MXPA97008422A - Carbapene steres - Google Patents

Abstract

A compound of the general formula (I), wherein R is (a), wherein Ra is hydrogen, optionally substituted alkyl (from 1 to 6 carbon atoms), or optionally substituted aryl, Ráes hydrogen, alkyl (from 1 to 6) optionally substituted carbon, or optionally substituted aryl, or R alpha and Ráforman together a 5-6 membered heterocyclic ring optionally with or without additional heteroatoms, R 1 is qluyl (from 1 to 6 carbon atoms) which is unsubstituted or substituted by fluorine, a group hydroxy which is optionally protected by an easily removable hydroxy protecting group, or by an amino group which is optionally protected by an easily removable amino protecting group, R2 is hydrogen or methyl, and R3 is selected from the group consisting of (a) a group of the formula (i), wherein R 1 is hydrogen or alkyl (from 1 to 6 carbon atoms), R 2 is hydrogen, alkyl (from 1 to 6 carbon atoms) optionally substituted by halogen, Quenil (from 1 to 6 carbon atoms), alkoxy (from 1 to 6 carbon atoms) -carbonyl, aryl, or heteroaryl, R3 is hydrogen, alkyl (from 1 to 6 carbon atoms), or alkoxy (from 1 to 6 carbon atoms) ) -carbonyl, and R4 is a pharmaceutically acceptable ester forming group, and (b) a group of the formula CH (R3) O.CO.Rb, wherein R3 is hydrogen, alkyl (from 1 to 6 carbon atoms), cycloaqyl (from 3 to 7 carbon atoms), methyl, or phenyl, and Rb is alkyl (from 1 to 6 carbon atoms) -cycloalkyloxy (from 3 to 7 carbon atoms), or alkoxy (from 1 to 6 carbon atoms-alkyl (from 1 to 6 carbon atoms, useful in the treatment of bacterial infections

Description

STERES OF CARBAPENEMAS This invention relates to a class of antibacterial compounds, in particular to a class of carbapenems, to processes for their preparation, to pharmaceutical and veterinary compositions comprising these compounds, to intermediates thereof, and to their use in antibacterial therapy. Carbapenems, such as imipenema, the compounds of the formula (A): (A) have a powerful and broad spectrum of antibacterial activity (see United States Patent North American Numbers US 3,950,357 and 4,194,047; Merck and Co).

However, these carbapenems tend to be vulnerable to hydrolysis by the renal enzyme dehydropeptidase-1 (DHP-1), and this limits their use in chemotherapy. In the case of imipenema, this problem can be overcome by co-administration of a DHP-1 inhibitor. Stability towards DHP-1 can also be imparted by chemical modification of the carbapenem nucleus, for example, by the incorporation of a 13-methyl substituent, as in the compound meropenem, the compound of the formula (B): (B) (see Shih D.H. et al., Heterocycles, 1984, 21, 29 and Sunagawa M. et al., J. Antibiotics, 1990, 43, 519). More recently, this has been extended to a 1/3-aminoalkyl substituent (see European Patent Number EP-0, 433, 759, Bristol-Meyers Squibb). An alternative approach to imparting better stability to DHP-1 utilizes carbapenems substituted by 2-carbon, for example, 2-aryl, 2-heteroaryl, and 2-heteroaromatic carbapenems (Patents Nos. US-4,543,257; US 4,260,627; 4,962,101; US 4,978,659; EP 0,14,493; EP 0,414,489; EP-0,414,489; EP-0,010,316 and EP 0,030,032 Merck &Co) and 2-methyl (substituted) carbapenems (Schmidt et al., J. Antibiotics, 41 , 1988, 780). U.S. Patent Number 1,593,524, Merck & Co. , discloses a number of five-membered heteroaromatic carbapenem derivatives including diazolyl and tetrazolyl compounds. However, in the case of the pyrazolyl derivatives, the heterocyclic compound is attached to the carbapenem nucleus through the C-4 position. Other structural modifications introduced at position 2 include a substituted vinyl group -C (Ra) = CHRb where, for example, Ra is hydrogen or methyl, and Rb is hydrogen or lower alkyl (European Patent Number EP 0,330,108; Fujisa a), or R a and R b are selected from hydrogen, lower alkyl, aminocarbonyl, lower alkoxy, cyano, nitro, and lower alkoxycarbonyl (European Patent Number EP-0, 430, 037, Banyu Pharmaceutical Co.). In the absence of a 1/3-methyl substituent,. this modification, however, does not seem to impart stability to the DHP-1. International Patent Application Number PCT / GB94 / 02347 describes compounds of the general formula (C): (C) where R is wherein: Ra is hydrogen, optionally substituted alkyl (from 1 to 6 carbon atoms), or optionally substituted aryl; R ^ is hydrogen, optionally substituted alkyl (from 1 to 6 carbon atoms), or optionally substituted aryl; or R and R ^ together form an optionally substituted 5 or 6 membered heterocyclic ring, with or without additional heteroatoms; Rc is alkyl (of 1 to 6 carbon atoms) which is unsubstituted or substituted by fluorine, a hydroxy group which is optionally protected by an easily removable hydroxy protecting group, or by an amino group which is optionally protected by a protecting group of easily removable amino; Rd is hydrogen or methyl; and -C 0 2 e is carboxy or a carboxylate anion, or the Re group is an easily removable carboxy protecting group. The present invention provides a compound of the general formula (I): (I) where R is: wherein: Ra is hydrogen, optionally substituted alkyl (from 1 to 6 carbon atoms), or optionally substituted aryl; R ^ is hydrogen, optionally substituted alkyl (from 1 to 6 carbon atoms), or optionally substituted aryl; or Ra and R ^ together form an optionally substituted 5 or 6 membered heterocyclic ring, with or without additional heteroatoms; R1 is alkyl (of 1 to 6 carbon atoms) which is unsubstituted or substituted by fluorine, a hydroxy group which is optionally protected by an easily removable hydroxy protecting group, or by an amino group which is optionally protected by a protecting group of easily removable amino; R2 is hydrogen or methyl; and R3 is selected from the group consisting of (a) a group of the formula: wherein R 1 is hydrogen or alkyl (of 1 to 6 carbon atoms), R 2 is hydrogen, alkyl (of the β carbon atoms) optionally substituted by halogen, alkenyl (of the β carbon atoms), alkoxy (of 1) to 6 carbon atoms) -carbonyl, aryl, or heteroaryl, R3 is hydrogen, alkyl (of 1 to 6 carbon atoms), or alkoxy (of 1 to 6 carbon atoms) -carbonyl, and R4 is a pharmaceutically acceptable ester-forming group, and (b) a group of the formula CH (Ra) O.CO.Rb, wherein Ra is hydrogen, alkyl (of 1 to 6 carbon atoms), cycloalkyl (of 3 to 7 carbon atoms), methyl, or phenyl; and R "is alkyl (of 1 to 6 carbon atoms) -cycloalkyloxy (of 3 to 7 carbon atoms), or alkoxy (of 1 to 6 carbon atoms) -alkyl (of 1 to 6 carbon atoms). compounds of the formula (I) have a broad spectrum of antibacterial activity, and show good stability towards DHP-1. Alkyl groups (of the β carbon atoms) suitable for R and R ^ include straight-chain alkyl groups and branched having from 1 to 6 carbon atoms, for example, methyl, ethyl, normal propyl, and isopropyl, preferably ethyl and methyl The representative examples of Ra and R ^ as alkyl (of 1 to 6 carbon atoms) are , when both are methyl or ethyl, A particularly preferred example is when Ra is ethyl and R is methyl The optional substituents suitable for the alkyl group (of 1 to 6 carbon atoms) for Ra and R ^ include, for example, halogen , hydroxy, alkoxy (of the ß carbon atoms), carboxy and a salt thereof, alkoxy (from 1 to 6 carbon atoms) -carbonyl, carbamoyl, mono- or di-alkyl (of 1 to 6 carbon atoms) -carbamoyl, sulfamoyl, mono- and dialkyl (of 1 to 6 carbon atoms) -sulfamoyl, amino, mono-y di-alkyl (of 1 to 6 carbon atoms) -amino, acyl (of 1 to 6 carbon atoms) -amino, ureido, alkoxy (of 1 to 6 carbon atoms) -carbonylamino, aminocarbonyloxy, and mono- and dialkyl (from 1 to 6 carbon atoms) -aminocarbonyloxy, 2,2,2-trichloroethoxycarbonylamino, aryl, heterocyclyl, oxo, acyl, heteroaryl, thioalkyl (from 1 to 6 carbon atoms), thioaryl, thioheterocyclyl, alkane (from 1 to 6 carbon atoms) -sulfinyl, arylsulfinyl, alkane (from 1 to 6 carbon atoms) -sulphonyl, arylsulfonyl, alkoxy (from 1 to 6 carbon atoms) -imino, hydroxy-imino, hydrazono, benzohydroxy-imoyl, and -thiophenecarbohydroxy-imoyl. Preferred substituents include carbamoyl, aryl, especially phenyl, and heteroaryl. Alkyl groups (of 1 to 6 carbon atoms) suitable for R include straight and branched chain alkyl groups having from 1 to 6 carbon atoms. Preferred alkyl groups include methyl, ethyl, isopropyl, of which ethyl is especially preferred. Preferably, the alkyl group (of 1 to 6 carbon atoms) of R, has a hydroxy, fluoro, or amino substituent, which is suitably at the 1-position of the alkyl group. Conveniently, R is (R) -1-hydroxyethyl. Suitably, R i is hi-dro-geno. When used herein, the term "aryl" includes phenyl and naphthyl. Suitably, an aryl group, including phenyl and naphthyl, may be optionally substituted by up to five, preferably up to three, substituents. A representative example Ra or R ^ which is an aryl group, is phenyl. Suitable optional substituents for the aryl group include halogen, alkyl (1 to 6 carbon atoms), arylalkyl (1 to 4 carbon atoms), alkoxy (1 to 6 carbon atoms), alkoxy (1 to 6) carbon atoms) -alkyl (from 1 to 6 carbon atoms), haloalkyl (from the ß carbon atoms), hydroxy, amino, mono- or di-N-alkyl (from the ß carbon atoms) amino, acylamino, carboxy, salts of carboxy, esters of carboxy, carbamoyl, mono- and di-N-alkyl (of the ß carbon atoms) -carbamoyl, alkoxy (of 1 to 6 carbon atoms) -carbonyl, alkoxy (of 1 to ß carbon atoms) -carboxylate, aryloxycarbonyl, alkoxy (of the ß carbon atoms) -carbonylalkyl (of the ß carbon atoms), aryl, oxy, ureido, guanidino, sulfonylamino, aminosulfonyl, thioalkyl (of the ß carbon atoms), alkyl (of the ß carbon atoms) -sulfinylalkyl (of 1 to 6 carbon atoms) -sulfonyl, heterocyclyl and heterocyclylalkyl groups (from 1 to 4 carbon atoms). In addition, two adjacent carbon atoms of the ring can be linked by an alkylene chain (of 3 to 5 carbon atoms), to form a carboxylic ring. When used in the present, the term "heteroatom" includes one or more of the elements oxygen, nitrogen, and sulfur. When used herein, the term "heteroaryl" includes simple and condensed aromatic rings containing up to four heteroatoms in each ring, each of which is selected from oxygen, nitrogen, and sulfur, whose rings may be unsubstituted or replaced by, for example, up to three substituents. Each heteroaryl ring suitably has 5 or 6 ring atoms. A fused heteroaryl ring can include carboxylic rings, and need only include a heteroaryl ring. When used herein, the terms "heterocyclyl" and "heterocyclic" suitably include, unless otherwise defined, simple and aromatic and nonaromatic fused rings, suitably containing up to 4 heteroatoms in each ring, each of which is selected from oxygen, nitrogen, and sulfur, whose rings may be unsubstituted or substituted, for example by up to three substituents. Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6 ring atoms. A fused heterocyclic ring system can include carboxylic rings, and needs to include only one heterocyclic ring. Preferably, a substituent for a heteroaryl or heterocyclyl group is selected from halogen, alkyl (from 1 to 10 carbon atoms), arylalkyl (from 1 to 4 carbon atoms) -alkoxy (from the ß carbon atoms), alkoxy (from the ß carbon atoms) -alkyl (from 1 to 6 carbon atoms), haloalkyl (from the ß carbon atoms) , hydroxy, amino, mono- and di-N-alkyl (of the ß carbon atoms) -amino, acylamino, salts of carboxy, esters of carboxy, carbamoyl, mono- and di-N-alkyl (of the ß atoms of carbon) -carbonyl, alkoxy (from 1 to 6 carbon atoms) -carboxylate, aryloxycarbonyl, alkoxy (from the ß carbon atoms) -carbonylalkyl (from the ß carbon atoms), aryl, oxy, ureido, guanidino, sulfonylamino groups , aminosulfonyl, thioalkyl (of the ß carbon atoms), alkyl (of the ß carbon atoms) -sulfinyl, alkyl (of the ß carbon atoms) -sulphonyl, heterocyclyl, and heterocyclylalkyl (of 1 to 4 carbon atoms) . Suitable hydroxy and amino protecting groups for use in R1 are those well known in the art, and which can be removed under conventional conditions, and without altering the remainder of the molecule. A comprehensive discussion of the ways in which hydroxy and amino groups can be protected, and methods for dissociating the resulting protected derivatives, is given, for example, in "Protective Groups in Organic Chemistry" (TW Greene, Wiley-Interscience, New York, 2nd edition, 1991). Particularly suitable hydroxy protecting groups include, for example, triorganosilyl groups, such as, for example, trialkylsilyl, and also organo-oxycarbonyl groups, such as, for example, allyloxycarbonyl, trichloroethyloxycarbonyl, 4-methoxybenzyloxycarbonyl, and 4-nitrobenzyloxycarbonyl. . Particularly suitable amino protecting groups include alkoxycarbonyl, 4-methoxybenzyloxycarbonyl, and 4-nitrobenzyloxycarbonyl. Since the carbapenem compounds of the present invention are intended for use in pharmaceutical compositions, it will further be understood that each is provided in a substantially pure form, eg, at least 50 percent pure, more adequately at least 75 percent pure , and preferably at least 95 percent pure (the percentage is on a weight / weight basis). Impure preparations of the compounds can be used for the preparation of the purest forms used in the pharmaceutical compositions. When some of the compounds of this invention are allowed to crystallize or recrystallize from organic solvents, there may be crystallization solvents present in the crystalline product. This invention includes within its scope these solvates. Similarly, some of the compounds of this invention can be crystallized or recrystallized from solvents containing water. In these cases, the water of hydration may be present in the crystalline product. This invention includes, within its scope, stoichiometric hydrates. The carbapenem antibiotic compounds according to the invention can be formulated to be administered in any convenient way for use in human or veterinary medicine, according to the techniques and procedures known per se in this field, with reference to other antibiotics, and accordingly, the invention includes within its scope a pharmaceutical composition comprising an antibiotic compound according to the present invention, together with a pharmaceutically acceptable carrier or excipient. The compositions can be formulated for administration by any suitable route, such as oral, parenteral, or local application, although oral administration is preferred. The compositions may be in the form of tablets, capsules, powders, granules, dragees, creams, or liquid preparations, such as sterile oral or parenteral solutions or suspensions. Tablets and capsules for oral administration may be in a unit dose presentation form, and may contain conventional excipients such as binding agents, for example acacia syrup, gelatin, sorbitol, tragacanth, or polyvinyl pyrrolidone.; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol, or glycine; tablet lubricants, for example magnesium stearate, talc, polyethylene glycol, or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulfate. The tablets can be coated according to methods well known in normal pharmaceutical practice. The oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. These liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters, glycerin, propylene glycol, or ethyl alcohol, - preservatives, for example methyl or propyl p-hydroxybenzoate, or sorbic acid; and if desired, conventional flavoring or coloring agents. The suppositories will contain a conventional suppository base, for example cocoa butter or other glyceride. For parenteral administration, fluid unit dosage forms are prepared using the compound and a sterile vehicle, with water being preferred. The compound, depending on the vehicle and the concentration used, can be suspended or dissolved in the vehicle. In the preparation of solutions, the compound can be dissolved in water for injection, and sterilized by filter before filling in a suitable vial or ampoule, and sealed. Conveniently, agents such as local anesthetic agents, preservatives, and pH regulators in the vehicle can be dissolved. To improve the stability, the composition can be frozen after being filled into the bottle and the water removed in vacuum, the dry lyophilized powder is then sealed in the bottle, and an accompanying bottle of water for injection can be supplied in order to to reconstitute the liquid before use. Parallel suspensions are prepared in substantially the same manner, with the exception that the compound is suspended in the vehicle instead of being dissolved, and sterilization can not be performed by filtration. The compound can be sterilized by exposure to ethylene oxide before being suspended in the sterile vehicle. Conveniently, a surfactant or a wetting agent is included in the composition, in order to facilitate a uniform distribution of the compound. The composition can contain 0.1 percent at 99. 5 percent by weight, preferably 10 to 60 percent by weight of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit preferably will contain 50 to 500 milligrams of the active ingredient. The dosage dosage as used for the treatment of adult humans, preferably will be 100 milligrams to 12 milligrams per day for an average adult patient (with a body weight of 70 kilograms), for example, 1,500 milligrams per day, depending on the route and the frequency of administration. These dosages correspond to approximately 1.5 to 170 milligrams / kilogram per day. Suitably, the dosage is from 1 to 6 grams per day. The daily dosage is suitably given by the administration of a compound of the invention several times in a period of 24 hours. Typically, 250 milligrams are administered four times a day, although, in practice, the dosage and frequency of administration that are most appropriate for an individual patient will vary with age, weight, and patient response, and there will be occasions when the doctor chooses a higher or lower dosage, and a different frequency of administration. These dosage regimes are within the scope of this invention. No toxicological effects are indicated when a compound of the invention is administered in the aforementioned dosage range. The present invention also includes a method for the treatment of bacterial infections in humans and animals, which method comprises administering a therapeutically effective amount of an antibiotic compound of the present invention. In a further aspect, the present invention also provides the use of a compound of the formula (I) for the manufacture of a medicament for the treatment of a bacterial infection. The compounds of the present invention are active against a wide range of Gram-positive and Gram-negative bacteria, and can be used to treat a wide range of bacterial infections, including those of immunocompromised patients. Among many other uses, the compounds of the invention are valuable in the treatment of infections of the skin, soft tissue, respiratory tract, and urinary tract in humans, and can also be used to treat mastitis in cattle. A particular advantage of the antibacterially active compounds of this invention is their stability to the / 3-lactamase enzymes, and therefore, they are effective against β-lactamase producing organisms. The present invention further provides a process for the preparation of a compound of the formula (I), which process comprises treating a corresponding compound of the formula (I), wherein R is an alkali metal cation, with a compound of the formula (i) or (ii): XCH (Ra) O.CO.Rb (ii) wherein X is an leaving group, such as halogen, more particularly bromine or iodine. The reaction is typically carried out between 0 ° C and 60 ° C, for example at room temperature, under an inert atmosphere, for example of argon, in a suitable organic solvent, for example N-methyl pyrrolidin-2-one. Other suitable solvent systems include N, N'-dimethyl formamide, and N, N "-dimethyl acetamide The compounds of the formula (i) can be prepared as described by F. Ameer et al., J. Chem. Soc, (1983), 2293. Compounds of the formula ICH (Ra) O.CO.Rb can be prepared from the corresponding chloride by means of the Finkelstein reaction, which is well known to those skilled in the art. the formula ClCH (Ra) O.CO.Rb, can be prepared by esterification of an acid of the formula RbCOOH, with chloromethyl chlorosulfate (Binderup et al., Synthetic Commun., 14 (9), 857-864 (1984)) ), or by the treatment of a compound of the formula ClCH (Ra) OCOCl with a compound of the formula HRb in dichloromethane / pyridine (Yoshimura et al, J. Antibiot, 1987, 40 (1), 81-90). compounds of the formula (I), wherein R is an alkali metal cation, such as sodium, are described in the In-Patent Application. No. PCT / GB94 / 02347, and hereinafter, in Preparation 1 A further process for the preparation of a compound of formula (I), comprises subjecting a compound of formula (II): (II) wherein R, R 1, and R i are as defined hereinabove, R 3 is an easily removable carboxy protecting group, X is oxygen or a group PRR 5 R, R 4, R 5 and R 6 may be the same or different , and is each, an optionally substituted alkyl group (of 1 to 6 carbon atoms), or an optionally substituted aryl group, preferably a normal butyl group or a phenyl group; to carbapenem ring forming conditions; and subsequently, and if necessary, performing any or all of the following steps: removing any protecting groups, - converting a first group R1 comprising a hydroxyl substituent, into an additional R group comprising an amino or fluorine group, - converting the product in a salt; and esterify the product as stipulated above. Suitable carbapenem ring forming conditions are well known in the art. When X is oxygen, suitable ring-forming conditions include treating the compound of the formula II with a trivalent organic phosphorus compound of the formula (III): PR7 (OR8) (OR9) (III) wherein: R is alkyl ( from 1 to 4 carbon atoms), alkoxy (from 1 to 3 carbon atoms), or phenyl optionally substituted by alkyl (from 1 to 3 carbon atoms), - and R ° and R9 may be the same or different, and is each alkyl (from 1 to 4 carbon atoms). carbon), allyl, benzyl, or phenyl optionally substituted by alkyl (from 1 to 3 carbon atoms) or by alkoxy (from 1 to 3 carbon atoms), - by analogy with the process described in European Patent Number EP-0 , 476, 649-A (Hoechst AG). Suitable reagents of the formula (III) include trimethyl phosphite, triethyl phosphite, dimethyl methylphosphonite, and diethyl methylphosphonite. Suitably, the reaction is carried out in an organic solvent, such as tetrahydrofuran, ethyl acetate, an aromatic solvent such as benzene, toluene, xylene, or mesitylene or a halogenated hydrocarbon solvent, such as dichloromethane, trichloromethane, or 1, 1, 2-trichloroethane, and at a temperature between 50 ° C and 180 ° C, preferably between 70 ° C and 165 ° C. When X is a PR R5R group, the compounds of formula (I) can be obtained by the Well-known Wittig cyclization route for carbapenems (Guthikonda et al., J. Med. Chem. 1987 30, 871). For example, when R, R, and R are each phenyl, the process comprises eliminating the ring closure of the triphenyl phosphine oxide elements. The ring closure can be suitably effected by heating the compound of the formula (II, X = PR R 5 R) to a temperature which is preferably in the range of 40 ° C to 145 ° C, more preferably 80 ° C to 140 ° C, in an inert solvent, such as benzene, toluene, or xylene, preferably under dry conditions, and under an inert atmosphere, and optionally in the presence of a radical scavenger, such as hydroquinone. When R4, R5, and R are each normal butyl, the cyclization can be carried out at a lower temperature, for example higher than 50 ° C, by analogy with the process described in International Patent Number WO 92/01695 (Beecham Group , for analogous penises). In the R substituent, a hydroxyl group or an amino group, if present, can optionally be protected. Suitable hydroxy protecting groups include organosilyl groups, for example a trialkylsilyl group such as trimethylsilyl, or tertiary butyl dimethylsilyl, or trichloroethyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, and allyloxycarbonyl. Suitable amino protecting groups include alloxycarbonyl, 4-methoxybenzyloxycarbonyl, and 4-nitrobenzyloxycarbonyl. Suitable values for the RJ protecting group include allyl, 4-methoxybenzyl, and 4-nitrobenzyl. The conditions necessary to remove the protecting group, of course, will depend on the precise nature of the protecting group. For example, when RJ is 4-methoxybenzyl, aluminum trichloride and anisole in dichloromethane can be used at -30 ° C to -70 ° C; when R is allyl (prop-2-en-1-yl), a combination of triphenyl phosphine, sodium 2-ethylhexanoate in ethyl acetate / MDC, and tetrakis- (triphenyl phosphine) palladium (0) can be used, and when R3 is p-nitrobenzyl, hydrogenation can be used in the presence of a palladium on carbon catalyst in an aqueous solvent, for example, aqueous 1,4-dioxane-ethahydrofuran-ethanol. The compounds of the formula (II), wherein X is oxygen, can be obtained by a process comprising reacting a compound of the formula (IV): wherein R, R1, and R are as defined hereinabove, with a compound of the formula (V): C1C0C02R3 (V) wherein R3 is an easily removable carboxy protecting group; under acylation conditions, by analogy with the process described in Tetrahedron Letters, 25, 1984, 2395. The compounds of the formula (II), wherein X is a group PR4R5R6 can be obtained from a compound of the formula (IV ) as defined hereinbefore, by the following sequence of steps: (a) reacting with a suitably protected glyoxylic acid derivative of the formula (VI), or a functional equivalent thereof, such as the hydrate: (OHC) ) C02R3 (IV) wherein R is an easily removable carboxy protecting group; under conditions of dehydration, for example azeotropic removal of water, - (b) treating the intermediate formed in step (a) with a halogenating agent, for example, thionyl chloride, in the presence of a suitable base such as 2, 6-lutidine, - and (c) treating the intermediate formed in step (b) with a phosphorus reagent of the formula (VII): PR4R5R6 (VII) wherein R4, R5, and R are as defined above in the present, in the presence of a suitable base, such as 2, 6-lutidine; The compounds of the formula (IV) can be prepared by the treatment of a compound of the formula (VIII): (V? D wherein R and R2 are as defined hereinabove, - with a compound of the formula (IX) wherein R is as defined hereinabove, and R is an acyl group, for example acetyl; in the presence of a base, such as, for example, lithium hexamethyldisilazide (LHMDS), - according to the procedures described in Tetrahedron Lett., 1987, 28, 507, and Can. J. Chem. 1988, 66, 1537. The compounds of the formula (IV) can also be prepared by the treatment of a compound of the formula (Villa): R R2 OSiRj14 (Vina) wherein R and R are as previously defined herein, and SIR314 is a trialkylsilyl, such as trimethylsilyl or tertiary butyl dimethylsilyl, with a compound of the formula (IXa): (Ka) wherein R and R are as previously defined herein, and R 13 is hydrogen or an amido protecting group, for example a trialkylsilyl group, such as trimethylsilyl; in the presence of a Lewis acid, such as, for example, zinc chloride or trimethylsilyl trifluoromethanesulfonate in an inert organic solvent such as a halogenated hydrocarbon solvent, for example dichloromethane, at room temperature. The compounds of the formula (Villa) can be prepared by treating the compounds of the formula (VIII) with trialkylsilyl chloride or trialkylsilyl triflate, and triethyl amide in MDC. If the amino protecting group R13 in (IXa) requires a subsequent removal, this can be achieved by conventional elements, such as treatment with light acid, for example methanol and hydrochloric acid or pyridinium p-toluenesulfonate, wherein R13 is trimethylsilyl . The compounds of the formula (VIII) are well known to those skilled in the art, and can be obtained by conventional synthetic methods, as described in the following Examples. The compounds of the formula (IX) are well known to those skilled in the art, and can be obtained by conventional synthetic methods, such as are described, for example, in Het., 1982, 17, 201 (IX, R1 is 1 -hydroxyethyl), and in European Patent Number EP-0,234,484 (IX, R 1 is 1-fluoroethyl). The compounds of the formula (I) wherein R 1 is an alkyl or cycloalkyl substituted by amino, can be conveniently prepared from a corresponding compound of the formula (I), wherein R 1 includes a hydroxy group, by a displacement of azide of Mitsunobu type of the hydroxy group thereof, followed by catalytic reduction, according to the procedure described in J. Chem. Soc., Perkin I, 1982, 3011. The compounds of the formula (I) can also be prepared by a process comprising reacting a compound of the formula (X): (X) wherein R1 and R2 are as defined hereinabove, R is an easily removable carboxy protecting group, and X is an leaving group, with a compound of the formula (XI): MR (XI) in where M is a metallo group, and R is as defined above in the present; in a cross-coupling reaction in the presence of a cross-coupling reaction catalyst selected according to the identity of M, and then and if necessary, removing any protecting group, and / or converting the product into a salt, and / or esterify the product as previously stipulated herein. •3 Suitable values for the RJ protecting group include 4-methoxybenzyl, and 4-nitrobenzyl. Examples of suitable leaving groups X include, for example, trifluoromentanesulfonyloxy, methanesulfonyloxy, 4-toluenesulfonyloxy, fluorosulfonyloxy, chlorine, bromine, iodine, and diphenoxyphosphoryloxy. Suitable metals for use in the metallo M group are well known in the art, and include tin, aluminum, zinc, boron, mercury, and zirconium. Preferred examples of the metallo group M include, for example, R14R15R16Sn, B (OR) 2 and ZnCl where R14, R15 and R16 may be the same or different, and are each alkyl (of 1 to 6 carbon atoms). Preferably, the metallo M group is an organostanna R14R15R16Sn, and R14 = R15 = R16 = methyl or normal butyl. Suitable cross-coupling catalysts are well known in the art, and include palladium compounds, in particular palladium (0) and palladium compounds (II), such as those described in "Palladium Reagents in Organic Synthesis, "RF Heck, Academic Press Ltd, 1985. The examples of the same include tris (dibenzylidene ketone) dipalladium (0), tetrakis (triphenyl phosphine) palladium (0), trans-dimethyl-bis ( triphenyl phosphine) aladium (II), and palladium (II) acetate, benzyl-bis (phosphine triphenyl) chloride palladium (II), bis (triphenyl phosphine) dichloride palladium (II) .These palladium reagents are preferably used in combination with a halide source, such as zinc chloride or lithium chloride, and optionally in the presence of a palladium phosphine ligand, for example, a compound such as a triaryl phosphine, for example tris (4-methoxyphenyl) phosphine) or phosphine tris (2, 4,6-trimethoxyphenyl), a triheteroaryl phosphine, for example trifurilic phosphine, or a triarylarsine, for example triphenylarsine When M is an organostannane R R15R16Sn-, a preferred catalyst system is tris (dibenzylidenacetone) dipaladio (0), in the presence d and zinc chloride and a phosphine compound. When M is ZnCl, a preferred catalyst is tris (dibenzylideneacetone) dipalladium (0) in the presence of a phosphine compound. Suitably, the reaction is carried out in an inert aprotic polar coordinating solvent, such as tetrahydrofuran, diethyl ether, dioxane, 2-dimethoxyethane, acetonitrile, dimethyl formamide, dimethyl sulfoxide, and the like, and under a dry inert atmosphere, such as argon. Suitably, the reaction is carried out initially at a low temperature, for example about -78 ° C, then the final phase of the reaction is carried out at room temperature. Analogous processes wherein M is organostannane, are described in European Patent Numbers EP-0,444,889 (Merck &Co), and EP-0,430,037 (Banyu Pharmaceutical Co). The compounds of the formula (X) are well known in the art, and can be obtained according to the procedures described in European Patent Number EP-0,444,889 (Merck &Co), EP-0, 430, 037, (Banyu Pharmaceutical Co.), and in Rano et al., Tet. Letters, 1990, 312853. The compounds of the formula (XI) are well known in the art, and can be obtained according to the procedure described in Heterocycles, 1992, 33 (2), 813. The following Examples illustrate the invention, but they do not intend to limit their scope in any way.

General instructions. Solutions were dried using anhydrous magnesium sulfate and the solvents were removed by evaporation under reduced pressure using a rotary evaporator. Column chromatography on silica gel, used silica gel Merck 60 of a particle size < 0.063 millimeters Example 1 (5R, 6S) -2- (l-ethyl-5-methyl-l, 2-pyrazol-5-yl) -6- [(IR) -1-hydroxyethyl] carbapen-2-em-3-carboxylate of 2-ethoxycarbonyl-E-but-2-enyl. (5R, 6S) -2- (1-ethyl-5-methyl-1, 2-pyrazol-5-yl) -6- [(IR) -1-hydroxyethyl] carbapen-2-em-3-carboxylate of sodium (200 milligrams) in N-methyl pyrrolidinone (2 milliliters), at room temperature under argon, was treated with a solution of ethyl E-2-bromomethylbut-2-enoate [F. Ameer et al. J. Chem. Soc. ., (1983) 2293], (253 milligrams) in N-methyl pyrrolidinone (1 milliliter). After 2 hours, the solution was diluted with ethyl acetate, washed with water (3 times), dried over anhydrous magnesium sulfate, and concentrated. The product was purified by chromatography on silica gel by evaporation, eluting with 50 percent ethyl acetate / hexane, and then ethyl acetate, to give the title compound as a pale yellow foam (153 milligrams, 58 percent); (Found: M +, 431.2065, C22H29N306 requires M 431.2056), -nma? (CH2C12) 3605 (w), 1774, 1712 cm "1; dH (CDCl3) 1.24-1.41 (9H, m), 1.82 (H, d, J4, 9Hz), 1.98 (3H, d, J7.3Hz), 2.28 (3H, s), 3.16 (lh, dd, J2.8.6.6Hz), 3.27 (HI, dd, J9.0, 18.5Hz), 3.57 (1H, dd, J9.9,18.5H), 4.07 (2H, q, J7.3Hz), 4.17-4.29 (3H, m), 5.03 and 5.11 (2HABq, J11.9Hz), 6.94 (lH, s) and 7.21 (lh, q, J7.3Hz).

Example 2 (5R, 6S) -6- [(R) -1-hydroxyethyl] -2- (l-ethyl-5-methyl-pyrazol-3-yl) carbapen-2-em-3-carboxylic acid 1-methylcyclohexyloxy -carbonyloxymethyl. (a) Iodomethyl 1-methylcyclohexylcarbonate The 1-methylcyclohexanol (4.57 grams) in dichloromethane (40 milliliters) was cooled in an ice bath, and treated with pyridine (3.24 milliliters). Chloromorphine chloromormate (3.65 milliliters) in dichloromethane (10 milliliters) was added dropwise through a pressure equalizing funnel. The mixture was stirred for two hours, then washed with water (2 times), dried (MgSO 4), and then evaporated to leave a reddish oil, which was dissolved in dichloromethane, and filtered through silica gel (ASTM 230-400 mesh), to give (after evaporation) chloromethyl 1-methylcyclohexylcarbonate as a colorless oil (8.97 grams),? max (H2Cl2) 2940-2865, 1763, 1444, 1346, 1292, and 1237 cm "1; d (CDC13) 1.25-1.70 (11H, m), 2.12-2.18 (2H, m), 5.69 (2H, s) The chloromethyl 1-methylcyclohexylcarbonate (2.07 grams) in acetone (7.5 milliliters) was treated with 2,6-lutidine (0.116 milliliters), then sodium iodide (2.25 grams) was added and the mixture was stirred for 1.5 hours. After that, more sodium iodide (1.5 grams) was added, and the stirring was continued.After a total of 2.5 hours, the acetone was removed, and water was added, and the layers were separated. The dichloromethane layer was washed with Na 2 S 2 3 3, 5% aqueous, dried (MgSO ^) and evaporated to leave an oil, which was taken up in hexane (50 milliliters) and loaded onto a column of silica gel. and the column was eluted with 5 percent ethyl acetate in hexane, to give iodomethyl 1-methylhexylcarbonate containing some of the starting chloromethyl compound, d (CDCl3) 1.26-1.35 (2H, m), 1.40-1.65 (9H , m, include do s in d 1.52), 2.10-2.20 (2H, m), 5.69 (s) and 5.91 (s) (together 2H, ratio 1: 5) ppm. (b) (5R, 6S) -6- [(R) -1-hydroxyethyl] -2- (1-ethyl-5-methyl-pyrazol-3-yl) carbapene-2-em-3-carboxylate from 1 methylcyclohexyloxycarbonyloxymethyl. Sodium (5R, 6S) -6- [(R) -1-hydroxyethyl] -2- (l-ethyl-5-methyl-pyrazol-3-yl) carbapen-2-em-3-carboxylate (200 milligrams) ) in N-methyl pyrrolidinone (2 milliliters) containing 2,6-lutidine (0.07 milliliters), was treated with iodomethyl-1-methylcyclohexylcarbonate (363 milligrams) in tetrahydrofuran (0.5 milliliters). The mixture was stirred under argon for 20 minutes. Ethyl acetate (20 milliliters) was added, and washed with water (3 x 25 milliliters), then with 5 percent Na2S20ß (20 milliliters), and then with 0.05M HCl, followed by saturated brine. After drying (MgSO 4), the ethyl acetate was evaporated to leave a gum, which was purified by chromatography on silica gel (ASTM 230-400 mesh) (2.5 x 12 cm column), loading in CH 2 Cl 2 hexane, and eluting with ethyl acetate / hexane mixtures, followed by ethyl acetate. The fractions containing the product were combined and evaporated, and then re-run through chromatography on silica gel (ASTM 230-400 mesh) (2 times), eluting with acetone / hexane (1: 1). The fractions containing the product were combined and evaporated. Hexane was added, and evaporated to give (5R, 6S) -6- [(R) -1-hydroxyethyl] -2- (1-ethyl-5-methylpyrazol-3-yl) carbapen-2-em-3. 1-methylcyclohexyloxycarbonyloxymethyl carboxylate (187 milligrams) as a solid foam? ma? (CH2C12) 3678, 3601, 2939, 1773, 1598, 1546, 1450, 1380, 1317, and 1241 cm "1; ? max (EtOH / nm 325 (10,924), 213 (e / dpAnol '1 9,391); d (CDCl 3) 1.2-1.5 (14H, m, including d, J6.4 to dl.35, t, J7.3 H a dl.51), 1.93 (lH, d J4.7 Hz), 2.05 - 2.2 (2H, m), 2.28 (3H, s), 3.18 (ÍH, dd, J2.7 &6.5 Hz), 3.29 ( ÍH, dd, J9.1 &18.7 Hz) 3.64 (ÍH, dd, J9.9 &18.8 Hz), 4.08 (2H, q J7.3 Hz), 4.15 - 4.30 (2H, m), 5.90 (2H , S), 7.05 (ÍH, s) ppm.

Example 3 (5R, 6S) -2- (1-ethyl-5-methylpyrazol-3-yl) -6- [(IR) -1-hydroxy-ethyl] carbapen-2-em-3-carboxylate of 2-methoxyprop -2-ylcarbonyloxymethyl. The product of Preparation 1 (200 milligrams, 0.61 mmol) was dissolved in N-methyl pyrrolidin-2-one (2 milliliters). A solution of 2-methoxyprop-2-ylcarbonyloxymethyl iodide (0.34 grams, 1.3 mmol) in N-methyl pyrrolidin-2-one (0.5 milliliters) was added to this solution at room temperature under argon, and after 0.5 hours, the reaction mixture was diluted with ethyl acetate (15 milliliters), and the solution was washed with water (3 x 15 milliliters), a 5 percent sodium thiosulfate solution (15 milliliters), and then saturated brine (15 mL). milliliters). The organic extract was dried (Na 2 S 4) and concentrated to an oil, which was purified by chromatography on silica gel, eluting with a gradient acetone / toluene mixture, to give a pale yellow solid, which was recrystallized from acetone / diethyl ether, to provide the title compound as a colorless oil (0.23 grams, 87 percent); (Found: M + 435.2007, C21H29N307 requires M 435.2006); ? ma? (CHC13) 3612, 3016, 2981, 2937, 1771, 1734 (sh), 1596 cm "1; dH (CDCI3) 1.38-1.45 (12H, m), 1.81 (ΔH, d, J4.9 Hz), 2.29 ( 3H, s), 3.18 (HH, dd, J2.8, 6.6 Hz), 3.30 (HH, dd, J9.1, 18.8 Hz), 3.64 (HH, dd, J9.9, 18.8 Hz), 4.08 (2H , q, Jl. 3 Hz), 4.16-4.29 (2H, m), 5.96 (H, d, J5.5 Hz), 6.03 (H, J5.5 Hz) and 7.02 (H, s) ppm.

Preparation 1 (5R, 6S) -6- [(R) -1-hydroxyethyl] -2- (l-ethyl-5-methylpyrazol-3-yl) carbapen-2-em-3-sodium carboxylate. (a) ethyl l-ethyl-5-methylpyrazole-3-carboxylate N-ethylhydrazine oxalate (12 grams) was cooled in glacial acetic acid (100 milliliters), in an ice bath, and treated with 2, 4- ethyl dioxovalerate (11.24 milliliters). After the addition was completed, the mixture was stirred at room temperature; after about 45 minutes, the mixture was heated to dissolve the insoluble ethylhydrazine oxalate. The mixture was stirred for another two hours, and then poured into water (about 300 milliliters) / ethyl acetate (about 700 milliliters), and solid K2CO3 was carefully added, with stirring, until the pH was neutral. After separation, the aqueous layer was back extracted with ethyl acetate. The combined ethyl acetate extracts were dried (gS? 4), and the solvents were removed to leave an oil. Chromatography on silica gel, loading in C ^ C ^ / exano, and eluting with a gradient elution of ethyl acetate / hexane mixtures (from 2: 8 to 1: 1), gave l-ethyl-5-methylpyrazole -3-ethyl carboxylate as an oil (13.2 grams); vmax (CH2Cl2) 1717, 1446, 1389 and 1219 cm * 1; d (CDCl3) 1.38 (3H, t, J7.2 Hz), 1.42 (3H, t, J7.3 Hz), 2.30 (3H, s), 4.17 (2H, q, J7.3 Hz), 4.38 (2H , q, J7.1 Hz), 6.55 (HH, s), (Found m / z 182.1055.C9H14N2O2 requires m / z 182.1055). (b) 1-Ethyl-5-ethylpyrazole-3-carboxylic acid The ethyl l-ethyl-5-methylpyrazole-3-carboxylate (10.93 grams) in ethanol (70 milliliters) was treated with KOH (3.69 grams), followed water (30 milliliters), and the mixture was stirred and heated under reflux for 6 hours. The ethanol was removed using a rotary evaporator, and ethyl acetate / water was added. The pH of the mixture was adjusted to 3.0, and the layers were separated. The aqueous layer was back extracted with ethyl acetate. The combined ethyl acetate layers were extracted with an excess of aqueous NaHCO. The NaHCO extract was poured into an excess of acid, and then the pH was adjusted to 3, and NaCl was added to the solution. The mixture was then extracted repeatedly with ethyl acetate, and the combined extracts were dried (MgSO 4) and evaporated. The residue was triturated with diethyl ether to give the acid as a solid (5.65 grams); umax (CH2C12) 2754, 2598, 1698, 1498, 1464, 1387, and 1233 cm "1; d (CDC13) 1.40 (3H, t, Jl. 3 Hz), 2.32 (3H, s) 4.19 (2H, q, J7.3 Hz), 6.61 (lH, s) ppm; (Found m / z 154.0740, C7H? Or N2? 2 requires m / z 154.0742). (c) N-methoxy-N-methyl-1-ethyl-5-methylpyrazole-3-carboxamide L-ethyl-5-methylpyrazole-3-carboxylic acid (5.25 grams) in dry dichloromethane (100 milliliters) containing N formamide, N-dimethyl (0.26 milliliter) was cooled in an ice bath, and treated with a solution of oxalyl chloride (3.27 milliliters) in dichloromethane (25 milliliters), added dropwise. The mixture was stirred cold for 25 minutes, and then allowed to warm to room temperature, when the evolution of a gas was observed. After 10 minutes the solvent was removed by evaporation in vacuo, and toluene was added and removed (twice) to ensure that any residual HCl and oxalyl chloride had been removed. The resulting acid chloride was redissolved in dry dichloromethane, and then treated with N, 0-dimethylhydroxylic hydrochloride (3.61 grams). The mixture was cooled in an ice bath, and treated with pyridine (6.0 milliliters). Then the mixture was allowed to stir at room temperature for 1.5 hours, and then diluted with ether (100 milliliters) was washed with brine. Then the organic layer was dried (gS? 4) and evaporated to leave an oil. This was passed through chromatography on silica gel, loading in dichloromethane, and eluting with ethyl acetate / hexane mixtures to give, after evaporation of the required fractions, the hydroxamate (5.2 grams) as a solid. ? ma? (CH2C12) 2982, 2937, 1641, 1489, 1445, 1379, and 975cm "1; d (CDCl3) 1.43 (3H, t, J7.3 Hz), 2.29 (3H, s), 3.42 (3H, s), 3.76 (3H, s,), 4.13 (2H, q, J7.3 Hz), 6.49 (HH, s); (Found m / z 197.1164, C9H15N3O2 requires m / z 197.1164). (d) 3-acetyl-l-ethyl-5-methylpyrazole N-methoxy-N-methyl-l-ethyl-5-methylpyrazole-3-carboxamide (3.12 grams) in dry tetrahydrofuran (60 milliliters) was cooled in a bath of ice, and treated with a 3.0 M solution of methyl magnesium bromide in ether (11.08 milliliters). After stirring for 1.5 hours, the mixture was poured into a mixture of methanol (100 milliliters) and 5 M accented HCl (10 milliliters) in an ice bath. Then the mixture was evaporated to lower the volume, and treated with a mixture of dichloromethane, water, and saturated brine. After separation, the aqueous layer was back extracted with dichloromethane. The combined dichloromethane extracts were dried (MgSO 4) and evaporated to leave an oil (2.26 grams), which solidified upon standing; ? ma? (CH2Cl2) 1680, 1446, 1425, 1380, 1324, 1208, and 945 cm "1; d (CDCI3) 1.44 (3H, t, J7.3 Hz), 2.30 (3H, s), 2.53 (3H, s) , 4.13 (2H, q, J7.3 Hz), 6.51 (lH, s); (Found: m / z 152.0949.) C8H12N20 requires m / z 152. 090). (e) (3S, 4R) -4- [(1-ethyl-5-methylpyrazol-3-yl) carbonyl-methyl] -3 - [(R) -1-tertiary butyl-dimethylsilyloxyethyl] azetidin-2-one. The 3-acetyl-l-ethyl-5-methylpyrazole (3.51 grams) in dry tetrahydrofuran (THF) (150 milliliters) under an argon atmosphere was cooled in an acetone / solid carbon dioxide bath, and then treated with a solution of ammonium bis (trimethylsilyl) amide (50 milliliters). The mixture was stirred for 45 minutes, and then (3R, 4R) -4-acetoxy-3- [(IR) -1-tertiary butyl-dimethylsilyloxyethyl] azetidinone (6.6 grams) was added as a solid under an argon blanket. The mixture was stirred cold for 3.5 hours. Then saturated aqueous ammonium chloride was added, followed by ethyl acetate, and the mixture was allowed to warm to room temperature. A little water was added, and the layers were separated, and the aqueous layer was back extracted with ethyl acetate. The combined ethyl acetate extracts were washed with saturated brine, dried, and evaporated. Chromatography on silica gel, eluting with ethyl acetate / hexane mixtures, gave the title compound (3.65 g), umax (C 2 C 12> 3411, 1761, 1678, 1376, 1151, and 838 cm "1; (CDC13) 0.064 (6H, s), 0.86 (9H, s), 1.20 (3H, d, J6, 3 Hz), 1.44 (3H, t, J7.3 Hz), 2.31 (3H, s), 2.89 ( ÍH, dd, Jl .8 &4.9 Hz), 3.15 (ÍH, dd, J10.0 &17.1 Hz), 3.50 (ÍH, dd, J3.5 &17.0 Hz), 4.06 - 4.25 (4H, m ), 6.11 (ÍH, s), 6.53 (ÍH, s). (Found m / z 379.2296, requires m / z 379.2291). (f) (2R and 2S) -2-. { (3S, 4R) -4 - [(1-ethyl-5-methylpyrazol-3-yl) carbonylmethyl] -3- [(R) -1-tertiary butyl-dimethylsilyloxy-ethyl] -2-oxoazetidinyl} Allyl-2-hydroxyacetate. (3S, 4R) -4- [(1-ethyl-5-methylpyrazol-3-yl) -carbonylmethyl] -3- [(R) -1-tertiary butyl-dimethylsilyloxy-ethyl] azetidin-2-one (3.6 grams), and allyl glyoxylate hydrate (1.66 grams) in toluene (100 milliliters), were heated under reflux in a Dean-Stark apparatus under an argon atmosphere for 3.5 hours. Thin layer chromatography of the reaction mixture showed that the reaction had almost proceeded to completion, so that more allyl glyoxylate hydrate (190 milligrams) was added, and the mixture was heated under reflux for another 45 minutes. The mixture was cooled, and toluene was removed to give (2R and 2S) -2-. { (3S, 4R) -4- [(1-ethyl-5-methylpyrazol-3-yl) carbonylmethyl] -3- [(R) -1-tertiary butyldimethylsilyloxyethyl] -2-oxoazetidinyl} Raw allyl-2-hydroxyacetate, which was used in the next stage, -? Raa? (CH2C12) 3681, 3518, 1758, 1676, 1448, 1376, 1326, 1209, 1148, 1092, 954, and 836 cm "1; d (CDCl3) among others 0.035 (s), 0.061 (s) (together 6H, ), 0.858 (s), 0.865 (s) (together 9H), 1.21 (d, J6.2 Hz), 1.24 (d, J6 .2 Hz), (together 3H), 1.44 (3H, t, J7.2) Hz), 2.31 (3H, s), 2.95 - 3.00 (ÍH, m), 3.25 - 3.64 (2H, m), 6.53 (s), 6.56 (s) ppm. (g) 2-. { (3S, 4R) -4 - [(1-ethyl-5-methylpyrazol-3-yl) carbonylmethyl] -3- [(R) -1-tertiary butyl-dimethylsilyloxyethyl] -2-oxoazetidinyl} -2- (Normal tri-butyl-phosphoranylidene) allyl acetate. The (2R and 2S) -2-. { (3S, 4R) -4- [(1-ethyl-5-methylpyrazol-3-yl) carbonylmethyl] -3- [(R) -1-tertiary butyl-dimethylsilyloxy-ethyl] -2-oxoazetidinyl] -2-hydroxyacetate of allyl (crude from the previous preparation) in dry tetrahydrofuran (125 milliliters) under argon, cooled to -20 ° C, and treated with 2,6-lutidine (1.98 milliliters), followed by thionyl chloride (1.24 milliliters). The mixture was stirred at -20 ° C for 30 minutes, and then allowed to warm to room temperature and filtered, washing the residue with tetrahydrofuran (20 milliliters). The filtrate was evaporated in vacuo, toluene (70 milliliters) was added, and it was removed in vacuo, and the residual oil was dried in vacuo. The oil was then recovered in 1,4 dioxane (40 milliliters) under an argon atmosphere, and treated with normal tributyl phosphine (3.11 milliliters). The mixture was stirred for 1 hour. Then 2,6-lutidine (1.59 milliliters) was added, and the mixture was stirred for another 30 minutes. The mixture was diluted with ethyl acetate, washed with water, then with brine, and dried (gS? 4). After removing the ethyl acetate, the crude product was chromatographed on silica gel, eluting with ethyl acetate / hexane mixtures, to give the phosphorane, which was used in the next step. (h) 2-. { (3S, 4R) -4- [(1-ethyl-5-methylpyrazol-3-yl) carbonylmethyl] -3- [(R) -1-hydroxyethyl] -2-oxoazetidinyl} -2- (tributyl normal-phosphoranilidene) allyl acetate. The phosphorane prepared above was recovered in 1,4-dioxane (60 milliliters), and treated with 5M HCl (20 milliliters). After 1 hour, the mixture was carefully treated with approximately 40 milliliters of saturated aqueous NaHCO 3, followed by solid NaHCO 3, until the pH was slightly alkaline. Saturated brine was added, and the mixture was extracted twice with ethyl acetate. The combined extracts were dried (gS? 4) and evaporated, the residue was chromatographed on silica gel, eluting with ethyl acetate / hexane mixtures, to give the hydroxy compound, (2.60 grams) umax (CH2Cl2). ) 3454, 1741, 1667, 1606, 1448, 1403, 1379, 1155, 1087, 953, and 811 cm "1. (i) (5R, 6S) -6- [(R) -1-hydroxyethyl] -2- (l-ethyl-5-methyl-pyrazol-3-yl) carbapen-2-em-3-carboxylic acid allyl. The 2-. { (3S, 4R) -4- [(1-ethyl-5-methylpyrazol-3-yl) -carbonylmethyl] -3- [(R) -1-hydroxyethyl] -2-oxoazetidinyl} -2- (normal tributyl-phosphoranylidene) allyl acetate (2.6 grams), in toluene (120 milliliters), containing hydroquinone (20 milligrams), heated under reflux in an argon atmosphere for 4 hours, allowed to stand for 64 hours , and then heated under reflux for another 2 hours. The mixture was cooled, and then loaded onto a column (4.5 x 12 centimeters) of silica gel (particle size 0.040 to 0.063 millimeters), eluting with ethyl acetate / hexane mixtures.; 1: 1; 6: 4; 7: 3; 8: 2; 9: 1 (250 milliliters of each), followed by ethyl acetate. This gave the carbapenem (436 milligrams), - uma? (CH2C12) 3604, 2976, 1774, 1716, 1600, 1546 1311, 1189 cm "1, -? Max (EtOH) / nm 321.5 (e 14,856), d (CDCl 3) 1.36 (d, -76.3Hz), 1.39 ( t, 7.3 Hz) (together 5H), 1.80 (ÍH, d, J5.0 Hz), 2.28 (3H, s), 3.19 (ÍH, dd, J2.7 &6.7 Hz), 3.28 (ÍH, dd, J9.0 &18.6 Hz), 3.60 (ÍH, dd, J9.9 &18.5 Hz), 4.08 (2H, q, J7.3 Hz), 4.16 - 4.30 (2H, m), 4.68 -4.90 (2H , m), 5.27 (HH, m, approximately d, Jca, 12Hz), 5.46 (m, approximately d, Jca, 17Hz), 5.93 - 6.08 (HH, m), 7.00 (HH, s) ppm, - [Found m / z 345.1693, C1 H23N3O4 requires / z 345.1689]. (j) (5R, 6S) -6- [(R) -1-hydroxyethyl] -2- (l-ethyl-5-methyl-pyrazol-3-yl) carbapen-2-em-3-carboxylate sodium. Allyl (5R, 6S) -6- [(R) -1-hydroxyethyl] -2- (l-ethyl-5-methylpyrazol-3-yl) carbapen-2-em-3-carboxylate (267 milligrams) in dichloromethane (3 milliliters) and ethyl acetate (3 milliliters) under argon, was treated with sodium 2-ethylhexanoate (183 milligrams), followed by triphenyl phosphine (24 milligrams), followed by tetrakis (triphenyl phosphine) palladium (0) (35 milligrams), and the mixture was stirred for 45 minutes. Then diethyl ether (100 milliliters) was added, and after stirring for 90 minutes, the mixture was centrifuged. The residual solid was dried under a stream of argon, and then in a desiccator. The solid was then recovered in water containing sodium chloride, and passed through chromatography on DIAION HP20SS resin, eluting with water, followed by water / tetrahydrofuran mixtures; tetrahydrofuran at 1 percent, 2 percent, and 3 percent. The fractions were monitored by high performance liquid chromatography, and those containing the product were combined, reduced in volume, and freeze-dried to give (5R, 6S) -6- [(R) -1-hydroxyethyl ] -2- (L-ethyl-5-methylpyrazol-3-yl) carbapen-2-ene-3-carboxylate sodium as a solid (168 milligrams), - ma? (KBr) 1761, 1608, 1577, 1381, 1225 cm "1;? Ma? (H20) / nm 298 (e 8.531); d (D20) 1.2? (D, Jca. 6 Hz), 1.27 (d, Jca. 1 Hz) (together 5H), 2.23 (3H) , s), 3.17 (2H, approximately d, Jca.9 Hz), 3.44 (HI, dd, J2.9 &6.0 Hz), 4.04 (2H, q J7.3 Hz), 4.15-4.25 (2H, m ), 6.4K1H, s) ppm.

Claims (10)

1. A compound of the general formula (I) ? where R is: wherein: Ra is hydrogen, optionally substituted alkyl (from 1 to 6 carbon atoms), or optionally substituted aryl; R ^ is hydrogen, optionally substituted alkyl (from 1 to 6 carbon atoms), or optionally substituted aryl; or Ra and R ^ together form an optionally substituted 5 or 6 membered heterocyclic ring, with or without additional heteroatoms; R is alkyl (of the β carbon atoms) which is unsubstituted or substituted by fluorine, a hydroxy group which is optionally protected by an easily removable hydroxy protecting group, or by an amino group which is optionally protected by an amino protecting group easily removable; R is hydrogen or methyl, - and RJ is selected from the group consisting of (a) a group of the formula: wherein Ri is hydrogen or alkyl (of the ß carbon atoms), R2 is hydrogen, alkyl (of 1 to 6 carbon atoms) optionally substituted by halogen, alkenyl (of the ß carbon atoms), alkoxy (from 1 to 6 carbon atoms) -carbonyl, aryl, or heteroaryl, R3 is hydrogen, alkyl (of the ß carbon atoms), or alkoxy (of the ß carbon atoms) -carbonyl, and R4 is a pharmaceutically acceptable ester-forming group, and (b) a group of the formula CH (Ra) O.CO.Rb, wherein R is hydrogen, alkyl (of 1 to 6 carbon atoms), cycloalkyl (of 3 to 7 carbon atoms), methyl, or phenyl; and Rb is alkyl (of 1 to 6 carbon atoms) -cycloalkyloxy (of 3 to 7 carbon atoms), or alkoxy (of 1 to 6 carbon atoms) -alkyl (of 1 to 6 carbon atoms).

2. (5R, 6S) -2- (1-ethyl-5-methyl-1, 2-pyrazol-5-yl) -6- [(IR) -1-hydroxyethyl] carbapen-2-em-3-carboxylate of 2-ethoxy-carbonyl-E-but-2-enyl.

3. (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2- (l-ethyl-5-methyl-pyrazol-3-yl) carbapen-2-em-3-carboxylate, 1-methyl -cyclohexyloxycarbonyloxymethyl.

4. (5R, 6S) -2- (1-ethyl-5-methylpyrazol-3-yl) -6- [(IR) -1-hydroxyethyl] carbapene-2-em-3-carboxylate of 2-methoxyprop-2 -carbonyloxymethyl.

5. A pharmaceutical composition comprising an antibiotic compound according to any of the preceding claims, together with a pharmaceutically acceptable carrier or excipient.

6. A method for the treatment of bacterial infections in humans and animals, which method comprises administering a therapeutically effective amount of an antibiotic compound according to any of claims 1 to 4.

7. The use of a compound according to any of claims 1 to 4, for the manufacture of a medicament for the treatment of a bacterial infection.

8. A process for the preparation of a compound of the formula (I) according to claim 1, which process comprises treating a corresponding compound of the formula (I), wherein R is an alkali metal cation, with a compound of the formula (i) or (ii): XCH (Ra) O.CO.Rb (ii) where X is an output group.

9. A process for the preparation of a compound of the formula (I) according to claim 1, which process comprises subjecting a compound of the formula (II): (II) where R, R, and R? are as defined hereinabove, R3 is an easily removable carboxy protecting group, X is oxygen or a group PRR5R6, and R4, R5 and R6 may be the same or different, and is each an alkyl group (from 1 at 6 carbon atoms) optionally substituted, or an optionally substituted aryl group, at carbapenem ring forming conditions; and subsequently, and if necessary, perform any or all of the follo steps: remove any protective groups; converting a first group R1 comprising a hydroxyl substituent, into an additional R1 group comprising an amino or fluoro group, - converting the product into a salt; and esterify the product.

10. A process for the preparation of a compound of the formula (I) according to claim 1, which process comprises reacting a compound of the formula (X): (X) wherein R1 and R2 are as defined hereinabove, RJ is an easily removable carboxy protecting group, and X is an leaving group, with a compound of the formula (XI): MR (XI) wherein M is a metallo group, and R is as defined above in the present; in a cross coupling reaction in the presence of a cross coupling reaction catalyst selected according to the identity of M, and then and if necessary, removing any protecting group, and / or esterifying the product. SUMMARY A compound of the general formula (I), wherein R is (a), - wherein Ra is hydrogen, optionally substituted alkyl (from 1 to 6 carbon atoms), or optionally substituted aryl; RQ is hydrogen, optionally substituted alkyl (from 1 to 6 carbon atoms), or optionally substituted aryl; or Ra and Rβ together form a 5- or 6-membered heterocyclic ring optionally substituted with or without additional heteroatoms; R is alkyl (from 1 to 6 carbon atoms) which is unsubstituted or substituted by fluorine, a hydroxy group which is optionally protected by an easily removable hydroxy protecting group, or by an amino group which is optionally protected by a protecting group of easily removable amino; R is hydrogen or methyl, - and RJ is selected from the group consisting of (a) a group of the formula (i), wherein Ri is hydrogen or alkyl (of 1 to 6 carbon atoms), R2 is hydrogen , alkyl (of 1 to 6 carbon atoms) optionally substituted by halogen, alkenyl (of 1 to 6 carbon atoms), alkoxy (of 1 to 6 carbon atoms) -carbonyl, aryl, or heteroaryl, R3 is hydrogen, alkyl (from 1 to 6 carbon atoms), or alkoxy (from 1 to 6 carbon atoms) -carbonyl, and R4 is a pharmaceutically acceptable ester-forming group, and (b) a group of the formula CH (Ra) O. CO.Rb, wherein Ra is hydrogen, alkyl (of 1 to 6 carbon atoms), cycloalkyl (of 3 to 7 carbon atoms), methyl, or phenyl; and R is alkyl (of 1 to 6 carbon atoms) -cycloalkyloxy (of 3 to 7 carbon atoms), or alkoxy (of 1 to 6 carbon atoms) -alkyl (of 1 to 6 carbon atoms), is useful in the treatment of bacterial infections. * * * * *