbonyl] -2-butenyl (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2] - (methoxyimino) acetamido-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-enecarboxylate as a colorless solid.

Elemental analysis for ^C 24 ^H 31 ^N 5 ° 9 ^S 2 (597.65):

calculated: 48.23% C, 5.23% H, 11.72% N, 10.73% S; Found: C 48.00, H 5.40, N 11.40, S -10.38%.

(g) (E) -2-Acetyl-2-butenyl- (6R, 7R) -7- [beta]) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl-8- oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a yellowish solid (from a mixture of ether and methylene chloride),

Elemental analysis for ^C 20 ^H 23 ^N 5 ^O 6 ^S 2 requires C, 48.67; H, 4.70; N, 14.19.

Found: C, 48.80; H, 5.23; N, 13.16.

h) (RS, -2- (Methoxycarbonyl) -2-cyclohexen-1-yl- (6R, 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.1] oct-2-ene-2-carboxylate as a colorless solid (from a mixture of methylene chloride and ether).

Elemental analysis for (535.60):

C, 49.34; H, 4.71; N, 13.08.

Found: C, 49.35; H, 4.90; N, 12.67.

i) 1-ethyl-4-methyl-2-η 6 (6R, 7R) -7- η (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-ylcarbonyl-1-methoxyfumarate as a colorless solid (from a mixture of methylene chloride and ether).

Mass spectrum: protonated ion of the molecule at m / e 568.

j) 1-ethyl-4-methyl-2-N E (6R, 7R) -7-E (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido-3-methyl- 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-yl] carbonyl] oxyoxymethyl maleate as a colorless solid (from a mixture of methylene chloride and ether).

Mass spectrum: protonated ion of the molecule at m / e 568.

k) (E) -2- (ethoxycarbonyl) -2-pentenyl- (6R, 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3- methyl 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid (from ether).

Elemental analysis for ^C 22 ^H 27 ^N 5 ^S 2 ° 7 ^{<537 '58)} calculated 49.15% C, 5.06% H, 13.03% N, 11.93% S;

Found: C, 48.66; H, 5.15; N, 12.82; S, 11.60.

l) 2- (p-nitrophenoxycarbonyl) allyl- (6R, 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido-3-methyl-8-oxo -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a yellow solid.

IR spectrum (KBr technique): inter alia, bands at 1,778, 1,739, 1,681 and 1,615 cm ^-1 .

m) (E) -2-EE (tetrahydro-2H-pyran-4-yl) oxy-carbonyl-2-hexenyl- (6R, 7R) -7-Ez) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid (from a mixture of methylene chloride and hexane) . Mass spectrum: protonated ion of the molecule at m / e 608.

(E) -2-L [(tetrahydro-2H-pyran-4-yl) oxy] carbonyl] -2-pentenyl- (6R, 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.1] oct-2-ene-2-carboxylate as a colorless solid (from a mixture of methylene chloride and hexane) .

IR (KBr): bands at inter alia 1781, 1715, 1683, 1619 and 1534 cm ^1st

o) (E) -2- [(tetrahydro-2H-pyran-4-yl) oxy] carbonyl] -2-butenyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl)] 2- (methoxyimino) acetamido] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid (from ethyl acetate / hexane).

Mass spectrum: protonated ion of the molecule at m / e 580.

(E) -2- (isobutoxycarbonyl) -2-pentenyl- (6R, 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido-3- methyl 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid.

Mass spectrum: protonated ion of the molecule at m / e 566.

q) (E) -2 - [[(RS) - (tetrahydro-2 H -pyran-2-yl, -methoxy] carbonyl] -2-hexenyl- (6R, 7R) -7- [(Z) -2- (2) amino-4-thiazolyl) -2- (methoxyimino) acetamido-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid.

Mass spectrum: protonated ion of the molecule at m / e 622.

r) (E) -2 - [[[(RS) -tetrahydro-2H-pyran-2-yl] methoxy] carbonyl] -2-butenyl- (6R, 7R) -7- (Z) -2- (2-amino) -4-thiazolyl) -2- (methoxyimino, acetajnido) -3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid (from mixture methylene chloride and hexane).

Mass spectrum: protonated ion of the molecule at m / e 594.

s) (E) -2 - [[[(RS) -tetrahydro-2H-pyran-2-yl] methoxy] -carbonyl-2-pentenyl- (6R, 7R) -7- [(Z) -2- (2-) amino-4-thiazolyl, -2- (methoxyimino) acetamido] -3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid ( from hexane).

XC spectrum (KBr technique): bands inter alia at 1781, 1718, 1662 and 1620 cm.

t) (E) -2 - [(cyclohexyloxy) carbonyl] -2-butenyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino, acetamido) - 3-Methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid (from ether / hexane).

Elemental analysis for ^C 25 ^H 31 ^N 5 ° 7 ^S 2 (577.64):

calculated C 51.98, H 5.41, N 12.12;

Found: C, 51.95; H, 5.96; N, 12.04.

u) (E, -2- (isopropoxycarbonyl) -2-butenyl- (6R, 7R) -7 - [(Z, -2- (2-amino-4-thiazolyl) -2- (methoxyimino, azetamido) -3-methyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid (ether / hexane).

Mass spectrum: protonated ion of the molecule at m / e 538.

(v) (E) -2 - [(cyclohexylmethoxy) carbonyl] -2-butenyl- (6R, 7R) -7- [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid (from ethyl acetate / hexane).

Mass spectrum: protonated ion of the molecule at m / e 592.

(w) (E) -2 - [[(3-methyl-2-butenyl, oxycarbonyl) -2-butenyl - (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl)] ) -2- (methoxyimino) acetamido-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid (from ether / pentane) .

Mass spectrum: protonated ion of the molecule at m / e 564 '.

(x) (E) -2 - [[[(E / Z) -3,7-dimethyl-2,6-octadienyl] N -oxy] carbonyl] -2-butenyl- (6R, 7R) -7-C ( Z) -2- (2-Amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2 -carboxylate as a colorless solid (ether / hexane). Mass spectrum: protonated ion of the molecule at m / e 632.

y) (E) -3- (5-bromo-2-furyl) -2- (ethoxycarbonyl) allyl- (6R, 7R) -7 - [(Z, -2- (2-amino-4-thiazolyl)) - 2- (methoxyimino, -acetamido) -3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid (from a mixture of ether and hexane, .

Elemental analysis for ^C 24 ^H 24 ^BrN 5 ° 8 ^S 2 (654.47):

C, 44.04; H, 3.70; N, 10.70; S, 9.80; Br and 12.21;

found: C, 44.31; H, 3.98; N, 10.54; S, 9.74; Br, 12.09.

z) 2- (ethoxycarbonyl) -2,4-hexadienyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl- 8-Oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid.

For C23H27N5O7S2 (549.61):

C, 50.26; H, 4.95; N, 12.74.

Found: C 49.95%, H 5.33%, N 12.10%.

aa) 2- (dimethoxyphosphinyl) allyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl-8-oxo-5 thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid (from ether / hexane).

Mass spectrum: protonated ion of the molecule at m / e 546.

ab) (E and / or Z) -4,4,4-trichloro-2- (ethoxycarbonyl) -2-butenyl- (6R, 7R) -7- (Z) -2- (2-amino-4- thiazolyl) -2- (methoxyimino) acetamido-3-methyl-8-oxo-5-thia-1-azabicyclo (4,2, oocok-2-ene-2-carboxylate as a colorless solid).

Mass spectrum: ion of the molecule at m / e 626.

ac) 2- (piperidinocarbonyl) allyl- (6R, 7R) -7 - ((Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido) -3-methyl-8-oxo-5 -thia-1-azabicyclo {4.2.0-oct-2-ene-2-carboxylate as a solid (from ethyl acetate).

X-ray spectrum (KBr technique): inter alia, bands at 1,779, 1,724, 1,677, 1,610, 1,535 and 1,452 cm ^-1 .

ad) (E) -2- (ethoxycarbonyl) -2-butenyl- (6R, 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3- (azidomethyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid.

Elemental analysis for ^C 21 ^H 24 ^N 8 ° 7 ^S 2 calculated C 44.67%, H 4.28%, N 19.85%, S 11.36%;

Found: C, 44.83; H, 4.31; N, 19.58; S, 11.27.

and e) (E) -2-Cyclohexymethoxy) carbonyl-2-butenyl- (6R, 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2-.

- (methoxyimino) acetamido-3- (azidomethyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-kaxboxylate as a colorless solid (from ether / hexane) .

-1 spectrum (KBr): inter alia bands at 2110, 1788, 1717, 1618 and 1532 cm.

Treatment of this compound with a 4.9N solution of hydrochloric acid in isopropyl alcohol gives (E) -2 - [(cyclohexylmethoxy) carbonyl] -2-butenyl- (6R, 7R) -7- [(Z) -2- (2-amino- 4-thiazolyl)

-2- (methoxyimino) acetamido-3- (azidomethyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate hydrochloride as a colorless solid (from isopropyl alcohol mixture) and hexane).

For C analýza proH ^ HNgClCS.1: 1 HCl (669.17):

C, 46.67; H, 4.97; N, 16.75; Cl, 5.30; S, 9.58;

Found: C, 46.28; C, 5.10; N, 16.54; Cl, 5.20; S, 9.39.

af) (E) -2- (isobutoxycarbonyl) -2-pentenyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3- (azidomethyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a yellowish solid (from ether / hexane).

Mass spectrum: protonated ion of the molecule at m / e 607.

ag) (E) -2- (Isobutoxycarbonyl) -2-butenyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3- (azidomethyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid.

Mass spectrum: protonated ion of the molecule at m / e 593.

ah) (E) -2 - ((2-ethoxyethoxy) carbonyl] -2-butenyl- (6R, 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) 3-Acetamido-3- (azidomethyl) -8-oxo-5-thia-1-azabicyclo [4.2.1.0 oct-2-ene-2-carboxylate as a colorless solid.

Mass spectrum: protonated ion of the molecule at m / e 609.

ai) (E) -2- (ethoxycarbonyl) -2-butenyl- (6R, 7R) -3- (acetoxymethyl) -8-oxo-7- [2- (3-thienyl) acetamido] -5-thia-1- Azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid of m.p. 88 ° C (from ether / hexane).

Elemental analysis for ^C 23 ^H 26 ^N 2 ° 8 ^S 2 (522.56):

H, 5.02; N, 5.36.

Found: C, 52.45; H, 4.85; N, 5.44.

aj) (E) -2- (isobutoxycarbonyl) -2-pentenyl- (6R, 7R) -3- (acetoxymethyl) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- ( methoxyimino) acetamido-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate. Elemental analysis for ^C 26 ^H 33 ^N 5 ° 9 ^S 2 ( ⁶² 3 »70):

C, 50.07; H, 5.33; N, 11.23.

Found: C, 50.03; H, 5.66; N, 11.20.

ak) (E) -2- (Isobutoxycarbonyl) -2-pentenyl- (6R, 7R) -7- t (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -8- oxo-5-thia-7-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid (from a mixture of methylene chloride and ether).

Elemental analysis for C ₂₃ ^H ₂₂ ^N 5 ° 7 ^S 2 (551.63):

C, 50.08; H, 5.30; N, 12.70.

Found: C, 49.85; H, 5.41; N, 12.46.

a1) (E) -2- (isobutoxycarbonyl) -2-pentenyl- (6R, 7R) -3 - [(carbamoyloxy) methyl] -7- [(Z) -2- (2-furyl) -2- (methoxyimo) Acetamido] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid (from a mixture of methylene chloride and ether).

Elemental analysis for ^C 26 ^H 32 ^N 4 ° 10 ^S ( ⁵⁹² → ⁶² ) ^: Calculated ^: C 52.70, H: 5.44, N, 9.45.

Found: C, 52.67; H, 5.59; H, 9.23.

Example 4 mmol of an antibiotic-active carboxylic acid from the beta-lactam type antibiotic, mmol of triphenylphosphine and 1.5 mmol of the desired alcohol of formula XI are dissolved in 5 ml of dimethylacetamide. A solution of 1.03 mmol of diethyl azodicarboxylate in dimethylacetamide was added dropwise. The reaction mixture is stirred for 4 hours, then diluted with 100 ml of ethyl acetate and washed three times with 50 ml of water each time and twice with 50 ml of 10% aqueous sodium chloride each time. The organic phase is dried over magnesium sulphate, filtered and evaporated. The residue is then purified by chromatography on silica gel, eluting with ethyl acetate / hexane (4: 1).

The following compounds were prepared in the same manner:

a) (RS) -2- (ethoxycarbonyl) -1,3-dimethyl-2-butenyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- ( methoxyimino) acetamido 3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid.

Mass spectrum: protonated ion of the molecule at m / e 552.

b) (RS) -2- (ethoxycarbonyl) -1-methylallyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3- methyl 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid (from ether / hexane).

Mass spectrum: protonated ion of the molecule at m / e 524.

Example 5

a) 0.51 g of (6R, 7R) -7-amino-3-azidomethyl-8-oxo-5-thia-1-azabicyclo [4.2.1.0] oct-2-ene-2-carboxylic acid is dissolved in 50 ml of acetone was then cooled to -10 DEG C. and 0.29 ml of diazabicycloundecene was added. After 15 minutes, 0.54 g of isobutyl (Z) -2- (bromomethyl) -2-pentenoate was added to this solution, and the reaction mixture was stirred overnight at 0 ° C. The solution is then diluted with 50 ml of butyl acetate and the crystals are filtered off.

Sodium chloride solution (30 ml) was added to the filtrate and the mixture was filtered. The organic phase was separated, dried, filtered and evaporated. The residue was chromatographed by flash column chromatography on silica gel, eluting with ethyl acetate / hexane (6: 4). The fractions containing the desired product are combined and evaporated. The residue is taken up in 20 ml of ethyl acetate and then a 4N solution of hydrochloric acid in ethyl acetate is added. The mixture is left at 0 ° C for 24 hours and the crystals are filtered off and dried under reduced pressure. 0.38 g of (E) -2- (isobutoxycarbonyl) -2-pentenyl- (6R, 7R) -7-amino-3-azidomethyl-8-oxo-5-thia-1-azabicyclo ~ 4.2 is obtained, Ooct-2-enecarboxylate hydrochloride.

Elemental analysis for ^C 26 ^{H H} I8 ° 5 5 ^C1 (459.95):

H, 5.70; N, 15.23.

Found: C, 46.87; H, 5.78; N, 15.14.

(b) 0.32 g of (E) -2- (xsobutoxycarbonyl) -2-pentenyl- (6R, 7R) -7-amino-3-azidomethyl-8-oxo-5-thia-1-azabicyclo ~ 4.2, O-O-2-ene-2-carboxylate hydrochloride is dissolved in 15 ml of methylene chloride and 0.24 g of (Z) -O-methyloxime S- (2-benzothiazolyl) -2-amine-4-thxazolglyoxylate is added. The reaction mixture was evaporated after 6 hours and the residue was chromatographed on a short column of silica gel using a 1: 1 mixture of ethyl acetate and hexane then ethyl acetate alone as the eluent. The fractions containing the desired product were combined and evaporated. The residue is dissolved in 20 ml of ethyl acetate and then 5 ml of a 4N solution of hydrochloric acid in ethyl acetate is added to the ethyl acetate solution. The crystals obtained are filtered off and recrystallized from isopropyl alcohol. 0.2 g of (E) -2- (isobutoxycarbonyl) -2-pentenyl- (6R, 7R) -7- [2Z] -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido is obtained. 3-azidomethyl-8-oxo-5-thxa-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate.

Elemental analysis for ^C 24 ^H 30 ^ClN 8 ° 7 ^S 2 (693.13):

C, 44.82; H, 4.86; N, 17.42.

found 43.41% C, 4, ´72% · Hy.16 ', 02.% N.

Example Ά.

Preparable gelatine capsules are prepared in the usual manner and have the following composition:

(E) -2- (isobutoxycarbonyl, -2-pentenyl- (6R, 7R, -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido) -3- ( azidomethyl) -8-oxo-

-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate 500 mg water-soluble polyvinylpyrrolidone (Luviskol) 20 mg mannitol 20 mg talc 15 mg magnesium stearic acid salt 2 mg

capsule fill weight 557 mg

Example B

Tablets of the following composition are prepared in the usual manner:

(E) -2- (isobutoxycarbonyl) -2-pentenyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino, acetamido) -3- ( azidomethyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate lactose

250 mg 70 mg maize starch 65 mg polyvinylpyrrolidone 10 mg magnesium stearate 5 mg tablet weight 400 mg

A granulate is prepared from the active ingredient, lactose, polyvinylpyrrolidone and 40 parts by weight of corn starch. To this, the remaining 25 parts by weight of corn starch and 5 parts by weight of magnesium stearate are admixed and the mixture is compressed into tablets.

Claims (23)

1. A process for the preparation of novel carboxylic acid esters of the general formula in which R represents a hydrogen atom or a group of the general formula ORb Ra CO wherein R a represents an optionally substituted 5-membered heteroaromatic group having a sulfur or oxygen atom and optionally one or two nitrogen atoms as ring heteroatoms, R b represents a hydrogen atom or a C 1 -C 7 alkyl group or an alkanoyl group R-denotes an alkyl group having from 1 to 7 carbon atoms, or -CI ^-Rd, wherein Rd denotes an alkanoyloxy group having up to 7 carbon atoms, a carbamoyloxy group, an azido group or a 5-membered nitrogen atom bonded via a nitrogen atom nitrogen containing a heteroaromatic group having up to 4 nitrogen atoms as ring heteroatoms optionally substituted by an alkyl group having 1 to 7 carbon atoms or a carbamoyl group, R ¹ represents a hydrogen atom or an alkyl group having 1 to 7 carbon atoms, R represents a hydrogen atom , (C 1 -C 7) alkyl, (C 1 -C 7) haloalkyl, (C 2 -C 7) alkenyl group or a (C 1 -C 7) alkoxycarbonyl group or, together with R ^1, form a C 1 -C 7 alkylene group, R is a hydrogen atom, a C 1 -C 7 alkyl group or a C 7 -C 7 alkoxycarbonyl group in the alkoxy moiety, R ⁴ denotes the group -COOR ⁵ , - COR ⁵ , -SO - R ⁵ , 7 8 9 -CONR R or -PO (OR) ₂ , wherein R represents a saturated or unsaturated hydrocarbon group of up to 12 carbon atoms in which optionally up to two methylene groups are replaced by oxygen atoms, R represents an alkyl group of 1 to 7 carbon atoms, r ' and R represents a hydrogen atom or an alkyl group having from 1 to 7 carbon atoms or together form an alkylene group having from 1 to 7 carbon atoms in which one methylene group is optionally replaced by an oxygen or sulfur atom or an imino or alkylimino group having 1 to 7 carbon atoms in the alkyl moiety, and R represents an alkyl group having 1 to 7 carbon atoms and, if a basic substituent is present, also their acid addition salts which are pharmaceutically acceptable, characterized in that the carboxyl group corresponding to the compound is esterified of formula (I) by treatment of a compound of formula (II) wherein X is hydroxy or cleavage epithelial and R ^1, R ^3, R ³ and R ⁴ have the above meanings, and then the ester obtained is optionally converted into an acid addition salt which is acceptable from a pharmaceutical standpoint. 2. A process according to claim 1, wherein the carboxylic acid corresponding to the compound of formula (I) in the form of a salt is treated with a compound of formula (II) wherein X is a leaving group and the other substituents are as defined in point 1. 3. A process according to claim 1, wherein the carboxylic acid corresponding to the compound of formula I is reacted in the presence of a condensing agent with a compound of formula II in which X is a hydroxyl group and the other substituents are as defined in point 1. A process according to any one of claims 1 to 3, wherein the corresponding carboxylic acid and the corresponding compound of formula (II) are used as starting materials to give esters of formula (I) in which Ra represents a 2-amino-4-thiazolyl group, 5-amino-1,2,4-thiadiazol-3-yl or 2-furyl, especially 2-amino-4-thiazolyl and the other substituents have the meaning given in 1. 5. A process as claimed in any one of Claims 1 to 4, wherein the corresponding carboxylic acid and the corresponding compound of formula (II) are used as starting materials to give esters of formula (I) wherein Rb is C1-C7alkyl and the other substituents are as defined in 1 to 4. AND Process according to one of Claims 1 to 5, characterized in that the corresponding carboxylic acid and the corresponding compound of formula (II) are used as starting materials to give esters of formula (I) in which R c is methyl or -CH 2 -R d and Rd is azido, and the other substituents are as defined in 1 to 5. Process according to one of Claims 1 to 6, characterized in that the corresponding carboxylic acid and the corresponding compound of formula (II) are used as starting materials to give esters of formula (I) wherein R ^{1 is} hydrogen and the other substituents are as defined above. referred to in points 1 to 6. 8. A process as claimed in any one of claims 1 to 7, wherein the corresponding carboxylic acid and the corresponding compound of formula (II) are used as starting materials to form esters of formula (I) in which R is C1-C7alkyl and the other substituents are as defined in one of items 1 to 7. 9. A process according to any one of Claims 1 to 8, wherein the corresponding carboxylic acid and the corresponding compound of formula (II) are used as starting materials to give esters of formula (I) in which R is hydrogen and the other substituents have the meanings given above. referred to in points 1 to 8. 10. Method according to one of claims 1 to 9, characterized in that starting from the corresponding carboxylic acid and the corresponding compound of formula II to give es4 Teruo 5 5 ¹ of the formula I in which R represents a group -C00R and R is alkyl of 1 to 7 carbon atoms, alkenyl of 2 to 7 carbon atoms or alkoxyalkyl of 1 to 7 carbon atoms in the alkyl and alkoxy moieties, and the other substituents are as defined in 1 to 9. 11. A process according to claim 10, wherein the corresponding carboxylic acid and the corresponding compounds of formula II are used as starting materials to form esters of formula R @ 1 in which R @ 1 -COOR is C1 -C7 alkyl. C 1 -C 7 alkoxyalkyl having 1 to 7 carbon atoms in the alkoxy and alkyl moieties, in particular isobutyl, isopropyl or 2-methoxyethyl, preferably isobutyl, while the other substituents are as defined in 1 to 10. Process according to one of Claims 1 to 3, characterized in that the corresponding carboxylic acid and the corresponding compound of the general formula II are used as starting materials to give (E) -2- (isobutoxycarbonyl) -2-pentenyl- (6R, 7R) -7-? (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido-3- (azidomethyl) -8-oxo-5-thia-1-azabicyclo [4.2.1.0 &lt; 2,7 &gt; O] α-2-ene-2-carboxylate. Process according to one of Claims 1 to 3, characterized in that the corresponding carboxylic acid and the corresponding compound of the formula (II) are used as starting materials to give (E) -2- (isobutoxycarbonyl) -2-butenyl- (6R). 7R) -7- (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino, acetamido) -3- (azidomethyl, -8-oxo-5-thia-1-azabicyclo [4.4.1.0 &lt; 2,7 &gt; Of oct-2-ene-2-carboxylate. Process according to one of Claims 1 to 3, characterized in that the corresponding carboxylic acid and the corresponding compound of formula (II) are used as starting materials to give (E, -2 - [(2-ethoxyethoxy) carbonyl] -2-butenyl- (6R, 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino, acetamido) -3- (azidomethyl) -8-oxo-5-thia-1-azabioyl] [ 4,2,0] oct-2-ene-2-carboxylate. Process according to one of Claims 1 to 3, characterized in that the corresponding carboxylic acid and the corresponding compound of the general formula II are used as starting materials to give (E) -2- (ethoxycarbonyl) -2-butenyl- (6R, 7R). - 7 - [(Z, -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido) -3- (azidomethyl, -8-oxo-5-thia-1-azabicyclo [4.2.1] O-oct-2-ene-2-carboxylate. Process according to one of Claims 1 to 3, characterized in that the corresponding carboxylic acid and the corresponding compound of the formula (II) are used as starting materials to give i. B2 (E) -2 - [[(3-methyl-2-butenyl) oxy] carbonyl] -2-butenyl- (5R, 7R) -7 - [(7)] -2- (2-amino-4-thiazolyl) 2- (methoxyimino) acetamido-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate. Process according to one of Claims 1 to 3, characterized in that the corresponding carboxylic acid and the corresponding compound of the formula II are used as starting materials to give (E) -2- (isopropoxycarbonyl) -2-butenyl- (6R, 7R). ) -7 - [(Z) -2- (2-Amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct- 2-ene-2-carboxylate. Process according to one of Claims 1 to 3, characterized in that the corresponding carboxylic acid and the corresponding compound of the general formula II are used as starting materials to give (E) -2- (isobutoxycarbonyl) -2-pentenyl- (6R, 7R) ) -7 - [(Z) -2- (2-Amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl-8-oxo-5-thia-1-azabieyclo [4.2.0] oct -2-ene-2-carboxylate. Process according to one of Claims 1 to 3, characterized in that the corresponding carboxylic acid and the corresponding compound of the formula II are used as starting materials to give (E) -2- (ethoxycarbonyl) -2-pentenyl- (6R, 7R). ) -7 - [(Z) -2- (2-Amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct- 2-ene-2-carboxylate. Process according to one of Claims 1 to 3, characterized in that the corresponding carboxylic acid and the corresponding compound of the formula (II) are used as starting materials to give (E) -2 - [(2-ethoxyethoxy) carbonyl] -2-butenyl- (6R, 7R) -7 - [(Z) -2- (2-Amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl-8-oxo-5-thia-1-azabicyclo [4.4.1.0 &lt; 2,7 &gt; 2,0-oct-2-ene-2-carboxylate. Process according to one of Claims 1 to 3, characterized in that the corresponding carboxylic acid and the corresponding compound of the general formula II are used as starting materials to give (E) -2- (isobutoxycarbonyl) -2-butenyl- (6R, 7R). ) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct -2-ene-2-carboxylate. Process according to one of Claims 1 to 3, characterized in that the corresponding carboxylic acid and the corresponding compound of the formula (II) are used as starting materials to give (E) -2- (tert-butoxycarbonyl) -2-butenyl- (6R). 7R) -7 - [(Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.1.0 &lt; 2,7 &gt; O, O-oct-2-ene-2-carboxylate. Process according to one of Claims 1 to 3, characterized in that the corresponding carboxylic acid and the corresponding compound of the formula II are used as starting materials to give (E) -2- (ethoxycarbonyl) -2-butenyl- (6R, 7R). ) -7 - [(Z) -2- (2-Amino-4-thiazolyl) -2- (methoxyimino) acetamido] -3-methyl-8-oxo-5-thiazabicyclo [4.2.0] oct-2 -en-2-carboxylate.