MC1991A1 - PHARMACOLOGICALLY ACTIVE CARBOXYLIC ACID ESTERS - Google Patents

Description

1

The present invention relates to esters of pharmacologically active carboxylic acids, particularly 8-lactam antibiotic carboxylic acids, that are separable under physiological conditions, characterized in that the alcohol component of the ester is a group with the general formula

N0

1 R4

i/*\ /R

R

He

R2/'V

where r! represents a hydrogen or a lower alkyl, R^ a hydrogen, lower alkyl, lower halogenal coyl, lower alkenyl, lower alkoxycarbonyl, aryl or heteroaryl or is with R^ a lower alkoylene, R^ is a hydrogen, lower alkyl or lower alkoxycarbonyl, R4 represents the group -COOR^-, -COR^, -SO2-R^f -CON^rS or -PO(Or9)2 R^ represents a saturated or unsaturated hydrocarbon radical having up to 12 carbon atoms, in which up to 2 methylene groups may be rem

2

placed by oxygen atoms, aryl or lower aryl-alkoyl, r6 represents a lower alkoyl or an aryl, R? and r8 each represent a hydrogen or a lower alkoyl or together a lower alkoylene in which a methylene group may be replaced by an oxygen atom or a sulfur atom or by an imino group or lower alkoyl imino and R^ represents a lower alkoyl,

and, to the extent that a basic substituent is present, 10 of their pharmaceutically acceptable acid addition salts.

The above esters are novel and possess interesting pharmacological properties. They are separated under physiological conditions to yield pharmacologically active free 15-carboxylic acids, which then exert their therapeutic effects. They can therefore be used to prevent or treat diseases and are suitable for enteral administration, particularly oral administration.

20 The object of the invention is: the above-mentioned esters separable under physiological conditions from pharmacologically active carboxylic acids, in particular carboxylic acids with antibiotic action in the field of beta-lactam antibiotics as such, and for the purposes 25 of application as therapeutic active substances; a process and intermediate products for their preparation; medicinal products containing them and a process for preparing such medicinal products; the application of these esters to prevent or combat diseases and 30 to prepare medicinal products, in particular agents with antibiotic action; as well as the application of certain starting materials to the esterification of carboxylic acids.

3

pharmacologically active boxyl acids, in particular carboxylic acids with antibiotic action from the 6-lactam antibiotic domain.

The expression "pharmacologically active carboxylic acid" used to define the carboxylic acid component of the esters according to the invention is to be understood in the broadest sense and includes all pharmacologically active compounds that contain a free carboxylic acid group as a structural element. The expression "carboxylic acid with antibiotic activity in the field of β-lactam antibiotics" is also to be understood in the broadest sense. It includes all antibiotic compounds that contain a β-lactam ring and a free carboxylic acid group as structural elements. Bicyclic β-lactam antibiotics are preferred in which the β-lactam ring is a component of the cyclic ring and the free carboxylic acid group is located in the α position relative to the nitrogen atom of the β-lactam. The carboxylic acid component 20 in the esters according to the invention is therefore preferably a penam-3-carboxylic, penem-3-carboxyli-ic, l-carbapenem-3-carboxylic, 3-cephem-4-carboxylic, l-oxa-3-cephem-4-carboxylic, l-dethia-2-oxa-3-cephem-, l-dethia-2-thia-3-cephem- or l-carba-3-cephem-4-carboxyli-25 acid radical.

In a particularly preferred embodiment, the carboxylic acid component of the esters of the invention is a pharmaceutically acceptable 3-cephem-4-carboxylic acid radical. In a particularly preferred embodiment, the invention relates to esters of the general formula

C*

4

/ORb

N H H H Ni • /S.

/•\ /w\: ./ \

Ra. • •

"I i 1-RC

0 /• \ t i

0

c/*xo

1 R4

R^'V

11

R2/NR3

where Ra represents an aryl or heteroaryl, Rb a hydrogen, lower alkanoyl or lower alkyl or cycloalkoyl in C3 to Cs possibly substituted by a carboxy, halogen, C3 to Cg cycloalkoyl or heteroaryl, Rc represents a hydrogen, halogen, lower alkyl, lower alkenyl, lower alkoxy or the -CG2~Rd or -CH2~S-Re group, Rd represents a lower alkanoyloxy, carba-moyloxy, azido or an aromatic group containing nitrogen linked via a nitrogen atom and Re represents a heteroaromatic group linked via a carbon atom, and R^, R^, r3 and R4 have the meaning given above.

The term "lower" is used to designate radicals and compounds having up to 7, preferably 15, down to 4 carbon atoms. The term "alcoyl" designates straight-chain or branched saturated hydrocarbon radicals, such as methyl, ethyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, and 2-ethylhexyl. The term "halo-alcoyl" designates a mono-, di-, or tri-substituted alkyl group with a halogen such as chloromethyl,

trichloromethyl and trifuloromethyl. The term "alkoxy" refers to an alkyl group linked via an oxygen atom. The term "alkoylene" refers to raC

5

Saturated hydrocarbon radicals with straight or branched chains, having 2 free valences, such as dimethylene, trimethylene and tetramethylene. The term "alkenyl" designates hydrocarbon radicals with straight or branched chains that contain at least one olefinic double bond such as vinyl, 1-propenyl and 2-propenyl.

The expression "saturated or unsaturated hydrocarbon radical having up to 12 carbon atoms in which up to 2 methylene groups can be replaced by 10 oxygen atoms" refers to open-chain and cyclic groups and their combinations. Examples of open-chain radicals, which can be straight-chain or branched, include: the alkyl, alkenyl, and al-coxyalcoyl groups as defined above, and the al-15 coxyalcoxyalcoyl and dialcoxyalcoyl groups, such as 2,3-dimethoxypropyl. Examples of cyclic groups and combinations of cyclic and straight-chain groups include: cycloalcoyl and cycloalcoylalcoyl groups possibly substituted by alkyl groups where the cyclic group contains up to 7 links and where up to 2 methylene groups can be replaced by oxygen atoms, such as tetrahydro-2H-pyran-4-yl(tetrahydro-2H-pyran-2-yl)methyl, cyclohexyl and cyclohexylmethyl.

The term "aryl" refers to 25 carbocyclic aromatic groups, preferably monocyclic groups, i.e., phenyl groups. These groups may be substituted by a lower alkyl, a lower alkoxy, a halogen, a trifluoromethyl, or a cyano. Unsubstituted or monosubstituted groups, such as phenyl, are preferred.

The term "heteroaryl" refers to heterocyclic aromatic groups, preferably heterocycles.

6

Monocyclic aromatics with 5 or 6 members. Aromatic heterocycles with 6 members preferably contain, as members of the heterocycle, an oxygen or sulfur atom, or an imino or lower alkyl group, and possibly one or two nitrogen atoms. Aromatic heterocycles with 6 members preferably contain one, two, or three nitrogen atoms. Examples include thienyl, thiazolyl, thiadiazolyl, and furyl. These groups are unsubstituted or substituted with a lower alkyl, lower alkyl, halogen, trifluoromethyl, nitro, amino, or cyano group. They are preferably unsubstituted or monosubstituted. Examples include 3-thienyl, 2-furyl, 2-amino-4-thia-zoly, and 2-bromo-5-furyl.

15 The expression "an aromatic group containing nitrogen linked via a nitrogen atom" refers to aromatic heterocyclic groups that contain up to 4 nitrogen atoms as members of the heterocycle. They preferably have 5 or 6 members and may be further 20 condensed by a 5- or 6-membered cycloalkane ring or by a benzene ring. They are preferably unsubstituted or substituted by a lower alkyl group or a carbamoyl group.

As an example of nitrogen-containing heterocyclic groups, 5-methyl-2-tetrazoyl can be cited. 25 The expression "heteroaromatic group linked via a carbon atom" preferably refers to monocyclic aromatic heterocyclic groups, in particular with 5 and 6 members, which contain as heteroatoms, preferably an oxygen or sulfur atom 30 and/or 1 to 4 nitrogen atoms, and to bicyclic aromatic heterocyclic groups, in particular with 8 to 10 members, which preferably contain as heteroatoms c.

an oxygen or sulfur atom and/or 1 to 5 nitrogen atoms. These groups are preferably unsubstituted or substituted by a lower alkyl, a lower alkoxy, a diyl lower alkane, a halogen, a trifluoromethyl, a lower alkoxycarbonyl or a carbamoyl.

Ra preferably represents a 5-membered heteroaromatic group, either unsubstituted or substituted with an amino group, having a sulfur or oxygen atom and possibly one or two nitrogen atoms as members of the heterocycle, in particular 2-amino-4-thiazolyl, 5-amino-1,2,4-thiadiazol-3-yl, or 2-furyl. In a particularly preferred embodiment, Ra represents a 2-amino-4-thiazolyl.

Rb preferably represents a hydrogen, lower alkyl or lower alkanoyl, in particular a lower alkyl.

Rc preferably represents a lower alkyl, in particular a methyl or the -CH2~Rd group, where Rd preferably represents an azido.

r1 preferably represents a hydrogen. r2 preferably represents a lower alkyl. r3 preferably represents a hydrogen. R4 preferably represents the -COOR^ group, and r5 preferably represents a lower alkyl, lower alkenyl, or lower alkoxyalkoyl. In a particularly preferred embodiment, R5 represents a lower alkenyl or a lower alkoxyalkoyl, in particular isobutyl, isopropyl, or 2-ethoxyethyl, where the meaning isobutyl is particularly preferred.

The compounds mentioned below are particularly preferred esters according to the invention:

8

(E)-2-(isobutoxycarbonyl)-2-pentenyl (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-(azi-do-methyl)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate.

5 (E)-2-(isobutoxycarbonyl)-2-butenyl (6R,7R)-7- [ (Z ) -

2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-(azido-methyl)-8-oxo-5-thia-l-azabicyclo[4 .2 . 0J oct-2-ene-2-carboxylate.

(E)-2-[(2-ethoxyethoxy)carbonyl]-2-butenyl(6R,7R)-107-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamidoj-

3-(azidomethyl-8-oxo-5-thia-l-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-(azido-15 methyl)-8-oxo-5-thia-l-azabicyclo[4.2.0] oct-ene-2-carboxy-late.

(E)-2- [ [(3-methyl-2-butenyl)oxy] carbonyl] -2-butenyl (6R,7R)-7-[( Z )-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido] -3-methyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-20 2-ene-2-carboxylate.

(E)-2-(isopropoxycarbonyl)-2-butenyl (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-methyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate.

(E)-2-(isobutoxycarbonyl)-2-pentenyl (6R,7R)-7 - [(Z)-25 2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-methyl-8-oxo-5-thia-l-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 [4.2.0]oct-2-ene-.2-carboxylate.

30 (E)-2-[(2-ethoxyethoxy)carbonyl]-2-butenyl (6R,7R)-

7- [ ( Z ) -2- ( 2-amino-4-thiazolyl ) -2-^aethoxyimino ) acetamido] -

3-methyl-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carbo-

<L

xylate.

(E)-2-(isobutoxycarbonyl)-2-butenyl (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-methyl 8-oxo-5-thia-l-azabicyclo[4.2.0] oct-2-ene-2-carboxylate.

(E)-2-(t-butoxycarbonyl1)-2-butenyl (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-methyl 8-oxo-5-thia-l-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-thia-azabicyclo[4.2.0]oct-2-ene-2-carboxylate.

Esters according to the invention, and insofar as they possess a basic group, their pharmaceutically acceptable acid addition salts, can be prepared by esterifying a pharmacologically active carboxylic acid with a compound of general formula

XI

r4

Ri/ \ /R R • II

R2 7 \3

where X represents a hydroxyl or leaving group, and R^, R^, r3 and R4 have the meaning given above,

or b) to prepare an ester of formula I above by acylating a compound of general formula

10

H H

E2. I

rS%'

:/s\

i R° % *

m

</ N0

1 R4

R^'V

II

R2/V

where Rl, R^, r3, r4 and Rc have the meaning given above,

with a carboxylic acid of general formula

N--0Rb

/k IV

Ra ' ^ COOH

where Ra and Rb have the meanings given above,

or one of their reactive derivatives, and c) if desired, by transforming the ester obtained into a pharmaceutically acceptable acid addition salt,

Esterification can be carried out according to variant a) of the process using methods known and common to all specialists. For example, a salt, in particular an alkali metal salt such as sodium or potassium salt, can be reacted with a carboxylic acid.

11

pharmacologically active with a compound of formula II where X represents an leaving group. Suitable leaving groups are, e.g., halogen atoms, such as bromine and iodine, and lower alkyl and 5-arylsulfonyloxy groups, such as methylsulfonyloxy and p-toluenesulfonyloxy. Suitable solvents are, e.g., dimethylformamide and dimethylacetamide. The reaction is preferably carried out within a temperature range of approximately -30°C to around room temperature, preferably at approximately 0°C.

It is also possible, however, to react the pharmacologically active free carboxylic acid in the presence of a condensing agent with a compound of formula II, where X represents a hydroxyl group. A suitable condensing agent is, for example, diethylazodicarboxylate/triphenylphosphine. Suitable solvents include, for example, dimethylformamide and dimethylacetamide. The reaction is preferably carried out within a temperature range from -30°C to around room temperature, preferably at approximately 0°C. Acylation can also be carried out according to variant b) of the process using methods known and common to all specialists. For example, the compound of formula III can be acylated with the carboxylic acid of formula IV, or one of its salts with a base, in which case a suitable condensing agent is used. Suitable condensing agents include, for example, carbodiimides, N,N'-disubstituted such as N,N'-dicyclohexylcarbodiimide, which is preferably used with N-hydroxybenzotriazole or N-hydroxysuccinimide, 2-halogen-pyridinium salts such as 2-chloro-1-methylpyridinium chloride, phosphorus oxychloride, and thionyl chloride.

12

and oxalyl chloride.

However, it is also possible to use the carboxylic acid of formula IV in the form of a reactive derivative. As reactive derivatives, mention should be made in particular of acid chlorides, acid anhydrides, mixed anhydrides (for example anhydrides with trifluoracetic acid, benzenesulfonic acid, mesitylenesulfonic acid, p-toluenesulfonic acid and p-chlorosulfonic acid) and the active thiolesters, for example the S-(2-benzothiazolyl)-thioester in question.

Acylation can be carried out, if necessary, in the presence of an acid-binding agent. In particular, sodium carbonate, potassium carbonate, triethylamine, pyridine, or N-methylmorpholine can be used as acid-binding agents. Suitable solvents include, for example, cyclic ethers such as tetrahydrofuran and dioxane, lower halogenated hydrocarbons such as chloroform and methylene chloride, dimethylformamide, and dimethylacetamide.

acetonitrile, acetone, and water, as well as mixtures thereof. The reaction temperature can vary over a wide range and is generally between -50°C and 50°C, preferably between about -10°C and 30°C. 25 The compounds of formula III used as starting materials are novel and are also the subject of the invention. They can be prepared by esterification of the corresponding 7-amino-3-cephem-3-carboxylic acids by analogy with variant a) of the process. 30 The preparation of the acid addition salts of the esters according to the invention, which have a basic substitution, can also be carried out by known processes and

13

common to all specialists. It is necessary to mention here both salts with pharmaceutically acceptable inorganic acids and salts with pharmaceutically acceptable organic acids. As examples of acid addition salts of esters according to the invention, mention should be made of salts with mineral acids, for example, hydrohalic acids, such as hydrochloric acid, hydrobromic acid and hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., salts with organic sulfonic acids, for example, with alkyl- and arylsulfonic acids, such as ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, etc., as well as salts with organic carboxylic acids, for example, with acetic acid, tartaric acid, maleic acid,

citric acid, benzoic acid, salicylic acid, ascorbic acid and similar.

The esters according to the invention can also be hydrated. Hydrates of this type are obtained mostly automatically during the preparation process or as a result of the hygroscopic properties of a product that is initially anhydrous. For preparations aimed at producing a hydrate, a wholly or partially anhydrous product can be subjected to a humid atmosphere. Pharmaceutically active carboxylic acids used as starting materials, in particular carboxylic acids with antibiotic activity in the beta-lactam antibiotic domain, belong to known classes of compounds. Representatives of these classes of compounds not specifically described above can be prepared by analogy with known representatives using known processes.

c

14

The compounds of formula II used as starting materials also belong to known classes of products. Representatives of this class of compounds not specifically described above can be prepared by analogy with known representatives using known processes. Reference is made in this regard to the publications cited below: German patent application published under No. 2,155,113 (published on May 10, 1972);

H.M.R. Hoffmann and J. Rabe, Angew. Chem. 95_r 795-796

10 (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 already mentioned above, the carboxylic acids corresponding to the esters according to the invention possess interesting pharmacological properties. They are particularly suitable for enteral, especially perioral, treatment of diseases.

The oral antimicrobial efficacy of the esters of carboxylic acids with antibiotic action according to the invention can be demonstrated, for example, in the animal experiment described below:

Experimental septicemia is induced in albino mice weighing 16 to 20 g by intraperitoneally injecting the experimental animals with a 4 sample 25 of a diluted culture of the experimental organism

'Escherichia coli 25922, which was grown overnight. The administered sample was then measured so that the dose administered was approximately 10 to 20 times greater than the dose required to kill 50% of the untreated experimental animals within 48 hours. The bacteria were injected as a suspension into the culture broth. Both for the control and the treatment group-

15

For each dose tested, groups of 5 experimental animals are used. The esters according to the invention are administered orally as a solution in Tween 80 (4%), and the 5 concentrations are chosen so that each experimental animal receives 500 µL. Treatments are carried out 1 and 3 hours after infection. The ED50 is the dose that protects 50% of the experimental animals and is calculated based on the survival rates 4 days after infection using the Probit method. The following table shows the ED50 values in mg per kg orally for representatives of the product class according to the invention. The table also contains data on the acute toxicity of the esters according to the invention for a single oral administration to mice.

PAINTING

Ester according to

DE50 in mg/kg

DI50 in mg/kg

1' invention p.o.

p.o.

Compound A

0.28

> 5000

Compound B

1.4

-

Compound C

0.89

> 5000

Compound 1: (E)-2-(isobutoxycarbonyl)-2-pentenyl (6R,7R)-25 7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-

acetamido]-3-(azidomethyl)-8-oxo-5-thia-l-aza-bicyclo[4.2.0] oct-2-ene-2-carboxylate.

16

(E)-2-(isobutoxycarbonyl)-2-pentenyl (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-3-methyl-8-oxo-5-thia-l-azabicyclo-C4.2.0]oct-2-ene-2-carboxylate. (E)-2-ethoxycarbonyl)-2-butenyl (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-3-methyl-8-oxo-5-thia-azabicyclo-[4.2.0]oct-2-ene-2-carboxylate.

The products according to the invention can be used as medicinal products, e.g. in the form of pharmaceutical preparations for enteral administration. The products according to the invention can be administered, for example, orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, or rectally, e.g. in the form of suppositories.

The preparation of pharmaceutical preparations can be carried out: in a common way for all specialists, by putting the 20 substances according to the invention into a galenic administration form, possibly in combination with other therapeutically interesting substances, with therapeutically acceptable, inert, non-toxic, suitable solid or liquid supports and possibly the usual pharmaceutical additives.

25. As supports of this kind, both inorganic and organic supports must be mentioned. For example, for tablets, coated tablets, and hard gelatin capsules, lactose, corn starch or its derivatives, talc, stearic acid, or its salts can be used as supports. For soft gelatin capsules, vegetable oils, waxes, fats, and semi-solid and liquid polyols can be used as supports (according to

Compound B:

5 Compound C:

17

Depending on the nature of the active substance, carriers may not be necessary in soft gelatin capsules. For preparing solutions and syrups, carriers such as water, five-polyols, sucrose, invert sugar, and glucose can be used. For suppositories, carriers such as natural or hardened oils, waxes, fats, and semi-liquid or liquid polyols can be used.

As pharmaceutical additives, we can use 10 of the usual preservatives, third-party solvents,

stabilizing agents, wetting agents, emulsifiers, softeners, colorants, flavorings, salts to modify osmotic pressure, buffers, coating products and antioxidants.

15 The esters according to the invention and their pharmaceutically acceptable acid addition salts and hydrates are envisaged for enteral application, in particular peroral.

Pharmaceutical preparations may contain the esters according to the invention, depending on the nature of the pharmacologically active carboxylic acid corresponding to the ester, in quantities of approximately 25–2000 mg, preferably 100–1000 mg, per unit dose. For the prevention and treatment of infectious diseases, a daily dose of approximately 0.05 g to approximately 4 g, particularly approximately 0.5 g to approximately 2 g, may be considered for adults. This dose may be administered as a single unit dose or divided into several doses.

The following examples are intended to clarify the invention, 30 without, however, limiting its scope in any way. All temperatures are given in degrees Celsius.

q

18

EXAMPLE 1

a) 1 g of sodium salt of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamidoj-3-methyl-8-oxo-5-thia-l-azabicyclo[4.2.OJ-

5-oct-2-ene-2-carboxylic acid is dissolved in 20 mL of dimethylformamide, cooled to 0°C, and mixed with 0.7 g of bromomethylacrylic acid ethyl ester. After 2 hours, 80 mL of water is added, and the mixture is extracted with 200 mL of ethyl acetate. The organic phase is washed three times with 50 mL of water each time, dried over magnesium sulfate, and concentrated to a volume of 20 mL. While stirring, 100 mL of ether is added, the precipitate is filtered using a filtering funnel, and dried under vacuum at room temperature. 2-(ethoxycar-15-bonyl)-allyl(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-methyl-8-oxo-5-thia-l-azabicyclo-14.2.0|-oct-2-ene-2-carboxylate is obtained as a white solid (from ethyl acetate/ether). Elemental analysis for C₂OH₂₃N₅O₇S₂(509,552): 20 C₆H₁₂N₅S₂

hold. 47.14 4.55 13.74 12.58

found 46.82 4.64 13.50 12.38

Similarly, we obtain:

b) 2-(ethoxycarbonyl)allyl (6R,7R)-7-[(Z)-2-(2-

25 amino-4-thiazolyl)-2-(methoxyimino)acetamido]— 3 — C(5-methyl-2H-tetrazol-2-ylJmethyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]— oct-2-ene-2-carboxylate as a white solid (from ethyl acetate/ether).

Elemental analysis for C22H25N9O7S2 (591,62): 30 C H N S

hold. 44.66 4.26 21.31 10.84

found 44.39 4.45 21.05 10.79

O

19

c) 2-(ethoxycarbonyl)allyl (6R,7R)-3-[(carbamoyl-oxy)-methyl]-7[(Z)-2-(2-furyl)-2-(methoxyimino)acetamido]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate as a white solid (from 5-d1-ethyl/-propyl ether acetate).

Elemental analysis for C22H24N4°10S (536,521):

CHNS

calc. 49.25 4.51 10.44 5.98

found 49.46 4.80 10.24 5.84

10 EXAMPLE 2

a) 2 g of sodium salt of (6R,7R)-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxy-imino)acetamido]-3-methyl-8-oxo-4-thia-l-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid are dissolved in 40 mL of dimethylformamide, cooled to 0°C, and mixed with 1.58 g of α-bromomethylacrylic acid. After 5 hours, 200 mL of water are added, and the mixture is extracted with 350 mL of ethyl acetate. The organic phase is washed three times with 100 mL of water each time, dried over magnesium sulfate, and concentrated to a volume of 20 mL. While stirring, 250 ml of isopropyl ether is added. The precipitated product is filtered with a filter funnel and dried under vacuum at room temperature. The 2-(t-butoxycarbonyl)allyl (6R,7R)-7-[(Z)-2-(2-amino-4-25 thiazolyl)-2-(methoxyimino)acetamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate is obtained as a white solid (from ethyl acetate/i-propyl ether).

Elemental analysis for C22H27N5O7S2 (537.61) 30 C H N S

calc. 49.15 5.06 13.03 11.93

found 48.78 5.14 13.03 12.15

20

Similarly, we obtain:

b)2-(t-butoxycarbonyl)allyl (6R,7R)-7-[(Z)-2-(2-ami-no-4-thiazolyl)-2-(methoxyimino)acetamido]-3-(azidomethyl)-8-oxo-5-thiazolyl-1-azabicycloI4.2.0]oct-2-ene-2-carboxylate

5 in the form of a beige solid (from ethyl acetate/i-propyl ether).

Elemental analysis for C22H26N8°7S2(5?8.63) + 0.15 mole of ethyl acetate:

CHNS

10 cal. 45.67 4.52 19.36 11.08

found 45.87 4.63 18.93 10.83

c) 2-(t-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-l-azabicyclo [4.2.0J

15 oct-2-ene-2-carboxylate as a white solid (from acetate d1 etiiyie/i-propyl ether).

Elemental analysis for C24H29N9O7S2 (619,683):

CHNS

calc. 46.52 4.72 20.39 10.35

20 found 46.33 4.84 20.12 10.60

d) 2-(t-butoxycarbonyl)allyl (6R,7R)-3-[(carbamoyl-oxy)-methyl]-7-C(Z)-2-(2-furyl)-2-(methoxyimino)acetamido]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate as a white solid (from acetate

25 of ethyl/high boiling point petroleum ether).

Elemental analysis for C24H28N40lOs (564,576) + 0.25 mole of ethyl acetate

CHNS

calc. 51.06 5.00 9.92 5.68

30 found 51.19 5.16 9.55 5.47

21

EXAMPLE 3

A 2.5 mmol solution of an alkali metal salt of a 6-lactam carboxylic acid with antibiotic activity in 20 mL of dry dimethylformamide is treated by cooling with ice water. This is followed by a 2.7 mmol solution of a corresponding halide of formula II in 2 mL of dry dimethylformamide. The cooling bath is removed, and the resulting solution is stirred overnight at approximately 0°C. The solution is then diluted 10-fold with 100 mL of ethyl acetate and extracted three times, each time with 50 mL of water and once with 50 mL of table salt solution. The organic phase is dried over magnesium sulfate, filtered, and concentrated. The residue is rapidly chromatographed on a short column of silica gel, eluting with ethyl acetate/hexane (8:2). The fractions of interest are collected and concentrated. A solution of the residue in 2 ml of methylene chloride is then added dropwise to 300 ml of a 1:1 mixture of ethyl acetate and hexane. The resulting crystals are separated by filtration and dried under reduced pressure.

The compounds mentioned below are prepared in this way:

a) (E)-2-ethoxycarbonyl)-2-butenyl (6R,7R)-7-[(Z)-25 2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-methyl-8-oxo-5-thia-azabicyclo[4.2.0]oct-ene-2-carboxylate as a colorless solid (from methylene/ether chloride).

Elemental analysis for C21H25N5O7S2 (523.55): 30 C H N S

calc. 48.17 4.81 13.38 12.25

found 47.90 4.97 13.26 12.23

22

b) (E)-2-(t-butoxycarbonyl)-2-butenyl (6R,7R)-7-L(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-methyl-8-oxo-5-thia-l-azrabicyclo [4.2.0]oct-2-ene-2-carboxylic in the form of a colorless solid

5 Elemental analysis for C23H29N5O7S2 (551,61):

CHNS

calc. 50.08 5.30 12.70 11.62

found 49.89 5.39 12.60 12.69

c) (E)-2-isobutoxycarbonyl)-2-butenyl (6R,7R)-7-

10 [ (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-

3-methyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate as a colorless solid (from ether/methylene chloride).

Mass spectrum: protonated molecular ion at m/e 552.

15 d) (E)-2-[(2-ethoxyethoxy)carbonyl]-2-butenyl (6R,

7R)-7- [( Z)-2-(2-amino-4-thiazolyl)-2-(methoxyiminoacetami-do]-3-methyl-8-oxo-5-thia-l-azabicyclo[4.2.0] oct-2-ene-2-carboxylate as a colorless solid.

Elemental analysis for C23H29N5O8S2 (567.60):

20 CHNS

calc. 48.67 5.15 12.34 11.30

found 48.37 5.41 12.57 13.31

e) (E)-2-[(RS)-2-ethylhexyloxycarbonyl]butenyl (6R,7R)-7-[(2)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)ace-

25 tamido]-3-methyl-8-oxo-5-thia-l-azabicyclo[4.2.0] oct-2-ene-2-carboxylate as a solid Mass spectrum: among other peaks at m/e 368.

f) (E)-2[C(RS)-2,3-dimethoxypropoxy] carbonyl]-2-butenyl (6R,7R)-7-E(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)

30 acetamido]-8-oxo-5-thia-l-azabicyclo[4.2.0] oct-2-ene-carboxylate in the form of a colorless solid.

c5

23

Elemental analysis for C24H31N5O9S2 (597.65):

CHNS

calc. 48.23 5.23 11.72 10.73

found 48.00 5.40 11.40 10.38

g) (E)-2-acetyl-2-butenyl (6R,7R)-7-[(Z)-2-(2-ami-no-4-thiazolyl)-2-(methoxyimino)acetamido]-3-methyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate as a yellowish solid (from methylene ether/chloride).

Elemental analysis for C20H23N5°6S2 (493.53):

C H N

calc. 48.67 4.70 14.19

found 48.80 5.23 13.16

h) (RS)-2-(methoxycarbonyl)-2-cyclohexene-l-yl

(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)ace tamido] -3-methyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene 2-carboxylate as a colorless solid (from methylene chloride/ether).

Elemental analysis for C22H25N5°7S2 (535,60):

C H N

calc. 49.34 4.71 13.08

found 49.35 4.90 12.67

i) 1-ethyl-4-methyl-2[[[(6R,7R)-7-[(Z)-2-(2-amino-

4-thiazolyl)-2-(methoxyimino)acetamido] -3-methyl-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-yl] carbonyl] methoxy] fumarate as a colorless solid (from methylene chloride/ether).

Mass spectrum: protonated molecular ion at m/e 568.

j) 1-ethyl-1-4-methyl-2-[[[[(6R,7R)-7-1(Z)-2-(2-ami-no-4-thiazolyl)-2-(methoxyimino)acetamido]-3-methyl-8-oxo-

5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-yl] carbonyl] oxy] methyl] maleate as a colorless solid (from methylene chloride/ether).

24

Mass spectrum: protonated molecular ion 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-l-azabicyclo £4.2. 0] oct-2-ene-ene-carboxylate in the form of a colorless solid (from ether).

Elemental analysis for C22H27N5°7S2 (537.58):

CHNS

calc. 49.15 5.06 13.03 11.93

found 48.66 5.15 12.82 11.60

10 1) 2-(p-nitrophenoxycarbonyl)allyl (6R,7R)-7-C(Z)—

2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido] -3-methyl-8-oxo-5-thia-l-azabicyclo[4.2.0] oct-2-ene-2-carboxylate as a yellow solid.

IR spectrum (KBr): among others Bands at 1778, 1739, 1681 15 and 1615 cm-1.

m) (E)-2-[£(tetrahydro-2H-pyran-4-yl)oxy] carbonyl]-2-hexenyl (6R,7R)-7-£(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino )acetamido] -3-methyl-8-oxo-5-thia-l-azabicycloX4.2.0] oct-2-ene-2-carboxylate as a colorless solid 20 (from methylene/hexane chloride).

Mass spectrum: protonated molecular ion at m/e 608.

n) (E)-2-££(tetrahydro-2H-pyran-4-yl]carbonyl-2-pentenyl (6R,7R)-7[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino )acetamido] -3-methyl-8-oxo-5-thia-l-azabicyclo £4.2.0]-25 oct-2-ene-2-carboxylate as a colorless solid (from methylene/hexane chloride).

IR spectrum (KBr): among others Bands at 1781, 1715, 1683, 1619, and 1534 cm~l.

o) (E)-2-[ £( tetrahydro-2H-pyran-4-yl)oxy] carbonyl]-30 2-butenyl (6R,7R)-7-£(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino )acetamido] -8-oxo-5-thia-l-azabicyclo £4.2.0]oct-2-ene-

C

25

2-carboxylate in the form of a colorless solid (from ethyl acetate/hexane).

Mass spectrum: protonated molecular ion at m/e 580.

p) (E)-2-(isobutoxycarbonyl)-2-pentenyl (6R,7R)-5 7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-

3-methyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-car-boxylate as a colorless solid.

Mass spectrum: protonated molecular ion at m/e 566.

q) (E)-2-[C(RS)-(tetrahydro-2H-pyran-2-y1)methoxy] 10 carbonyl]-2-hexenyl (6R,7R)-7-[(Z)-2-(amino-4-thiazolyl)-2-(methoxyimino)acetamido] -3-methyl-8-oxo-5-thia-l-azabi-cyclo[4.2.0]oct-2-ene-2-carboxylate as a colorless solid.

Mass spectrum': protonated molecular ion at m/e 622. 15 r) (E)-2-[[[(RS)-tetrahydro-2H-pyran-2-yl] methoxy]

carbonyl]-2-butenyl (6R,7R)-7-L(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-methyl-8-oxo-5-thia-l-azabicy-clo£4 .2.0]oct-2-ene-2-carboxylate as a colorless solid (from methylene/hexane chloride). 20 Mass spectrum: protonated molecular ion at m/e 594.

s) (E)-2-E E E(RS)-tetrahydro-2H-pyran-2-yl]methoxy] carbonyl]-2-pentenyl (6R,7R)-7-L(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido] -3-methyl-8-oxo-5-thia-l-azabicy-clo [4 . 2 . 0] oct-2-ene-2-carboxylate as a colorless solid (from hexane).

Ir spectrum (KBr): among others Bands at 1781, 1718, 1662 and 1620 cm~l.

t) (E)-2-[(cyclohexyloxy)carbonyl]-2-butenyl (6R,7R)-7- ["(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-30 3-methyl-8-oxo-5-thia-l-azabicyclo E4.2.0]oct-2-ene-2-carboxylate as a colorless solid (from ether/hexane).

26

Elemental analysis for C25H31N5O7S2 (577.64):

C H N

calc. 51.98 5.41 12.12

found 51.95 5.96 12.04

5 u) (E)-2-(isopropoxycarbonyl)-2-butenyl (6R,7R)-7-

[ (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-methyl-8-oxo-5-thia-l-azabicyclo[4.2.0] oct-2-ene-2-carboxylate as a colorless solid (from ether/hexane).

10 Mass spectrum: protonated molecular ion 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-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate as a colorless solid (from ethyl acetate/hexane).

Mass spectrum: protonated molecular ion at m/e 5 92.

w) (E)-2-[[(3-methyl-2-butenyl)oxy] carbonyl]-2-butenyl (6R,7R)-7-1(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimi-no)acetamido]-3-methyl-8-oxo-5-thia-l-azabicyclo{4.2.Q]oct-20 2-ene-2-carboxylate as a colorless solid (from ether/pentane).

Mass spectrum: protonated molecular ion at m/e 564.

x) (E)-2- [ [ [(E/Z)-3,7-dimethyl-2,6-oxtadienyl]oxy] carbonyl]-2-butenyl (6R,7R)-7-E(Z)-2-(2-amino-4-thiazolyl)-25 2-(methoxyimino)acetamido]-3-methyl-8-oxo-5-thia-l-azabicy-clo [4.2.0]oct-2-ene-2-carboxylate as a colorless solid (from ether/hexane).

Mass spectrum: protonated molecular ion at m/e 632.

y) (E)-3-(5-bromo-2-furyl)-2-(ethoxycarbonyl)allyl 30 (6R,7R)-7-[(Z)-2-(2-amino~4-thiazolyl)-2-(methoxyimino)acetamido] -3-methyl-8-oxo-5-thia-l-azabicyclo[4.2.0] oct-2-ene-2-carboxylate as a colorless solid (from ether/hexane).

<

27

Elemental analysis for C24H24BrN50sS2 (654,47):

C H N S Br calc. 44.04 3.70 10.70 9.80 12.21

found 44.31 3.98 10.54 9.74 12.09

5 z) 2-(ethoxycarbonyl)-2,4-hexadienyl (6R,7R)-7-

I(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-methyl-8-oxo-5-thia-l-azabicyclo £4.2. 0] oct-2-ene-2-carboxylate in the form of an incoloured solid.

Elemental analysis for C23H27N5O7S2 (549.61): 10 C H N

calc. 50.26 4.95 12.74

found 49.95 5.33 12.10

aa) 2-(dimethoxyphosphinyl)allyl (6R,7R)-7-Σ(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-methyl-158-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate as a colorless solid (from 11-ether/hexane).

Mass spectrum: protonated molecular ion at m/e 546.

20 ab) (E and/or Z)-4,4,4-trichloro-2-(ethoxycarbonyl)-

2-butenyl (6R,7R)-7-Σ(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido] -3-methyl-8-oxo-5-thia-l-azabicyclo Σ4.2.0]oct-2-ene-2-carboxylate in the form of a colorless solid.

25 Mass spectrum: molecular ion at m/e 626.

ac) 2-(piperidinocarbonyl)allyl (6R,7R)-7-C(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido] -3-methyl-8-oxo-5-thia-l-azabicyclo £4.2.0] oct-2-ene-2-carboxylate as a colorless solid (from ethyl acetate 30).

IR spectrum (KBr): among others Bands at 1779, 1724, 1677, 1610, 1535 and 1452 cm~l.

28

ad) (E)-2-(ethoxycarbonyl)-2-butenyl (6R,7R)-7-C( Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-(azido methyl)-8-oxo-5~thia-l-azabicyclo [4.2.0] oct-2-ene-carboxy-late as a colorless solid.

5 Elemental analysis for C21H24N8O7S2 (564.57):

CHNS

calc. 44.67 4.28 19.85 11.36

found 44.83 4.31 19.58 11.27

ae) (E)-2-[(cyclohexylmethoxy)carbonyl]-2-butenyl

10 (6R,7R)-7-[~(Z)-2-( 2-amino-4-thiazolyl ) -2- (methoxyimino ) acetamido] -3-(azidomethyl)-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid (from ether/hexane).

IR spectrum (KBr): among others Bands at 2104, 1788, 1717, 15, 1618 and 1532 cm-1.

Treatment of this compound with 4.9N hydrochloric acid in isopropanol yields the hydrochloride of (E)-2-[(cyclohexylmethoxy)carbonyl]-2-butenyl(6R,7R)7-C(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamidol-203-(azidomethyl)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-

2-carboxylate in the form of a colorless solid (from i-propanol/hexane).

Elemental analysis for C26H32N8O7S2, 1:1 HCl (669.17): C H N Cl S

25 calc 46.67 4.97 16.75 5.30 9.58

found 46.28 5.10 16.54 5.20 9.39

af) (E)-2-(isobutoxycarbonyl)-2-pentenyl (6R,7R)-7-["(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido] -

3-(azido-methyl)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-30 2-carboxylate as a yellowish solid (from ether/hexane).

Mass spectrum: protonated molecular ion at m/e 607.

29

ag) (E)-2-(isobutoxycarbonyl)-2-butenyl (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3- (azido-methyl)-8-ox-o-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylate as a colorless solid.

5 Mass spectrum: protonated molecular ion at m/e 593.

ah) (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-l-azabicycloI4.2.0]oct-

2-ene-2-carboxylate as a colorless solid. 10 Mass spectrum: protonated molecular ion at m/e 609.

ai) (E)-2-(ethoxycarbonyl)-2-butenyl (6R,7R)-3-(acetoxymethyl)-8-oxo-7-[2-(3-thienyl)acetamido]-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate as a colorless solid with a Pf of 88° (from ether/he-

15 xane).

Elemental analysis for C23H26N2°8S2 (522.56):

C H N

calc. 52.86 5.02 5.36

found 52.45 4.85 5.44

20 aj) (E)-2-(isobutoxycarbonyl)-2-pentenyl (6R,7R)-

3-(acetoxy-methyl)-7-C(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate.

Elemental analysis for C26H33N5O9S2 (623,70); 25 C H N

calc. 50.07 5.33 11.23

found 50.03 5.66 11.20

ak) (E)-2-(isobutoxycarbonyl)-2-pentenyl (6R,7R)-7- [( Z)-2-(2-amino-4-triazolyl)-2-(methoxyimino)acetamido]-30 8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate as a colorless solid (from methylene chloride/ether).

30

Elemental analysis for C23H29N5O7S2 (551,63):

C H N

calc. 50.08 5.30 12.70

found 49.85 5.41 12.46

5 al) (E)-2-(isobutoxycarbonyl)-2-pentenyl (6R,7R)-

3- [(carbamoyloxy)methylj -7[(Z)-2-(2-furyl)-2-(methoxyimino )acetamido]-8-oxo-5-thia-l-azabicyclo R.2. 0J oct-2-ene-2-carboxylate as a colorless solid (from methylene chloride/ether).

10 Elemental analysis for C26H32N4°10S (592.62):

C H N

calc. 52.70 5.44 9.45

found 52.67 5.59 9.23

15 EXAMPLE 4

One mmol of a carboxylic acid with antibiotic activity from the 6-lactam antibiotic family is dissolved.

1 mmol of triphenylphosphine and 1.5 mmol of the desired formula II alcohol are mixed in 5 mL of dimethylacetamide. The resulting solution is treated dropwise with a solution of 1.03 mmol of diethylazodicarboxylate in dimethylacetamide. The mixture is stirred for 4 hours, then diluted with 100 mL of ethyl acetate and washed 3 times with 50 mL of water each time and 2 times with 50 mL of a 10% aqueous solution of table salt each time. The organic phase is dried over magnesium sulfate, filtered, and concentrated. The residue is then purified over silica gel by eluating with ethyl acetate/hexane (4:1). The compounds mentioned below are prepared in this manner:

a) (RS)-2-(ethoxycarbonyl)-1,3-dimethyl-2-butenyl (6R,7R)-7-C(Z)-2-(2-amino(4-thiazolyl)-2-(methoxyimino)

31

acetamido]-3-methyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-

2-ene-2-carboxylate as a colorless solid. Mass spectrum: protonated molecular ion at m/e 552.

b) (RS)-2-(ethoxycarbonyl)-1-methylally (6R,7R)-7-5 [ ( Z ) -2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-

3-Methyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-3-carboxylate as a colorless solid (from

11ether/hexane).

Mass spectrum: protonated molecular ion at m/e 524. 10 EXAMPLE 5

a) Dissolve 0.51 g of (6R,7R)-7-amino-3-azi-domethyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 50 mL of acetone, cool to -10°C, and mix with 0.29 mL of DBU. After 15 minutes, mix this solution with 0.54 g of isobutyl(Z)-2-(bromomethyl)-2-pentenoate and shake overnight at 0°C. Then dilute the solution with 50 mL of ethyl butyl and filter the crystals through a filtering funnel. Mix the filtrate with 30 mL of Cuicinders salt solution and filter the mixture through a filtering funnel. The organic phase is separated, dried, filtered, and concentrated. The residue is rapidly chromatographed on a short silica gel column, eluting with ethyl acetate/hexane (6:4). The 25 fractions of interest are collected and then concentrated. The residue is absorbed into 20 mL of ethyl acetate and mixed with 4N hydrochloric acid in ethyl acetate. After 24 hours at 0°C, the crystals are separated by filtration and dried under reduced pressure. 0.38 g of (E)-2-(isobutoxycarbonyl)-2-pentenyl (6R,7R)-7-amino-3-azidomethyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-carboxylate hydrochloride is obtained.

32

Elemental analysis for Ci8H26N5°5c-'- (459.95):

C H N

calc. 47.00 5.70 15.23

found 46.87 5.78 15.14

5 b) 0.32 g of (E)-2-(isobutoxycarbonyl)-2-pentenyl(6R,7R)-7-amino-3-azidomethyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene, 2-carboxylate hydrochloride is dissolved in 15 mL of methylene chloride, after which it is mixed with 0.24 g of S-(2-benzothiazolyl)-2-amino-4-thiazolglio-10 xylate(Z)-O-methyloxime. After 6 hours, the reaction mixture is concentrated, and the residue is rapidly chromatographed on a short silica gel column by eluting with ethyl acetate/hexane (1:1) and then with ethyl acetate. The fractions of interest are collected. 15 The residue is dissolved in 20 ml of ethyl acetate, after which it is mixed with 5 ml of 4N hydrochloric acid in acetic acid. The resulting crystals are filtered with a filter funnel and recrystallized from isopropanol. 0.2 g of (E)-2-(isobutoxycarbonyl)-20 2-pentenyl (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-azidomethyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate is obtained.

Elemental analysis for C24H30Cin3O7S2 (693.13): C H N

25 calc. 44.82 4.86 17.42

found 43.41 4.72 16.02

EXAMPLE A

A gelatin capsule with the following composition is prepared in the usual manner: 30 (E)-2-(isobutoxycarbonyl)-2-pentenyl (6R,7R)-7 [(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-3-(azidomethyl)-8-oxo-5-thia-l-aza-

33

bicyclo[4.2.0]oct-2-ene-2-carboxylate 500 mg Luviskol (polyvinylpyrrolidone solu-

(ble in water) 20 mg

Mannitol 20 mg

5% Talc 15 mg, magnesium stearate 2 mg

Weight of one filled capsule: 557 mg

EXAMPLE B

10. A tablet with the following composition is prepared in the usual way:

( E ) -2-(isobutoxycarbonyl)-2-pentenyl (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido] -3-(azidome-15 thyl)-8-oxo-5-thia-l-azabicycloI4.2.0]

oct-2-ene-2-carboxylate 250 mg lactose 70 mg corn starch 65 mg polyvinylpyrrolidone 10 mg

20 mg magnesium stearate

Weight of one tablet: 400 mg

Using the active substance, lactose, polyvinylpyrrolidone, and 40 parts by weight of corn starch, a granule is prepared in the usual way. This is mixed with the remaining 25 parts by weight of corn starch and 5 parts by weight of magnesium stearate, and the mixture is compressed to make tablets.

34

Claims (33)

DEMANDS 1. Process for preparing separable esters under physiological conditions of carboxylic acids with pharmacological action, in particular 5-carboxylic acids with antibiotic action in the antibiotic domain 8-lactam, where the alcohol component of the ester is a group with the general formula V ]_/*\ /J r2/ V where r! represents a hydrogen or a lower alkyl, R2 a hydrogen, lower alkyl, lower halogenal alkyl, 10 a lower alkenyl, lower alkoxycarbonyl, aryl or heteroaryl or is with r^ a lower alkoylene, is a hydrogen, lower alkyl or lower alkoxycarbonyl, R^ represents the group -CO₂R₅-, -CO₂, -SO₂-R₅, -CON₂S or -PO(Or₂)₂ r₅ represents a saturated or unsaturated hydrocarbon radical having up to 12 carbon atoms, in which up to 2 methylene groups can be replaced by oxygen atoms, aryl or lower aryl alkyl, r₆ represents a lower alkyl or aryl, R? and r8 each represent a lower hydrogen or alkyl group, or together a lower alkoylene group in which a methylene group can be replaced by an oxygen atom or a sulfur atom or by an imino group or lower alkyl group, and R^ represents a lower alkyl group, 25 and, insofar as a basic substituent is present, of their pharmaceutically acceptable acid addition salts, 35 characterized in that a) a pharmacologically active carboxylic acid, in particular a 6-lactam antibiotic carboxylic acid, is esterified with a compound of general formula X ! R4 II R2 V where X represents a hydroxyl or leaving group, and R^, r3 and r4 have the meaning given above, or b) to prepare an ester of general formula /ORb îî H H H He M * * THAT n /-\ /N\: \ Ra • • • 11 | \ !—Rc ° c/ V 1 c/'xo 1 R4 R^'V II R2/XR3 where Ra represents an aryl or heteroaryl, Rb a hydrogen, a lower alkanoyl or a lower alkyl or cycloalkoyl in C^a Cg possibly substituted by a carboxy, halogen, cycloalkoyl in C3 to Cg or heteroaryl, Rc represents a hydrogen, halogen, lower alkyl, lower alkenyl, lower alkoxy or the -CF^-Rd group or 36 -CH2-S-Re, Rd represents a lower alkanoyloxy, carba-moyloxy, azido or an aromatic group containing nitrogen linked via a nitrogen atom and Re represents a heteroaromatic group linked via a carbon atom, and R^, R^, r3 and R^ have the meaning given above, We acyl a compound with the general formula H H h2nN: :/s\ I i !—Rc r w m 0 (/*N0 1 R4 R^'V R2/V where Rl, R^, r3, r4 and rc Qnt have the meaning given above, 10 with a carboxylic acid of general formula N^°Rb II IV Ra / ^ COOH where Ra and Rb have the meanings given above, or one of its reactive derivatives and c) if desired, the resulting ester is transformed 37 into a pharmaceutically acceptable acid addition salt. 2. A method according to claim 1, characterized in that in variant a) of the method, the reaction is made 5. The pharmacologically active carboxylic acid in the form of a carboxylic acid salt with a compound of formula I where X represents an exit group. 3. A method according to claim 1, characterized in that in variant a) of the method, the reaction is made 10 the pharmacologically active carboxylic acid in the presence of a condensing agent with a compound of formula II where X represents a hydroxy group. 4. A process according to any one of claims 1-3, characterized in that an ester is prepared in which the com- 15. A carboxylic acid component is a radical penam-3-carboxylic, penem-3-carboxylic, l-carbapenem-3-carboxylic, 3-cephem-4-carboxylic, l-oxa-3-cephem-4-carboxylic, l-dethia-2-oxa-3-cephe, l-dethia-2-thia-3-cephem or l-carba-3-cephem-4-carboxylic acid pharmaceutically ac- 20 acceptable. 5. A process according to claim 4, characterized in that the carboxylic acid component is a pharmaceutically acceptable 3-cephem-4-carboxylic radical. 6. A method according to claim 1-3, characterized 25 in that we prepare an ester of general formula yORb î? H H H 0 ✓—1\ / — RC 0' </xo 1 R4 R1/'V I! R2/'V 38 where Ra, Rb, Rc, R^, R2, r3 and R4 have the meaning given in claim 1. 7. A method according to claim 6, where Ra represents an unsubstituted 5-membered heteroaromatic group 5 or substituted by an amino with a sulfur or oxygen atom and possibly one or two nitrogen atoms as links of the heterocycle. 8. A method according to claim 7, where Ra represents a 2-amino-4-thiazolyl, 5-amino-1,2,4-thiadiazol- 10 3-yl or 2-furyl, in particular 2-amino-4-thiazolyl. 9. A method according to any one of claims 6-8 where Rb represents a hydrogen, lower alkyl or lower alkanoyl, in particular a lower alkyl. 10. A method according to any one of claims 6-9, 15 where Rc represents a lower alkyl, in particular me- thyle, or the group -CH2~Rd and Rd represents an azido. 11. Method according to any one of claims 1-10, where R 1 represents hydrogen. 12. A method according to any one of claims 1-11, 20 where R2 represents a lower alkyl. 13. Method according to any one of claims 1-12, where R3 represents hydrogen. 14. A method according to any one of claims 1-13, where R4 represents the group -CO00R5 and R5 represents an alkyl 25 lower, lower alkenyl or lower alkoxyalcoyl. 15. A process according to claim 14, where R5 represents a lower alkyl or a lower alkoxyalkyl, in particular an isobutyl, isopropyl or 2-methoxyethyl, preferably an isobutyl. 30 16. A method according to any one of claims 1-3, characterized in that the (E)-2-(isobutoxycarbonyl)-2-pentenyl(6R,7R)-7-(Z)-2-(2-amino-4-thiazolyl)- is prepared 39 2-(methoxyimino)acetamido] -3-(azidomethyl)-8-oxo-5-thia- 1-azabicyclo [4.2.0]oct-2-ene-2-carboxylate. 17. A process according to any one of claims 1-3, characterized in that the (E)-2-(isobutoxycar- 5 bonyl)-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. 18. A process according to any one of claims 1-3, characterized in that the (E)-2-[(2-ethoxy- 10 ethoxy)carbonylj-2-butenyl (6R,7R)-7 [(Z)-2-(2-amino-4- thiazolyl)-2-(methoxyimino)acetamidoj -3-(azidomethyl-8-oxo-5-thia-l-azabicyclo[4.2. OJ oct-2-ene-2-carboxylate. 19. A process according to any one of claims 1-3, characterized in that the (E)-2-(ethoxycarbonyl)- is prepared 15 2-butenyl (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxy imino)acetamidoj-3-(azidomethyl)-8-oxo-5-thia-l-azabicy-clo[4.2.0]oct-2-ene-2-carboxylate. 20. A process according to any one of claims 1-3, characterized in that the (E)-[[(3-methyl-2-bute- 20 nyl)oxy]-carbonyl]-2-butenyl (6R,7R)-7-[(Z)-2-(2-amino-4- thiazolyl)-2-(methoxyimino)acetamido]-3-methyl-8-oxo-5-thia 1-azabicyclo C4.2.0Joct-2-ene-2-carboxylate. 21. A process according to any one of claims 1-3, characterized in that the (E)-2-(isopropoxycar- 25 bonyl)-2-butenyl (6R,7R)-7[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido] -3-methyl-8-oxo-5-thia-l-azabicy-clo[4.2.0J oct-2-ene-2-carboxylate. 22. A process according to any one of claims 1-3, characterized in that the (E)-2-(isobutoxycarbo- 30 nyl)-2-pentenyl (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamidoj-3-methyl-8-oxo-5-thia-l-azabicy-clo[4.2. 0J oct-2-ene-2-carboxylate. 40 23. A process according to any one of claims 1-3, characterized in that it prepares (E)-2-(ethoxycarbonyl)-2-pentenyl (6R,7R)-7-[{Z)-2-{ 2-amino-4-thiazolyl)-2-(methoxyimino )acetamido]-3-methyl-8-oxo-5-thia-l-azabicyclo[4.2.0] 5 oct-2-ene-2-carboxylate. 24. A process according to any one of claims 1-3, characterized in that it prepares (E)-2-[(2-ethoxyethoxy)carbonyl]-2-butenyl(6R,7R)-7JT(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-methyl-8-oxo-5-thia-l-azabicy- 10 clo[4.2. 0] oct-2-ene-2-carboxylate. 25. A process according to any one of claims 1-3, characterized in that it prepares (E)-2-(isobutoxycarbonyl)-2-butenyl (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(metho-xyimino)acetamido]-3-methyl-8-oxo-5-thia-l-azabicyclo[4.2.0] 15 oct-2-ene-2-carboxylate. 26. A process according to any one of claims 1-3, characterized in that it prepares (E)-2-(t-butoxycarbonyl)-2-butenyl (6R,7R)-7-Q(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-methyl-8-oxo-5-thia-l-azabicyclo 20 [4.2.0]oct-2-ene-2-carboxylate. 27. A process according to any one of claims 1-3, characterized in that the (E)-2-(ethoxycarbonyl)-2-butenyl (6R,7R)-7-E(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-methyl-8-oxo-5-thia-azabicyclo [4.2.0] is prepared. 25 oct-2-ene-2-carboxylate. 28. A process for preparing medicinal products, in particular antibiotic agents containing as an active substance an ester that can be obtained according to claims 1-27, characterized in that a 30 galenic administration form the active substance and possibly another compound with therapeutic action with a therapeutically inert support. 41 29. A method for preparing drugs for oral administration, in particular antibiotic agents, containing as an active substance an ester which can be obtained according to any one of claims 1-5 27, characterized in that the active substance and optionally another therapeutically active compound are put in a galenic administration form with a therapeutically inert carrier commonly used for oral medication. 30. Application of esters that can be obtained according to one of claims 1-27 to the preparation of agents with therapeutic action, in particular with antibiotic action. 31. Application of esters obtainable according to any one of claims 1-27 to the preparation of agents 15 with therapeutic action, particularly antibiotic, to be administered orally. 32. Application of compounds of general formula x I R4 v ii r2 / V where Rl, R^, r3, r4 and x have the meanings given in claim 1, to the esterification of therapeutically active carboxylic acids, in particular carboxylic acids with antibiotic action from the 6-lactam antibiotic domain. 33. Compounds of general formula 42 H H h2\; -:/s\ 1 to -~Rc </ V 0^ \) I R4 R1/-v fl R^'V III R-*-, R^, r3, r4 and £C have the meaning given in claim 1. DUPLICATE CERTIFIED CONFORM TO THE ORIGINAL in PDF r-coniermnt References m.. nwf added striped null \osé CUJSWU Council in * 26 b,HH3ouI fté Industrial Princess CharloHe MONTE-CARLO By proc'Haîioft <£« f- \ o ■LU mua Za q- Rode d &P, ?A>