WO2001004127A1

WO2001004127A1 - Vinylpyrrolidinone derivatives with substituted thiazole ring

Info

Publication number: WO2001004127A1
Application number: PCT/EP2000/006151
Authority: WO
Inventors: Peter Angehrn; Paul Hebeisen; Ingrid Heinze-Krauss; Malcolm Page
Original assignee: F. Hoffmann-La Roche Ag
Priority date: 1999-07-07
Filing date: 2000-07-01
Publication date: 2001-01-18
Also published as: AU6267100A

Abstract

The invention is concerned with cephalosporin derivatives of general formula (I) wherein X is chlorine, bromine, fluorine, trifluoromethyl, methyl, carboxy or hydroximethyl; R1 is hydrogen or lower alkanoyl; R2 is hydrogen or an in vivo cleavable group; Y1 is a group -CHR3-; Y2 is one of the groups -CHR?3-, -CHR3-CHR3¿- and -CHOH-CHR3-; R3 is the same or different and selected from hydrogen, hydroxy-lower alkyl and amino-lower alkyl, and readily hydrolyzable ester of compounds of formula I, as well as pharmaceutically acceptable salts of said compounds of formula I and of their esters and salts, with the manufacture of compounds aforesaid; and with their use as pharmaceutically active substances in the treatment and prophylaxis of infectious diseases.

Description

Vinylpyrrolidinone Derivatives with substituted thiazole ring

The present invention relates to cephalosporin derivatives of the general formula

wherein X is chlorine, bromine, fluorine, tnfluoromethyl, methyl, carboxy or hydroxymethyl;

R¹ is hydrogen or lower alkanoyl;

R² is hydrogen or an in vivo cleavable group;

Y¹ i a group -CHR³-

Y² is one of the groups -CHR³-, -CHR³-CHR³- and -CHOH-CHR³-;

R³ is the same or different and selected from hydrogen, hydroxy-lower alkyl and amino-lower alkyl, and readily hydrolyzable ester of compounds of formula I, as well as pharmaceutically acceptable salts of said compounds of formula I and of their esters and salts.

Furthermore, the invention is concerned with the manufacture of compounds aforesaid; with their use as pharmaceutically active substances, particularly for the treatment and prophylaxis of infectious diseases, and with pharmaceutical preparations containing a compound of formula I for the treatment and prophylaxis of infectious diseases, especially infectious diseases caused by methicillin resistant Staphylococcus aureus (MRSA).

Preferred compounds of formula I are compounds wherein

X is chlorine

R¹ is hydrogen or acetyl;

R² is hydrogen or a group of the formula

in which R is hydrogen or lower alkyl, preferably methyl; R³ is hydrogen or hydroxymethyl, as well as readily hydrolyzable esters thereof, of pharmaceutically acceptable salts of said compounds and hydrates of these compounds and of their esters and salts.

When Y² is the group - CHOH-CHR³, the partial structure

has the formula

In a preferred embodiment the partial structure

represents the group

Particularly preferred compounds of formula I are A: (6R,7R)-7-[(Z)-2-(2-amino-5-chloro-thiazol-4-yl)-2-hydroxyimino- acetylamino]-8-oxo-3-[(E)-(R)-2-oxo-[l,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia- l-aza- bicyclo[4.2.0]oct-2-ene-2-carboxylic acid,

B: (6R,7R)-7-[(Z)-2-(2-amino-5-chloro-thiazol-4-yl)-2-hydroxyimino- acetylamino]-3-[(E)-(R)- -(5-methyl-2-oxo-[l,3]dioxol-4-yl-methoxycarbonyl)-2-oxo- [l,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2- carboxylic acid,

C: (6R,7R)-7-[(Z)-2-(2-amino-5-chloro-thiazol-4-yl)-2-hydroxyimino- acetylamino]-3-[(E)-(3'R,5^,S)-5^,-hydroxymethyl-2-oxo-[ l,3']bipyrrolidinyl-3- ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid,

D: (6R,7R)-7- [(Z)-2-(2-amino-5-chloro-thiazol-4-yl)-2-hydroxyimino- acetylamino] -3-[(E)-(3'R, 5'S)-5'-hydroxymethyl- -(5-methyl-2-oxo-[ l,3]dioxol-4- ylmethoxycarbonyl)-2-oxo- [ 1.3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia- l-aza- bicyclo [4.2.0] oct-2-ene-2-carboxylic acid,

E: (6R,7R)-7-[(Z)-2-(2-amino-5-chloro-thiazol-4-yl)-2-hydroxyimino- acetylamino]-8-oxo-3-[(E)-(S)-2-oxo-[l,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-l-aza- bicyclo[4.2.0]oct-2-ene-2-carboxylic acid,

F: (6R,7R)-7-[(Z)-2-(2-amino-5-chloro-thiazol-4-yl)-2-hydroxyimino- acetylamino]-3-[(E)-(S)- -(5-methyl-2-oxo-[l,3]dioxol-4-yl-methoxycarbonyl)-2-oxo- [l,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2- carboxylic acid.

The compounds of the present formula I are useful in the treatment of infectious diseases caused by bacterial pathogens, in particular methicillin resistent Staphylococcus aureus (MRSA) and 3-lactamase producing gramnegative bacteria.

As used herein, the term "lower alkyl" refers to both straight and branched chain saturated hydrocarbon groups preferably having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, tertiary butyl and the like. "Lower alkanoyl" is a "lower alkyl"-CO-group in which "lower alkyl" is as above.

As used herein, the term "hydroxy-lower alkyl" refers to both straight and branched chain saturated hydrocarbon groups as defined above carrying a hydroxy group which is preferably in the terminal position, e.g. hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like. As used herein, the term "amino-lower alkyl" refers to both straight and branched chain saturated hydrocarbon groups as defined above carrying an amino group which is preferably in the terminal position, e.g. aminomethyl, 2-aminoethyl, 3-aminopropyl, and the like.

The definition "in vivo cleavable group" used above under the symbol R" refers to groups which are split off in the animal organism leaving the active compound I where R" is hydrogen. Such groups are preferably of the carbamate type such as groups of the formulas -COOCH₂C(=CHR)-COOR, -COOCHROCOR, -COOCHROCOOR, -COOCH(OCOR)OCOR, -COOCH₂COCH₂OCOR and

in which R is hydrogen or lower alkyl. Other groups can also be employed such as - CH₂C(=CHR)-COOR in which R is as above.

A preferred in vivo cleavable group has the formula

As used herein pharmaceutically acceptable salts useful in this invention include salts derived from metals, salts from amino acids and salts of mineral or organic acids. Examples of preferred metal salts are those derived from the alkali metals, for example, lithium (Li⁺), sodium (Na⁺) and potassium (K⁺), from the earth alkali metals, for example magnesium (Mg⁺⁺), salts derived from amino acids such as, for example, salts with arginine or lysine. Examples of salts of mineral acids are for example chlorides, sulphates or phosphates, and examples of salts of organic acids mesylates, napsylates, besylates, maleates, salicylates, tartrates, lactates, citrates, benzoates, succinates, acetates and the like. Especially preferred are chlorides, sulfates, phosphates, lactates and mesylates.

As readily hydrolyzable esters of the compounds of formula I there are to be understood compounds of formula I, wherein carboxy groups present are esterified to form a readily hydrolyzable ester, thus forming a "pro-drug" which is split in the organism to form the corresponding active carboxylic acid. Examples of such readily hydrolyzable ester groups are of the formula -CHROCOR, in which R is hydrogen or lower alkyl, e.g. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl, 1-pivaloyloxyethyl, of the formula -CHROCOOR⁰, in which R is hydrogen or lower alkyl and R° is hydrogen, lower alkyl or lower cycloalkyl, e.g. methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl, 1- isopropoxycarbonyloxyethyl, l-[((cyclohexyloxy)carbonyl)oxy]ethyl, of the formula - CH₂C(=CHR)-COOR, in which R is hydrogen or lower alkyl, eg. 2-[(2- methylpropoxy)carbonyl]-2-pentenyl, of the formula

-CH(OCOR)OCOR in which R is lower alkyl, e.g. methyl, and of the formula -CH₂COCH₂OCOR in which R is hydrogen or lower alkyl, e.g. methyl, and of the formula

in which R is hydrogen or lower alkyl, e.g. (5-methyl-2-oxo-l,3-dioxol-4-yl)-methyl.

Other esters, e.g. the lactonyl esters (e.g. the phthalidyl and thiophthalidyl ester) and the lower alkanoylaminomethyl esters (e.g. the acetamidomethyl ester) can also be used.

The products in accordance with the invention can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral or parenteral application. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, or parenterally e.g. in the form of injection solutions.

The manufacture of the pharmaceutical preparations can be effected in a manner which is familiar to any person skilled in the art by bringing the substances in accordance with the invention, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, the usual pharmaceutical adjuvants.

As such carrier materials not only inorganic carrier materials are suitable, but also organic carrier materials. Thus, there can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules, for example, lactose, maize starch or derivatives thereof, talc, stearic acid or its salts. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active substance no carriers are, however, required in the case of soft gelatine capsules.) Suitable carrier materials for the manufacture of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and glucose. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. The pharmaceutical preparations can also contain other therapeutically valuable substances.

As pharmaceutical adjuvants there come into consideration the usual preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents and antioxidants.

Depending on the nature of the pharmacologically active compound the pharmaceutical preparations can contain the compound for the prevention and treatment of infectious diseases in mammals, human and non-human. A daily dosage of about 10 mg to about 4000 mg, especially about 50 mg to about 3000 mg, is usual, with those of ordinary skill in the art appreciating that the dosage will depend also upon the age, conditions of the mammals, and the kind of diseases being prevented or treated. The daily dosage can be administered in a single dose or can be divided over several doses. An average single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, and 2000 mg can be contemplated.

A representative compound (A above) of the present invention was tested and compared with two analogues known from EP-A-849269:

Compound X: Corresponding compound without substituent in 5-position of the thiazol nucleus;

Compound Y: Corresponding compound in which the 5-position of the thiazole nucleus is replaced by a nitrogen atom, viz. the 5-amino- [ l,2,4]thiadiazol-3-yl derivative.

In vitro activity was determined by minimum inhibitory concentration by the agar dilution method in Mueller Hinton agar, inoculum = 10⁴ CFU/spot.

In vitro activity (MIC [μg/ml])

The compounds of the formula I in accordance with the invention as well as their pharmaceutical acceptable salts, hydrates, or readily hydrolyzable esters can be manufactured in accordance with the invention by a process which comprises

(a) treating a compound of the general formula

in which R², Y¹ and Y² are defined as in claim 1, or an ester or a salt thereof, the amino group and the carboxylic groups present in the compound of formula II being unprotected or protected, with a carboxylic acid of the general formula

in which R^f is hydrogen or an amino protecting group, R¹⁰ is hydrogen, lower alkanoyl or a hydroxy protecting group and X is as defined above, or with a reactive functional derivative thereof and subsequently splitting of amino, hydroxy and/or carboxy protecting groups present, or (b) cleaving off the amino, hydroxy and/or carboxy protecting group(s) in a compound of the general formula

in which X is as X but carboxy is protected, R²⁰ is as R² or an amino protecting group, Y rlO and Y ₇2"0 are as Y and Y" or contain a hydroxy or amino protecting group, Rf is hydrogen or an amino protecting group, R¹⁰ is hydrogen, lower alkanoyl or a hydroxy protecting group, R^h is hydrogen or a carboxy protecting group, provided that at least one of R^f, R^h, R¹⁰ and R²⁰ is or at least one ofX j Y¹ and Y contains a corresponding protecting group, or a salt thereof or

(c) for the manufacture of compounds of formula I in which R" is an in vivo cleavable group, reacting a compound of formula I, in which R² is hydrogen, with a compound yielding such in vivo cleavable group, or

(d) for the manufacture of a readily hydrolyzable ester of a compound of formula I subjecting a carboxylic acid of formula I to a corresponding esterification, or

(e) for the manufacture of salts or hydrates of a compound of formula I or hydrates of said salts converting a compound of formula I into a salt or hydrate or into a hydrate of said salts.

The reaction of compounds of formula II and III or a reactive derivative of formula III according to embodiment (a) can be carried out in a manner known per se. Carboxy groups in compounds of formula II can be protected, for example, by esterification to form a readily cleavable ester such as a silyl ester (e.g. the trimethylsilyl ester), a tert-butyl, allyl, p-methoxybenzyl or a benzhydryl ester.

The amino group present in the acylating agent of formula III can be protected. Possible protecting groups R^f are, for example, protecting groups which are cleavable by acid hydrolysis (e.g. the formyl, the tertbutoxycarbonyl or trityl groups), by basic hydrolysis (e.g. the trifluoroacetyl group), by hydrazinolysis (e.g. the phthalimido group) or by catalytic cleavage in presence of Pd (the allyloxycarbonyl group). Preferred protecting groups are the allyloxycarbonyl, the tert-butyloxy-carbonyl, the chloroacetyl, bromoacetyl and iodoacetyl groups, especially the chloroacetyl group. These last- mentioned protecting groups can be cleaved off by treatment with thiourea. The 7-amino group in compounds II can be protected, for example, by a silyl protective group such as the trimethylsilyl group.

In reacting a 7-amino compound of formula II with a carboxylic acid of formula III or a reactive functional derivative thereof, for example, a free carboxylic acid can be reacted with an aforementioned ester of a compound of formula II in the presence of a carbodiimide such as dicyclohexylcarbodiimide in an inert solvent, such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide.

According to another embodiment, a salt of an acid of formula II (e.g. a trialkylammonium salt such as the triethylammonium salt) is reacted with a reactive functional derivative of a carboxylic acid of formula III in an inert solvent (e.g. dimethylformamide or dimethylacetamide).

A further embodiment involves converting an N-protected carboxylic acid or a salt thereof into an acid chloride by treatment with phosphorus pentachloride or thionyl chloride in an inert solvent such as methylene chloride. The acid chloride obtained is then reacted with a 7-amino compound of formula II or a salt thereof.

Amino protecting groups and carboxy protecting groups present in the reaction product obtained in any of the embodiments aforesaid can subsequently be split off as detailed below.

According to a further embodiment, which is a preferred acylation, since the amino group present in the acylating agent of formula III need not be protected, involves the use of a reactive functional derivative of the acylation agent of formula III, for example, a mixed anhydride of thiophosphoric acid and of the carboxylic acid, a 1-hydroxybenzo- triazole ester or a 2-benzothiazolyl thioester. For instance, a mixed anhydride of thiophosphoric acid may be reacted with the compound of formula II preferably in a polar solvent as dimethyl formamide (DMF), dichloromethane, or a mixture of DMF/i- propanol/water in presence of a base as e.g. triethylamine. The 1-hydroxybenzotriazole ester as well as the 2-benzthiazolyl thioester may be reacted with the compound II in an inert organic solvent such as a chlorinated hydrocarbon e.g. methylene chloride, or in dimethylformamide, dimethylacetamide, acetone, ethyl acetate or in a mixture of such solvents with water. The reaction of a 7-amino compound of formula II with the carboxylic acid of formula III or a reactive derivative thereof can conveniently be carried out at a temperature between about -40°C and +60°C, e.g. at room temperature.

Embodiment (b) of the process of the present invention involves deprotection (removal) of amino, hydroxy and/or carboxy protecting groups in compounds of the general formula IV, i.e.

amino protecting groups present as R and/or R" and/or in Y¹⁰ and Y²⁰ (in which case amino-lower alkyl groups are protected)

hydroxy protecting groups present as R and/or in Y¹⁰ and Y²⁰ (in which case hydroxy -lower alkyl groups and/or the hydroxy group of the residue

-CHOH-CHR³ are/is protected)

carboxy protecting groups present as R and X

and can be carried out as follows:

Removal of amino protecting groups

As mentioned above the amino protecting groups may be cleaved off by acid hydrolysis (e.g. the formyl, the tert-butoxycarbonyl or trityl group), e.g. aqueous formic acid, trifluoroacetic acid or by basic hydrolysis (e.g. the trifluoroacetyl group). Further protecting groups may be cleaved off by hydrazinolysis (e.g. the phthalimido group). The allyloxycarbonyl group may be cleaved off by Pd catalysed transfer to nucleophiles (e.g. with tributyltin hydride or dimedone in an inert solvent such as methylene chloride at a temperature between -50°C and +50°C. The chloroacetyl, bromoacetyl and iodoacetyl groups are cleaved off by treatment with thiourea.

Amino-protecting groups which are cleavable by acid hydrolysis are preferably removed with the aid of a lower alkanecarboxylic acid which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. The reaction is carried out in the acid or in the presence of a co-solvent such as a halogenated lower alkane, e.g. methylene chloride. The acid hydrolysis is generally carried out at room temperature, although it can be carried out at a slightly higher or slightly lower temperature (e.g. a temperature in the range of about -30°C to +40°C). Protecting groups which are cleavable under basic conditions are generally hydrolyzed with dilute aqueous alkali at 0°C to 30°C. The chloroacetyl, bromoacetyl and iodoacetyl protecting groups can be cleaved off using thiourea in acidic, neutral or alkaline medium at about 0°C-30°C. Removal of hydroxy protecting groups

The term "hydroxy protecting group" refers to protecting groups as conventionally used in the art such as trityl (triphenylmethyl), trimethylsilyl, tert.-butyl-dimethylsilyl, dimethylphenylsilyl, lower alkanoyl, acetyl, tetrahydropyranyl, benzyl, p-nitrobenzyl and the like.

Preferred hydroxy protecting groups are such as are commonly known in the art, e.g. for protection of hydroxyimino groups (R¹ = hydrogen in compounds of formula I), usually trityl, lower alkanoyl, especially acetyl, tetrahydropyranyl.

These protecting groups are e.g. removed as follows:

-trityl in acidic solvents like 90% formic acid at about 0 to 50°C or triethylsilane in trifluoroacetic acid at about -20 to 25°C; in organic solutions of hydrochloric acid at about -50 to 25°C;

-acetyl with weak inorganic bases like sodium bicarbonate in methanol or ethanol/water at about 0 to 50°C;

-tetrahydropyranyl with weak organic acids like p-toluenesulfonic acid in an alcohol, e.g. ethanol, at about 0°C to the boiling point of the mixture.

Removal of protecting groups at the carboxy function

The term "carboxylic acid protecting group" refers to protecting groups conventionally used to replace the acidic proton of a carboxylic acid. As carboxy protecting groups one may utilize an ester form which can be easily converted into a free carboxy group under mild conditions, for example, methoxymethyl, methylthiomethyl, 2,2,2-trichloroethyl, 2-haloethyl, 2-(trimethylsilyl)ethyl, tert-butyl, allyl, benzyl, triphenylmethyl (trityl), diphenylmethyl, p-nitrobenzyl, p-methoxybenzyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, i-propyl-dimethylsilyl. Preferred are benzyhydryl, tert- butyl, p-nitrobenzyl, p-methoxybenzyl and allyl.

These protecting groups may be removed as follows:

benzhydryl trifluoroacetic acid with anisol, phenol, cresol or triethylsilane at about -40°C to room temperature; hydrogen with Pd/C in an alcohol such as ethanol or in tetrahydrofuran; BF3-etherate in acetic acid at about 0 to 50°C; tert-butyl formic acid or trifluoroacetic acid with or without anisol, phenol, cresol or triethylsilane and a solvent such as dichloromethane at about -10°C to room temperature;

p-nitrobenzyl sodium sulfide in acetone/water at about 0°C to room temperature; or hydrogen with Pd/C in an alcohol such as ethanol or in tetrahydrofuran;

p-methoxybenzyl formic acid at about 0 to 50°C; or trifluoroacetic acid and anisol, phenol or triethylsilane at about -40°C to room temperature;

allyl palladium(O) catalyzed transalkylation reaction in the presence of tri-n-butyltinhydride and acetic acid, see for example J. Org. Chem. (1987) 52, 4984-4993.

In manufacturing compounds of formula I, in which R" is an in vivo cleavable group in accordance with embodiment (c) of the process of the present invention, a compound of formula I, in which R² is hydrogen is reacted with a compound yielding such in vivo cleavable group, which has been defined above.

For instance, compounds of formula I in which R₂ is a group -COOCH₂C(=CHR)- COOR, -COOCH(R)OCOR, -COOCH(R)OCOOR, -COOCH(OCOR)OCOR, - COOCH₂COCH₂OCOR or

in which R is hydrogen or lower alkyl,

can be prepared by acylation of compounds of formula I wherein R² is hydrogen with the corresponding carbonic acid 4-nitrophenyl ester of the formula

in which R²¹ is as above indicated for R², except hydrogen, in an inert organic solvent such as dimethylsulfoxide, dimethylformamide or acetone, at about room temperature in the presence of alkali metal caproate. For the preparation of compounds of formula I wherein R² is -CH₂C(=CH₂)-COOR a compound of formula I in which R² is hydrogen is reacted with 2-(4-nitro- phenoxycarbonyloxymethyl)-acrylic acid ethyl ester and alkali metal caproate in a solvent and at temperatures as above. This reaction proceeds with the loss of carbon dioxide.

In order to manufacture a readily hydrolyzable ester of the carboxylic acids of formula I in accordance with embodiment of the process provided by the present invention, a carboxylic acid of formula I is preferably reacted with a corresponding halide, preferably an iodide, containing the desired ester group. The reaction can be accelerated with the aid of a base such as an alkali metal hydroxide, an alkali metal carbonate or an organic amine such as triethylamine. The esterification is preferably carried out in an inert organic solvent such as dimethylacetamide, hexamethylphosphoric acid triamide, dimethyl sulfoxide or, especially, dimethylformamide. The reaction is preferably carried out at a temperature in the range of about 0 - 40°C.

The synthesis of readily hydrolyzable esters of the compounds of formula I wherein R² is hydrogen, is accomplished via alkylation of a carboxy group, preferably at the stage of the fully protected compound of formula I. Protecting groups for R¹ are preferably trityl and in position R² tert.-butyloxycarbonyl (BOC). Removal of the tert.-butyloxycarbonyl and trityl-protecting groups is accomplished by conventional methods, and the desired readily hydrolyzable ester is isolated as the hydrochloride salt by precipitation from e.g. dioxane.

The manufacture of the salts and hydrates of the compounds of formula I or the hydrates of said salts in accordance with embodiment (e) of the process provided by the present invention can be carried out in a manner known per se; for example, by reacting a carboxylic acid of formula I or a salt thereof with an equivalent amount of the desired base, conveniently in a solvent such as water or an organic solvent (e.g. ethanol, methanol, acetone and the like). Correspondingly, salt formation is brought about by the addition of an organic or inorganic salt. The temperature at which the salt formation is carried out is not critical. The salt formation is generally carried out at room temperature, but it can be carried out at a temperature slightly above or below room temperature, for example in the range of0°C to +50°C.

The manufacture of the hydrates usually takes place automatically in the course of the manufacturing process or as a result of the hygroscopic properties of an initially anhydrous product. For the controlled manufacture of a hydrate, a completely or partially anhydrous carboxylic acid of formula I or salt thereof can be exposed to a moist atmosphere (e.g. at about +10°C to +40°C). Further methods for the manufacture of the compounds according to the invention are known in the art. Compounds of formula I can for example be manufactured in analogy to the methods described in EP-A 620 225, in EP-A 849 269 and according to Examples given below.

Example 1

(Z)-2-(2-amino-5-chloro-thiazol-4-yl)-2-trityloxyimino-acetic acid 1-benzotriazolyl ester

To a solution of (Z)-2-(2-aminothiazol-4-yl)-2-trityloxyimino-acetic acid (5.00 g, 11.64 mmol) in DMF ( 15ml) in an argon atmosphere at room temperature was added N- chorosuccinimide ( 1.55 g, 11.64 mmol). After 18 hours stirring the reaction mixture was concentrated to 15 ml, poured into water (about 400 ml) and the resulting precipitate was filtered, washed with water and then with a small amount of ethyl acetate and diethyl ether and dried in vacuum at 50°C to afford 4.2 g (75.5%) of (Z)-2-(2-amino-5-chloro-thiazol- 4-yl)-2-trityloxyiminoacetic acid as a beige solid.

13C NMR (CDCL₃) δ 108.5, 125.6, 126.2, 126.6, 12.3, 134.7, 141.8, 146.5, 162.1, 163.3.

In an argon atmosphere 4.2 g (9.78 mmol) of (Z)-2-(2-amino-5-chloro-thiazol-4-yl)-2- trityloxyimino-acetic acid were dissolved in 100ml of tetrahydrofuran, 1.4 g (10.56 mmol) of 1-hydroxy-benzotriazole and 2.2 g ( 10.56 mmol) of dicyclohexylcarbodiimide were added and stirring at room temperature effected for 1 hour. The reaction mixture was filtered and the solvent evaporated off under reduced pressure at 30°C. Precipitated urea was filtered off and diethyl ether added to the filtrate. The product precipitated, was filtered off and dried under reduced pressure at 50°C overnight.

3.6 g (62.2 %) of (Z)-2-(2-amino-5-chloro-thiazol-4-yl)-2-trityloxyimino-acetic acid 1- benzotriazolyl ester was obtained as a yellowish solid.

This compound is used for acylation as in the following example 2.

Example 2

(6R,7R)-7- [(Z)-2-(2-Amino-5-chloro-thiazol-4-yl)-2-hydroxyimino-acetylamino] -8-oxo- 3- [(E)-(R)-2-oxo-[ l,3']bipyrrolidinyl-3-ylidenemethyl)]-5-thia- l-aza-bicyclo[4.2.0]oct-2- ene-2-carboxylic acid.

To a solution of 2.65 g (4.8 mmol) (E)-(6R,7R)-3- [(R)-l'-allyloxycarbonyl-2-oxo- [l,3']bipyrrolidinyl-3-ylidenemethyl]-7-amino-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2- ene-2-carboxylic acid trifluoroacetic acid salt ( 1:0.91) (EP-A 849 269) in 50 ml dichloromethane were added 8 ml bis-trimethylsilyl-acetamide and 2.5 g (8.1 mmol) of (Z)-(5-chloro-2-formylamino-thiazol-4-yl)-acetoxyimino-acetic acid chloride. The mixture was stirred 15 min at 0°C and 1 h at room temperature and then poured into a mixture of 1 L ethyl acetate and 150 ml acetone. The solution was washed twice with 100 ml water and reduced to a volume of 50 ml, upon which the product crystallized. It was collected by filtration, washed with ethyl acetate, diethylether and dried in vacuo yielding 2.28 g. This material was suspended in 150 ml dichloromethane, treated with 2 ml bis- trimethylsilyl-acetamide, 55 mg bis-triphenyl-phosphonium palladium-II-chloride, 3.5 ml glacial acetic acid and 7.6 ml tributyltinhydride. The mixture was stirred for 30 min, the precipitate collected by filtration, resuspended in 70 ml methanol and treated for 3 h at room temperature with 7 ml 25% hydrochloric acid. Upon pouring into 700 ml diethylether a solid separated which was purified by gel chromatography (MCI gel Mitsubishi; wateπacetonitrile = 9:1 and wateπacetonitril = 4:1) yielding 660 mg of the desired product.

IR(KBr): 1762 (C=O) cm^"1 MS(ISP): 568.1 (MH⁺)

The (Z)-(5-chloro-2-formylamino-thiazol-4-yl)-acetoxyimino-acetic acid chloride used above can be prepared as follows:

At -20°C, 410 mg (1.25 mmol) (Z)-(5-chloro-2-formylamino-thiazol-4-yl)-acetoxyimino- acetic acid potassium salt (1:1) (WO 97/12890) were added to a supsension of 313 mg (1.5 mmol) phosphorus pentachloride in 3 ml dichloromethane. The mixture was stirred for 3 h at -20°C, 9 ml n-hexane were added and the precipitate collected by filtration, washed with hexane and dried. 450 mg of (Z)-(5-chloro-2-formylamino-thiazol-4-yl)- acetoxyimino-acetic acid chloride were obtained as a yellow powder.

Example 3 (E)-(6R,7R)-7-[(Z)-2-(2-Amino-5-chloro-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3- [(3'R,5'S)(5'-hydroxymethyl-2-oxo-[l,3']bipyrrolidinyl-3-ylidenemethyl)]-8-oxo-5-thia- l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

To a suspension of 466 mg (0.795 mmol) (E)-(6R,7R)-3-[(3'R₎5'S)-l'-allyloxycarbonyl-5^*- hydroxymethyl-2-oxo-[ l,3']bipyrrolidinyl-3-ylidenemethyl]-7-amino-8-oxo-5-thia-l-aza- bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoro-acetic acid salt (compound A) in 10 ml dichloromethane were added 1.5 ml bis-trimethylsilyl-acetamide and 310 mg (1 mmol) of (Z)-(5-chloro-2-formylamino-thiazol-4-yl)-acetoxyimino-acetic acid chloride. The mixture was stirred 1 h at room temperature and then poured into a mixture of 200 ml ethyl acetate and 20 ml acetone. The solution was washed twice with 50 ml water and reduced to a volume of 20 ml upon which the product crystallized. It was collected by filtration, washed with ethyl acetate, diethylether and dried in vacuo yielding 212 mg. This material was suspended in 10 ml dichloromethane, treated with 0.2 ml bis-trimethylsilyl- acetamide, 5.5 mg bis-triphenyl-phosphonium palladium-II-chloride, 0.35 ml glacial acetic acid and 0.76 ml tributyltinhydride. The mixture was stirred for 30 min, the precipitate collected by filtration, resuspended in 7 ml methanol and treated for 3 h at room temperature with 0.7 ml 25% hydrochloric acid. Upon pouring into 70 ml diethylether a solid separated which was purified by gel chromatography (MCI gel Mitsubishi; water, wateπacetonitrile = 9:1 and wateπacetonitril = 4:1) yielding 40 mg of the desired product.

IR(KBr): 1774 (C=O) cm^"1 MS(ISP): 597.9 (MH⁺)

The above starting compound A was prepared as follows: Mixture of (3R,3'R,5'S)- and (3S,3'R₎5'S)-3-bromo-5'-(tert-butyl-dimethyl- silanyloxymethyl)-2-oxo-[l,3']bipyrrolidinyl- -carboxylic acid allyl ester

A solution of 37.9 g (120.5 mmol) (2S,4R)-4-amino-2-(tert-butyl-dimethyl- silanyloxymethyl)-pyrrolidine-l -carboxylic acid allyl ester and 16.7 ml (120.5 mmol) triethylamine in 600 ml dichloromethane was treated with a solution of 15.51 ml ( 120.5 mmol) 2-bromo-4-chloro-butyryl chloride in 70 ml dichloromethane at -6°C. After 1 h the reaction mixture was poured into 500 ml ice/water, the phases were separated and the aqueous phase extracted with 400 ml dichloromethane. The combined organic phases were washed with with 500 ml brine and water, dried and evaporated. The residue was redissolved in 300 ml tetrahydrofuran and added under ice cooling dropwise to a suspension of 8 g sodium hydride (55-65%) in 880 ml tetrahydrofuran. After completion of the addition, the ice bath was removed and the reaction mixture was stirred for 30 min at room temperature before it was quenched with 500 ml of buffer pfi 7. The mixture was filtrated, the filtrate concentrated in vacuo and added to 500 ml diethylether and 300 ml water. The phases were separated, the organic phase washed with 500 ml brine and dried over magnesium sulfate. The residue obtained after evaporation of the solvent was purified by column chromatography (silica gel, ethyl acetate : n-hexane = 1:2, 1:1) yielding 91.8 g (62 %) of the product.

IR(KBr): 1700 (C=O) cm^"1 MS(ISP): 463.3 (MH⁺)

Mixture of (3R,3'R,5'S)- and (3S,3'R, 5'S) -3- [l'-allyloxycarbonyl-5'-(tert-butyl-dirnethyl- silanyloxymethyl)-2-oxo-[l,3']bipyrrolidinyl-3-yl]-triphenyl-phosphonium bromide

A mixture of 109 g (236 mmol) (3R,3'R,5'S)- and (3S,3'R,5'S)-3-bromo-5'-(tert-butyl- dimethyl-silanyloxymethyl)-2-oxo-[l,3']bipyrrolidinyl- -carboxylic acid allyl ester and 74.4 g (284 mmol) triphenylphosphine was heated at 100°C for 3.5 h. The mixture was cooled to room temperature and dissolved in dichloromethane and added dropwise under stirring to diethylether. The precipitate was collected by filtration washed with diethylether and dried yielding 127.68 g (75 %).

IR(KBr): 1681 (C=O) cm^"1 MS(ISP): 643.3 (M⁺)

(E)-(2R,6R,7R)-3-[(3'R,5'S)-l'-Allyloxycarbonyl-5'-[(tert-butyl-dimethyl-silanyl)- methoxy]-2-oxo-[l,3']-bipyrrolidinyl-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8- oxo-5-thia-l-aza-bicyclo[4.2.0]oct-3-ene-2-carboxylic acid benzhydryl ester

A solution of 53.5 g (73.9 mmol) (3R,3'R,5'S)- and (3S,3'R, 5'S) -3- [l'-allyloxycarbonyl- 5'-(tert-butyl-dimethyl-silanyloxymethyl)-2-oxo-[l,3']bipyrrolidinyl-3-yl]-triphenyl- phosphonium bromide and 36.6 g (73.9 mmol) [6R-(6alpha,7beta)]-7-[[(l,l- dimethylethoxy)carbonyl] amino] -3-formyl-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-3-ene-2- carboxylic acid diphenylmethyl ester in 1 L butyleneoxide: ethylenechloride = 1:1 was refluxed for 1.5 h. The residue obtained after evaporation of the solvent was purified by column chromatography (silica gel, ethyl acetate : n-hexane = 2:1, 1:1) yielding 36 g (57 %) of the desired product.

IR(KBr): 1784 (C=O) cm^"1 MS(ISP): 859.4 (MH⁺)

Mixture of (E)-(5R,6R,7R)- and -(5S,6R,7R)-3-[(3'R,5'S)-l'-allyloxycarbonyl-5'-[(tert- butyl-dimethyl-silanyl)-methoxy] -2-oxo- [ 1 ,3'] -bipyrrolidinyl-3-ylidenemethyl] -7-tert- butoxycarbonylamino-5,8-dioxo-4-thia-l-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester

To a solution of 48.41 g (56.35 mmol) (E)-(2R,6R,7R)-3-[(3'R,5'S)-l'-allyloxycarbonyl-5'- [(tert-butyl-dimethyl-silanyl)-methoxy]-2-oxo-[l,3']-bipyrrolidinyl-3-ylidenemethyl]-7- tert-butoxycarbonylamino-8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-3-ene-2-carboxylic acid benzhydryl ester in 500 ml dichloromethane was added at 0-5°C a solution of 13.89 g (56.35 mmol) of meta-chloro-perbenzoic acid (70%) in 300 ml dichloromethane. After completion of the addition, the reaction mixture was stirred for additional 30 min before 500 ml of a 5% sodium thiosulfate solution was added. The phases w^rere separated, the organic phase was washed once with each 5% sodium thiosulfate, 5% sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography (silica gel, ethyl acetate : n-hexane = 1:1, ethyl acetate) yielding 86.2 g (86%) of the desired product.

IR(KBr): 1795 (C=O) cm^"1 MS(ISP): 875.4 (MH⁺)

(E)-(6R,7R)-3-[(3'R₎5'S)-l'-Allyloxycarbonyl-5'-(tert-butyl-dimethyl-silanyloxymethyl)-2- oxo-[ l,3']bipyrrolidinyl-3-ylidenemethyl]-7-tert-butoxycarbonylamino-8-oxo-5-thia-l- aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester

A solution of l l.lg (12.7 mmol) (E)-(5R,6R,7R)- and -(5S,6R,7R)-3-[(3'R,5'S)-l'- allyloxycarbonyl-5'-[(tert-butyl-dimethyl-silanyl)-methoxy]-2-oxo-[ l,3']-bipyrrolidinyl- 3-ylidenemethyl]-7-tert-butoxycarbonylamino-5,8-dioxo-4-thia-l-aza-bicyclo[4.2.0]oct- 2-ene-2-carboxylic acid benzhydryl ester and 6.5 g sodium iodide (43.4 mmol) in 250ml acetone was treated with 8.2 ml trifluoroacetic anhydride at -20°C for 30 min. The reaction mixture was poured into a mixture of ethyl acetate and water/ice. The phases were separated and the aqueous phase was extracted once with ethyl acetate. The organic phases were washed twice with 10 % sodium thiosulfate, once with brine and dried over magnesium sulfate. The product was purified by column chromatography (silica gel, ethyl acetate: n-hexane = 1:1) (Yield 9.44 g, 84.5%).

IR(KBr): 1787 (C=O) cm^"1 MS(ISP): 859.4 (MH⁺)

(E)-(6R,7R)3[(3'R,5'S)-l'-Allyloxycarbonyl-5'-hydroxymethyl-2-oxo-[l,3']bipyrrolidinyl- 3-ylidenemethyl]-7-amino-8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid trifluoro-acetic acid salt (Compound A).

At 0-5°C 4.9 g (mmol) (E)-(6R,7R)-3-[(3'R,5'S)-l'-allyloxycarbonyl-5'-(tert-butyl- dimethyl-silanyloxymethyl)-2-oxo-[l,3']bipyrrolidinyl-3-ylidenemethyl]-7-tert- butoxycarbonylamino-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester was treated with 5.1 ml triethylsilane and 70 ml ice-cold trifluoroacetic acid for 30 min. The reaction mixture was evaporated and the residue dried and triturated with 200 ml diethylether. The solid which formed was collected by filtration and dried in vacuo ( 16.2 g, 76.2%).

Microanalysis calculated with 1.58% water and 0.94 equivalents trifluoroacetic acid: C 46.92 H 4.64 N 9.57 S 5.47 F 9.15 found: C 47.16 H 4.51 N 9.62 S 5.50 F 9.21

Example 4

(E)-(6R,7R)-7- [(Z)-2-(2-Amino-5-chloro-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3- [(3'R,5'S)(5'-hydroxymethyl-2-oxo- [ l,3']bipyrrolidinyl-3-ylidenemethyl)]-8-oxo-5-thia- l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

To a suspension of 380 mg (0.795 mmol) (E)-(6R_>7R)-3- [(3'R,5'S)-l'-allyloxycarbonyl-5'- hydroxymethyl-2-oxo- [ l,3']bipyrrolidinyl-3-ylidenemethyl] -7-amino-8-oxo-5-thia-l-aza- bicyclo [4.2.0] oct-2-ene-2-carboxylic acid in 10 ml dichloromethane were added 1.5 ml bis-trimethylsilyl-acetamide and 310 mg ( 1 mmol) of (Z)-(5-chloro-2-formylamino- thiazol-4-yl)-acetoxyimino-acetic acid chloride. The mixture was stirred 1 h at room temperature and then poured into a mixture of 200 ml ethyl acetate and 20 ml acetone. The solution was washed twice with 50 ml water and reduced to a volume of 20 ml upon which the product crystallized. It was collected by filtration, washed with ethyl acetate, diethylether and dried in vacuo yielding 212 mg. This material was suspended in 10 ml dichloromethane, treated with 0.2 ml bis-trimethylsilyl-acetamide, 5.5 mg bis-triphenyl- phosphonium palladium-II-chloride, 0.35 ml glacial acetic acid and 0.76 ml tributyltinhydride. The mixture was stirred for 30 min, the precipitate collected by filtration, resuspended in 7 ml methanol and treated for 3 h at room temperature with 0.7 ml 25% hydrochloric acid. Upon pouring into 70 ml diethylether a solid separated which was purified by gel chromatography (MCI gel Mitsubishi; water, wateπacetonitrile = 9:1 and water: acetonitril = 4:1 ) yielding 40 mg of the desired product.

IR(KBr): 1774 (C=O) cm^"1 MS(ISP): 597.9 (MH⁺)

The following example illustrates pharmaceutical preparations containing the cephalosporin derivatives provided by the present invention: Example A

Production of dry ampoules for intramuscular administration:

A lyophilisate of 1 g of (6R, 7R)-7-[(Z)-2-(2-Amino-5-chloro-thiazol-4-yl)-2- hydroxyimino-acetylamino] -8-oxo-3- [(E)-(R)-2-oxo- [ l,3']bipyrrolidinyl-3-ylidene- methyl] -5-thia-l-aza-bicyclo[4.2.0] oct-2-ene-2-carboxylic acid is prepared in the usual manner and filled into an ampoule. The sterile water ampoule contains 10% propylene glycol. Prior to the administration, the lyophilisate is treated with 2.5 ml of a 2% aqueous lidocaine hydrochloride solution.

Example B

Interlocking gelatin capsules each containing the following ingredients are manufactured in the usual manner:

(6R,7R)-7-[(Z)-2-(2-amino-5-chloro-thiazol-4-yl)-2-hydroxyimino- acetylamino]-3-[(E)-(R)-l'-(5-methyl-2-oxo-[l,3]dioxol-4-yl- methoxycarbonyl)-2-oxo-[l,3']bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia- l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid 500 mg

Luviskol (water-soluble polyvinylpyrrolidone) 20 mg

Mannitol 20 mg

Talc 15 mg

Magnesium stearate 2 mg 557 mg

Claims

1. Cephalosporin derivatives of the general formula

wherein

X is chlorine, bromine, fluorine, tnfluoromethyl, methyl, carboxy or hydroxymethyl;

R¹ is hydrogen or lower alkanoyl;

R² is hydrogen or an in vivo cleavable group;

Y¹ is a group -CHR -

is one of the groups -CHR³-, -CHR³-CHR³- and -CHOH-CHR³-;

R^ό is the same or different and selected from hydrogen, hydroxy-lower alkyl and amino-lower alkyl,

and readily hydrolyzable esters of compounds of formula I, as well as pharmaceutically acceptable salts of said compounds of formula I and of their esters and salts.

2. Compounds of claim 1, in which X is chlorine.

3. Compounds of claim 1 or 2, in which R is hydrogen or acetyl.

4. Compounds of any one of claims 1-3, in which R" is hydrogen.

5. Compounds of any one of claims 1-3, in which R" is the group

in which R is hydrogen or lower alkyl.

6. Compounds of claim 5, in which R is methyl.

7. Compounds of any one of claims 1-6, in which R³ is hydrogen or hydroxymethyl.

8. Compounds of any one of claims 1-7, in which the group

represents

9. Compounds according to claim 8, which are

(6R,7R)-7-[(Z)-2-(2-amino-5-chloro-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8- oxo-3-[(E)-(R)-2-oxo-[l,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-l-aza- bicyclo[4.2.0]oct-2-ene-2-carboxylic acid,

(6R,7R)-7-[(Z)-2-(2-amino-5-chloro-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3- [(E)-(R)-l'-(5-methyl-2-oxo-[l,3]dioxol-4-yl-methoxycarbonyl)-2-oxo-[l,3]- bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid,

(6R,7R)-7-[(Z)-2-(2-amino-5-chloro-thiazol-4-yl)-2-hydrox)^rimino-acetylamino]- 3-[(E)-(3'R,5'S)-5'-hydroxymethyl-2-oxo-[l,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5- thia- 1 -aza-bicyclo[4.2.0] oct-2-ene-2-carboxylic acid,

(6R,7R)-7-[(Z)-2-(2-amino-5-chloro-thiazol-4-yl)-2-hydroxyimino-acetylamino]- 3-[(E)-(3'R, 5^,S)-5'-hydrox>'methyl-l'-(5-methyl-2-oxo-[ l,3]dioxol-4- ylmethoxycarbonyl)-2-oxo-[ 1.3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-l-aza- bicyclo [4.2.0] oct-2-ene-2-carboxylic acid,

(6R,7R)-7-[(Z)-2-(2-amino-5-chloro-thiazol-4-yl)-2-hydroxyimino-acetylamino]-8- oxo-3-[(E)-(S)-2-oxo-[l,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-l-aza- bicyclo[4.2.0]oct-2-ene-2-carboxylic acid, (6R,7R)-7-[(Z)-2-(2-amino-5-chloro-thiazol-4-yl)-2-hydroxyimino-acetylamino]-3- [(E)-(S)- -(5-methyl-2-oxo-[l,3]dioxol-4-yl-methoxycarbonyl)-2-oxo-[l,3]- bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

10. Compounds as in any one of claims 1 to 9 for use as pharmaceutically active substances, particularly for the treatment and prophylaxis of infectious diseases.

11. Process for the manufacture of the compounds of claim 1, which process comprises

(a) treating a compound of the general formula

in which R^1" is hydrogen or an amino protecting group, R¹⁰ is hydrogen, lower alkanoyl or a hydroxy protecting group and X is as defined above, or with a reactive functional derivative thereof and subsequently splitting off amino, hydroxy and/or carboxy protecting groups present, or

(b) cleaving off the amino, hydroxy and/or carboxy protecting groups in a compound of the general formula

in which X is as X but carboxy is protected, R is as R or an amino protecting group, Y and Y are as Y and Y or contain a hydroxy or amino protecting group, R^f is hydrogen or an amino protecting group, R¹⁰ is hydrogen, lower alkanoyl or a hydroxy protecting group, R*¹ is hydrogen or a carboxy protecting group, provided that at least one of R^f, R^h, R¹⁰ and R²⁰ is or at least one of X^h, Y¹⁰ and Y²⁰ contains a corresponding protecting group, or a salt thereof or

(c) for the manufacture of compounds of formula I in w^τhich R^" is an in vivo cleavable group, reacting a compound of formula I, in which R is hydrogen, with a compound yielding such in vivo cleavable group, or

12. A pharmaceutical preparation containing a compound according to any one of claims 1 to 9 and a therapeutically inert carrier, particularly for the treatment and prophylaxis of infectious diseases.

13. The use of the compounds according to any one of claims 1 to 9 in the treatment and prophylaxis of infectious diseases or for the manufacture of medicaments for the treatment and prophylaxis of infectious diseases.

14. Compounds according to any one of claims 1 to 9, whenever prepared according to the process claimed in claim 11 or by an obvious chemical equivalent thereof.

15. The novel compounds, formulations, processes and methods substantially as described herein.