CS248749B2 - Production method of the 6-(subst.)hydroxymethylpenicilan acids - Google Patents

Description

The present invention relates to novel 6- (substituted hydroxymethylpenicillanic acids), their esters and pharmaceutically acceptable salts, to pharmaceutical compositions containing said compounds, to a process for their preparation and to their use as β-lactamase inhibitors and as intermediates for their production.

One of the most well-known classes of antibacterial agents that is widely used is the group of substances known as β-lactam antibiotics. These compounds are characterized by the presence of a core containing a 2-azetidinone (/ lactam ring condensed to either a thiazolidine or dihydro-1,3-thiazine ring. If the core contains a thiazolidine ring, the corresponding compounds are generally referred to as penicillins, whereas if the core contains dihydrothiazine ring, such compounds are referred to as cephalosporins.

Typical examples of penicillins commonly used in clinical practice are benzylpemcilin (penicillin G], phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin, typical examples of common cephalosporins are cephalothin, cephalexin and cephaloline.

Despite the widespread use and widespread acceptance of β-lactam antibiotics as valuable chemotherapeutic agents, however, these substances have the major disadvantage that some of them are not effective against certain microorganisms. It is believed that in many cases this resistance of a particular microorganism to a given β-lactam antibiotic is due to the microorganism being produced by β'-lactamase.

β-Lactamases are enzymes that cleave the β-lactam ring of penicillins and cephalosporins to produce products that do not show antibacterial activity. However, some substances have the ability to inhibit β-lactamase and when used in combination with penicillin or cephalosporin, this may increase the antibacterial activity of this penicillin or cephalosporin against certain microorganisms. An increase in antibacterial activity is reported when the antibacterial activity of the combination of a? -Lactamase inhibitor and a? -Lactam antibiotic is significantly higher than the sum of the antibacterial activities of the individual components.

Accordingly, the invention provides 1,1-dioxides of 6- (subst.) Hydroxymethylpenicillanic acids, and salts and esters thereof, which are useful both as D-lactamase inhibitors and as intermediates for the preparation of these inhibitors.

European Patent Application 50,805 describes compounds of formula III

where n is 0, 1 or 2,

R _a represents a cyano group or a carbonyl radical,

R ₂ is hydrogen, lower alkyl or halogen and

R ₃ represents a hydrogen atom or an easily hydrolyzable group which are useful as inhibitors / lactamases. The same application describes 6-oxopenicillanic acid esters corresponding to sulfoxides and sulfones, as well as a process for their use in the preparation of compounds of formula III by reaction with a phosphate of formula

М ₂ С == Р (С ₆ Н ₅ ) ₃ .

British Patent Application No. 2,053,220 A discloses, inter alia, certain 6-methylene-1,1-dioxopenicillanic acids and esters of formula III wherein n is 2 and R ₁ and R ₂ are each independently in each case a hydrogen atom, an optionally substituted alkyl group, an aryl group, an optionally substituted cycloalkyl group, an aralkyl group or an optionally substituted amino group, or both together with the carbon atom to which they are attached, form a three to seven membered carbocyclic or heterocyclic ring.

U.S. Pat. No. 4,287,181 discloses 1,1-dioxides and esters of certain 6-substituted penicillanic acids wherein the substituent at the 6-position is a radical of formula

OR ₄

AND

R _{4 -} CH wherein, inter alia, R ₃ represents a hydrogen atom or an alkanoyl group and R ₄ represents a hydrogen atom, a C 1 -C 4 alkyl group, a phenyl group, a benzyl group or a pyridyl group, these compounds being useful as β- lactamases.

The present invention discloses novel 6- (substituted hydroxymethylpenicillanic acid derivatives of formula II)

in which

R ¹ represents a radical R ^a or R ^b, wherein R ^a represents a carboxyl protecting group selected from the group consisting of tetrahydropyranyl, allyl, benzyl, 4-nitrobenzyl, benzhydryl, 2,2,2-trichloroethyl, t-butyl and phenacyl radical, and R ^b represents a hydrogen atom or an ester residue readily hydrolyzable in vivo, selected from the group consisting of a 3-phthalidyl residue, a 4-crotonolactonyl residue, a t-butyrolacton-4-yl residue, a residue of formula (-COCOR '),

II o

, / ϊ i ·;

CO COOR a

R ⁴

- CHOCOR ¹⁴ wherein each of R ⁴ and R ⁵ is each a hydrogen atom or a methyl group, R ⁶ is a C 1 -C 5 alkyl group and R ¹⁴ is a radical of formula

wherein X ₂ is a substituent at position 3 of the known / cephalosporin-type lactam antibiotic and R ¹⁵ is a substituent at position 6 or 7 of the known β-lactam antibiotic of the penicillin or cephalosporin type, with the above-mentioned penicillin residues being particularly preferred groups R ¹⁴ , in which R ¹⁵ represents

2-phenylacetamido, 2-phenoxyacetamido, D-2-amino-2-phenylacetamido, D-2-amino-2- (4-hydroxyphenyl) acetamido,

2-carboxy-2-phenylacetamido, 2-carboxy-2- (2-thienyl) acetamido, 2-carboxy-2- (3-thienyl) acetamido, D-2- (4-ethyl-2,3-dioxopiperazinocarbonylamino) - 2-phenylacetamido,

D-2- (4-ethyl-2,3-dioxopiperazinocarbonylamino) -2- (4-hydroxyphenyl Jacetamido) or

2,2-dimethyl-4-phenyl-5-imidazolidinon-1-yl,

R ¹⁸ is hydrogen, C 2 -C 5 alkanoyl, C 2 -C 5 alkoxycarbonyl, pyrazinecarbonyl, benzoyl, CF ₃ , CO or CONR ⁸ R ⁹ , one of R ¹² and R ¹³ is the hydrogen atom and the other of these are vinyl, C1-C4alkylsulfonyl, furyl, thienyl, N-methylpyrrolyl or N-acetylpyrrolyl, the remainder

CH (R ^{/ 1} ) NR ¹⁶ R ¹⁷ , —CNR ⁸ R ⁹ ,

S — CN ⁸ R ⁹ ,

II

NH

with the proviso that when R ¹² or R ^{13 is a} radical of formula

and p is 0, then R ^{7 is} not hydrogen or methyl, in which formulas m is 2 or 3, p is 0 or 1, t is 0, 1 or 2,

X 1 is sulfur, oxygen or NR ¹ ',

R ⁷ is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, allyloxy, hydroxyl, carboxyl, C 2 -C 5 alkoxycarbonyl, C 1 -C 5 alkylcarbonyl, phenyl benzyl, naphthyl, pyridyl, NR ⁸ R ⁹ , CONR ⁸ R ⁹ , NHCOR ¹⁰ , nitro, chloro, bromo, trifluoromethyl or NR ⁸ R ⁹ , CONR ⁸ R ⁹ , NHCOR ¹⁰ , nitro, chloro, bromo, trifluoromethyl or the radical NR ^8,

R ⁸ and R ⁹ are each independently hydrogen, C 1 -C 4 alkyl, phenyl or benzyl,

R 10 represents C 1 -C 4 alkyl, trifluoromethyl or phenyl;

R is hydrogen, methyl, ethyl or acetyl group, and R16 _{and R17,} b _u d independently of one another are hydrogen, alkyl having 1 to 4 carbon atoms or a hydroxyalkyl group with 2-4 carbon atoms or R ^LFI and R ' ⁷ together with the nitrogen atom to which they are attached form pyrrolidino, piperidino, morpholino, thiomorpholino or 4-methylpiperazino, and their pharmaceutically acceptable salts and salts on the carboxyl group.

Compounds of formula II * are generally useful as chemical intermediates for the preparation of the corresponding 6- (subst.) Methylene-1,1-dioxopenilcianates described in our related Czechoslovak patents 248,733,248,746,248,148.

Additionally, however, those compounds of the formula II 'wherein R' is as of thanks or said ester residue readily hydrolyzable in vivo, ^Rb are acceptable because of their inhibitory activity on / З-lactamase, particularly if used in association with the β-lactam antibiotic.

Particularly preferred compounds of formula (II *) are those wherein one of R ¹² and R ¹³ is hydrogen and the other is vinyl, 2-furyl, 2-thienyl, N-methylpyrrol-2-yl, N-acetylpyrrol-2-yl, 3-hydroxy-2-pyridyl 244849;

a group ;; 4-Methoxy-2-pyridyl group; the rest of the formula

and R ^s; zenamenaxatom · hydrogen or acetylo-. group. .

Particularly preferred carboxy protecting groups in the meaning of the symbol R ^ ^and also for the bromo allylovárskupinaj -benzylovS, terc.butylováx group ¹ and 2; 2 .2-tť.ichlorethylová group being especially preferred is allyl fk given the relatively easy implementation and removal.

Especially preferred ester groups which are readily hydrolyzable in vivo, i.e. as R ^b as defined above, are preferred groups.

CH3 R ^ c = c- 1 6 , -CVCOR 1 and -COCO jR у 0 .0 Rr. '5- ’ R II 0

and in particular those in which R ⁴ and R ⁵ represent -; R @ 2 is as defined above.

In addition to a method for producing compounds of formula (I), the invention also provides a method of treating a bacterial infection in a mammal, including a human, comprising administering to a mammal in need thereof an antibacterially effective amount of a compound of the formula wherein R ¹ is R ^b .

Further, the invention provides pharmaceutical compositions for the treatment of bacterial infections in mammals, including humans, comprising an antibacterially effective amount of a compound of formula (1Г) wherein R ¹ is a residue of R ^b .

Compounds of general formula ΙΓ, in 4 cte. R ¹ · R REM represents the above defined ^Rb are useful as inhibitors of ^{1, 1} enzyme β-lactamases. In this way, they are mentioned *. The compounds increase the efficacy of the .beta.-lactam antibiotics ¹ (penicillins and aacephalosporins), in particular against those microorganisms which are resistant to ¹ 'or ¹ '; ^: Partially resistant and / towards / Maktamovémuuantibiotiku also due to n; dukoe of enzymes (β-lactamasi) - 'decomposing! or partially degrading the .beta.-lactam antibiotic. In this way, the spectrum of activity of D-lactam antibiotics is increased.

The invention also discloses a method of treating bacterial infection in a mammal, including a human, comprising: that the mammal in need of such 'treatment used herein, & ^ U- ¹ active antibacterial amount rpenic-řlinw eefaldspo- ¹ or taurine;'některé'z particularly below trvedených substances and compounds: ^obeei№ho: Formula ΙΓ in množstvrinhibUjícím-lactamase.

Although the compounds of the invention I teach them increase .aktivitu ^ -laktaniových aiitibiotik generally ¹ výhodoir combine with penicillata · nem cefalospOTinem or in clinical practice has been established; / ¹ as - is; amoxicillin, ampicillin, spalcilins azlocilinV azthreonam, bacampioillin,::> carberiicillin, carberlicillin ^L mdanyl, carbenicillin-phenylhefaclor, · cefadroxil, cephaloram,; cefamandole, 'cefamandole naphtha,' cefaparol, cefatrizine, cefazoline, cefbuperazone,: cefonicide, cefmenoxime, cefodizime, cefoperazone, cephoramide; cefotaxime cefioth, cefoxitin, cefpiramide, cefpirom, cefsulodin, ceftazidime, ceftizoxime, ceftriaxone cefuraxime, cefacetril, cephalexin cephaloglycine, cephaloridine, cephalothin; cefapirin, cefradine, cyclacilin, epicillin, furazlocilin, hetacillin, lenampicillin, levopropylcillin, mecilinam, meslocillin, penicillin G, penicillin V, phenethicillin, piperacillin, pirbenicillin, pivampicillin, sarmoxicillin; isarpieiliniHunciniii / otheripicillin and ticarcilin, including their pharmaceutically acceptable salts.

The invention further provides combinations of the .beta.-lactam inhibitors according to the invention

7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3- (5,6-dihydro-4-pyrindenium) methyl-3-cephem-4-carboxylate,

7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3- (N-methylpyrrolidinium) methyl-3-cephem-4-carboxylate; and

7- [D- (2- (4-carboxy-5-imidazolecarboxamido) -2-phenylacetamido] -3- [4- (2-sulfonatoethyl) pyridinium] -3-cephem-4-carboxylic acid.

Although the compounds of the invention may be administered separately from the β-lactam antibiotic, combined dosage forms are preferred. The pharmaceutical composition, whether orally or parenterally, comprises the [beta] -lactamase inhibitor of the invention and the [beta] -lactam antibiotic in a weight ratio of 1: 3 to 3: 1, the total amounts of these substances in the composition sufficient to cope with bacterial infection. a mammal in a single or, more usually, multiple administration.

Compounds of the invention wherein one of the radicals R ¹² and R ¹³ contains a basic nitrogen atom may form acid addition salts. The invention includes such salts with pharmaceutically acceptable acids. Examples of such acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, malic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, sugar acid, benzenesulfonic acid, p-toluenesulfonic acid, chlorobenzenesulfonic acid and 2-naphthalenesulfonic acid.

Furthermore, those compounds of the invention wherein R ¹ is hydrogen form cationic salts, and such salts with pharmaceutically-acceptable cations are also within the scope of the invention. Examples of such cations are sodium, potassium, ammonium, calcium, magnesium and zinc, as well as amine cations derived from amines such as diethanolamine, choline, ethylenediamine, ethanolamine, N-methylglucamine and procaine.

The invention relates to penicillanic acid derivatives which correspond to the formula

c / - / _? Binding of a substituent with a dotted line (III-III-III-III) to a bicyclic nucleus means that the substituent is below the plane of the nucleus and is said to be in the "configuration". In contrast, attachment of a substituent to a bicyclic nucleus through a reinforced line () means that the substituent is above the plane of the nucleus, the latter arrangement being referred to as the ^-configuration. herein means that the substituent may be either in the α-configuration or in the β-configuration.

The present invention relates to a process for the preparation of the compounds of the above formula (II) and their salts, characterized in that the compound of the formula (IX):

R ¹ has the above meanings except hydrogen, is reacted with an equimolar amount of alkylmagnesium halide having 1 to 4 carbon atoms and an aldehyde of formula R ¹² R ¹³ CO, the above-mentioned halide is appropriate chloride, bromide or iodide and R ¹² and R ¹³ are as defined above, in an ethereal solvent at a temperature of from -80 ° C to 25 ° C, to give the product of formula II "

in which

R ^1, R ¹² and R ¹³ are as defined above, followed, к preparing compounds of formula ΙΓ wherein R ¹⁸ is other than hydrogen, to the product with an acyl chloride or acyl bromide of the formula R ¹⁸ C 1 or R ¹⁸ Br, wherein R ¹⁸ is as hereinbefore defined, or the corresponding acid anhydride, in the presence of an equimolar amount of a tertiary amine and in the presence of an inert organic solvent, and the resulting penicillanic acid derivative to 244849 is optionally converted to its pharmaceutically acceptable acid addition salt or cationic salt.

The process according to the invention is possible. described by the following reaction scheme:

In the process of the invention, the corresponding 6α-bromo-1,1-dioxopenicillanic acid ester of formula (IX) is converted to the corresponding Grignard reagent by reaction with an equimolar amount of low molecular weight Grignard reagent such as methylmagnesium bromide, ethylmagnesium chloride or n-butylmagnesium iodide. in an ether solvent, preferably tetrahydrofuran or ethyl ether, at a temperature of from -80 to 25 ° C, usually at a temperature of -78 ° C. After stirring for several minutes, an equimolar amount of the corresponding aldehyde of formula (I) is added

R12R13 Cl2 ₌ O and stirring is continued until the reaction is substantially complete, which usually takes about 10 minutes to 4 hours (at the same temperature). Desired ester. of formula II 'is then isolated by standard methods. For example, an aqueous ammonium chloride solution and the product are added to the reaction mixture. is extracted with a water-immiscible solvent. The resulting product of formula (II) is then further purified, for example by chromatography on silica gel.

Products. of formula (II), obtained as described above, are esters in which R 1 is either a carboxyl function protecting group R ^a , as defined above, or an ester residue readily hydrolyzable in vivo R ^b , also defined above.

Those esters in which R 1 is a radical R ^a , se. optionally converted to the corresponding carboxylic acids (Rb = hydrogen). However, if desired, the carboxylic acids of formula (II) can be converted to the corresponding compounds in which R 1 represents an ester residue readily hydrolyzable in vivo.

Thus, an ester of the general formula ΙΓ (R 1 = R a), where R a is a carboxyl-protecting group as defined above, can be converted to the corresponding acid or ester of the general formula ΙΓ (R 1 = R b) wherein R b is a hydrogen atom or . Typically, a carboxyl function protecting group is removed from a compound of formula ΙΓ (R 1 = R a) to give the corresponding carboxylic acid. The particular method chosen to remove the protecting group depends on the nature of the ester moiety Ra, but the choice of a suitable method will not cause problems to those skilled in the art.

How . As mentioned above, a particularly preferred carboxyl protecting group is Ra allyl. Although this group can be cleaved with mild acidic or alkaline hydrolysis to a satisfactory result, a particularly preferred method of cleaving is the use of a soluble palladium (O) complex, namely tetrakis (triphenylphosphine) palladium (0) as a catalyst.

This method has already been described by Jeffery and Mc Comble in J. Org. Chem., 47, 587-590 (i982). Typically, the allyl ester in an inert solvent such as ethylene dichloride, chloroform or ethyl acetate is mixed with a catalytic amount of tetrakis (triphenylphosphine) palladium (O), for example about 5 to about 5, under a nitrogen atmosphere. % by mol of this complex, based on. to an allyl ester, and about an equivalent weight amount of triphenylphosphine.

To this mixture is added sodium or potassium salt of 2-ethylhexanoate in equimolar amount based on the starting allyl ester, and the resulting mixture is stirred at room temperature until precipitation of the desired salt is complete.

For example, salts of formula (I) wherein R ¹ is sodium or potassium. The reaction is usually complete in about 2 to 20 hours. The resulting salt is then isolated, for example by filtration.

Compounds of formula (II) wherein R 1 is an ester-forming moiety readily hydrolyzed in vivo can be prepared directly from the corresponding compounds wherein R 1 is hydrogen using conventional esterification techniques. The particular embodiment depends on the exact structure of the ester-forming moiety, but the choice of a suitable method will not cause difficulties for the skilled person. When R 1 is a radical selected from the group consisting of a 3-phthalidyl radical, a 4-crotonolactonyl radical, a χ-butyrolacton-4-yl radical and a radical of formulas

R4

I —COCOR ⁶

AND

R5

and R4 —COCOOR ⁶ R5 where R4, R5 and ^R6 are as defined above, it is possible to prepare such compounds al- by the corresponding compound of the invention

wherein R ¹ is hydrogen, a halide of formula

R ^b Q is a 3-phthalidyl halide, 4-crotonolactonyl halide, γ-butyrolacton-4-yl halide or a compound of formula г f · · 6. Iз

QCOCOR or qCoCQOR

IF15

R ^b R where

Q represents a halogen atom and R4, ^R5 and ^R6 are as defined above. The terms "halogen" and "halide" refer to chlorine, bromine and iodine atoms, and derivatives thereof. The reaction is typically carried out by dissolving a salt of a compound of formula ΙΓ in which R 1 is hydrogen in a suitable polar organic solvent, for example Ν, Ν-dimethylformamide, and adding about one mole equivalent of the corresponding halide of formula R ^b Q. After the reaction is complete, the product is isolated by standard techniques. Often it is sufficient to dilute the reaction mixture with excess water, extract the product with a water-immiscible organic solvent and then evaporate the solvent. Commonly used starting material salts are alkali metal salts such as sodium and potassium salts, salts with tertiary amines such as triethylamine, N-ethylpiperidine, Ν, dim-dimethylaniline and N-methylmorpholine, and quaternary ammonium salts such as tetrabutylammonium and tetramethylammonium salts . The reaction is carried out at a temperature in the range of about 0 to 100 ° C. usually at about 25 ° C. The reaction time required to complete the reaction varies depending on a number of factors, such as the concentration of the reactants and the reactivity of the reagents. Thus, as for the halogen derivatives, iodide reacts faster than bromide and it reacts faster than chloride. When using a chloro derivative, it is sometimes advantageous in practice to add up to one mol equivalent of an alkali metal iodide, thereby accelerating the reaction. In view of the above factors, reaction times of from about 1 to about 24 hours are generally employed.

The starting aldehydes of formula r12r13co R1 ² and R1 ³ are as defined above, are either commercially available or can be prepared from readily available starting materials by methods known in the art, e.g.

1. Oxidation of the corresponding primary alcohols described above as necessary precursors of Wittig reagents using, for example, oxidizing agents such as potassium dichromate, a mixture of chromic acid and pyridine, catalytic oxidation in the presence of noble metals and manganese dioxide.

2. Reaction of the corresponding methyl-substituted aromatic hydrocarbon, for example with selenium dioxide.

3. Reduction of the corresponding C 1 -C 4 alkoxycarbonylderivatives in the alkoxy moiety at low temperature in the presence of an ethereal solution.

18 pouštědla. Examples of suitable metal hydrides are lithium aluminum hydride and diisobutylaluminum hydride,

4. Reaction of the respective aromatic hydrocarbon precursor with n-butyllithium and dimethylformamide.

The starting 6a-bromo-1,1-dioxopenicillanic acid esters of formula IX are usually prepared from 6,6-dibromo-1,1-dioxopenicillanic acid by reaction with sodium bicarbonate and sodium bisulfite, followed by acidification. The resulting 6α-bromo-1,1-dioxopenicillanic acid is then converted to the ester of formula IX.

As noted above, the compounds of formula II ', wherein R ¹ is hydrogen, and salts thereof, in combination with β-actam antibiotics, exhibit synergistic activity in in vitro antibacterial assays. This efficacy is demonstrated by the measurement of the minimum inhibitory concentrations (MIC) in µg / ml against a number of microorganisms. The following section describes the procedure recommended by the International Collaborative Study on Antibiotic Sensitivity Testing [Ericcson and Sherris, Acta, Pathologica et Microbiologia Scandinav. Supp. 217, section B: 64-68 [1971]], using brain-heart infusion agar and repeated inoculation equipment.

Overnight culture in test tubes is diluted 100-fold and used as a standard inoculum (20,000 -10 10 cells per approximately 0.002 ml is plated on agar surface; each dish contains 20 ml brain and heart infusion agar). 12-fold dilutions of the test substance, with an initial test compound concentration of 200 gg / ml, were evaluated after incubation for 18 hours at 37 ° C, with individual colonies disregarded. the lowest concentration of test compound or combination of compounds capable of causing complete inhibition of growth of the organism when evaluated with the naked eye.

Those compounds of formula (II) wherein R &^lt; 1 > is hydrogen, and salts thereof, in combination with known [beta] -actam antibiotics are useful as industrial antimicrobial agents, for example in water treatment, sewage and sludge treatment, paint and wood protection, even in topical applications as disinfectants. When using the disclosed compounds for such applications, it is often advantageous to mix the active ingredient with a non-toxic carrier such as a vegetable or mineral oil or a softening cream. Similarly, they may be dissolved or dispersed in liquid diluents or solvents such as water, alkanols, glycols or mixtures thereof. In most cases, it is expedient to use concentrations of the active ingredient ranging from about 0.1 to 10% by weight of the total composition.

As also mentioned above, the compounds of the general formula ΙΓ, where R ¹ is a radical R ^b , are of much greater importance as potent inhibitors of microbial / Mactamas. In this way, these compounds increase the antibacterial activity of [beta] -actam antibiotics (penicillins and cephalosporins) against a number of microorganisms, in particular against producing microorganisms (Mactamase.). The MIC of the antibiotic itself and the compound of the formula IT where R ¹ is hydrogen, and these values are then compared to the MIC values for the combination of the antibiotic with the compound of the formula II 'where R ¹ is hydrogen. the combination is significantly higher than would be expected based on the efficacy of the individual components, which is considered an increase in efficacy.

The MIC values of said combinations are measured using the method described by Barry and Sabath c, "Manual of Clinical MicrobiolO gy", ed. Lenette, Spaulding and Truant, 2nd edition, 1974, American Cociety for Microbiology.

Compounds of formula ΙΓ wherein R ¹ represents a hydrogen atom or an ester moiety readily hydrolyzable in vivo, enhance the antibacterial activity of β-actam antibiotics in. in vivo, i.e., they reduce the amount of antibiotic required to protect the test mouse from the otherwise lethal inoculum of certain β-lactamase producing bacteria. To determine such potency, mice are induced by acute · experimental infections by intraperitoneal inoculation with a standardized culture of the test organism suspended in · · 5% porcine gastric mucin.

Severity The infection is standardized so that the mouse receives a lethal dose of the organism. (lethal dose means the minimum inoculum of the organism required to reliably kill · 100% of infected untreated control mice). Groups of infected mice are then dosed orally or intraperitoneally with varying doses of test compound in combination with an antibiotic. After completion of the test, the efficacy of this combination is determined by counting the surviving animals in the dose-treated group. combination.

Efficacy is expressed as a percentage of surviving animals at a given dose or calculated as a PD 50 value (dose protecting 50% of the test animals from infection).

The ability of said compounds of formula II 'to enhance the efficacy of β-lactam antibiotics against β-lactamase-producing bacteria makes these compounds suitable for co-administration with (--activating antibiotics) in the treatment of bacterial infections in mammals, especially humans. when the compound of the invention is admixed with a β-lactam antibiotic or when R ^b is CH (R ⁴ ) OCOR ¹⁴ where R ⁴ and R ¹⁴ are as defined above, the lactam antibiotic chemically binds to the compound of the invention, thereby Alternatively, the compound of the invention may be administered as a separate agent during treatment with the β-lactam antibiotic.

In some cases, it is preferred to pre-medicate the patient with a compound of the invention prior to initiation of treatment with the β-lactam antibiotic.

When using a compound of formula II * in which R ¹ is a residue of R ^b as defined above to enhance the potency of the β-lactam antibiotic, the mixture of this compound with the β-lactam antibiotic or the compound of the invention itself when R ^b means the radical CH (R ⁴ ) OCOR ¹⁴ , preferably applied in the form of a composition comprising standard pharmaceutical carriers or diluents.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier, a β-lactam antibiotic, and / or the aforementioned compound of formula ΙΓ normally contains about 5 to 80% by weight of a pharmaceutically acceptable diluent.

By combining the above compounds of the invention with another β-lactam antibiotic, these compounds can be administered orally or parenterally, i.e., intramuscularly, subcutaneously, or intraperitoneally. Although the dosage used in human medicine is ultimately determined by the attending physician, normally the ratio of the daily doses of the compound of formula ΙΓ, where R ¹ is the radical R ^b , and the β-lactam antibiotic, is in the range of about 1: 3 to 3: Further, when using a compound of the invention in combination with a β-lactam antibiotic, the daily oral dose for each component normally ranges from about 10 to 200 mg per kilogram body weight, and the daily dose of each component for parenteral administration is normally ranges from about 10 to 40 mg / kg body weight. These daily doses are usually administered in several divided doses. In some cases, the attending physician may prescribe doses beyond those limits, if necessary.

It is understood that some β-lactam compounds are effective when administered orally or parenterally, while others are only effective when administered parenterally. Thus, if a compound of the invention is to be used simultaneously (i.e., in a mixture) with a? -Lactam antibiotic effective only for parenteral administration, a combination formulation suitable for parenteral administration will be required. If the compound of the invention is to be used concurrently (in admixture) with a β-lactam antibiotic effective for both oral and parenteral administration, combination formulations suitable for either oral or parenteral administration may be prepared. Furthermore, it is possible to orally administer the compositions containing the active compounds according to the invention, while simultaneously administering the [beta] -lactam antibiotic. It is also possible to administer parenterally the compositions containing the above-mentioned compounds of the invention and at the same time orally administer the [beta] -lactam antibiotic.

The invention is illustrated by the following non-limiting examples. Proton and C ¹³ nuclear magnetic resonance spectrum in the examples were measured at 60, 90, 250 and 300 MHz using a solution of the product in deuterochloroform, deuterium oxide, or acetone-d perdeuterodimeethylsulfoxidu, and peak positions are expressed in ppm versus tetramethylsilane. Signal shapes are indicated by the following abbreviations:

s singlet d doublet dd doublet of doublets t triplet q quartet m multiplet w wide signal

Example 1

Allyl-6a- (N-methylpyrrol-2-yl) hydroxymethyl-1,1-dioxopenicillanate

520 mg (1.48 mmol) of allyl-6α: -bromo-1,1-dioxopenicillanate are dissolved in 10 ml of dry tetrahydrofuran, the solution is cooled to -78 ° C and 0.52 ml of a 2.85 M solution is added thereto. of methylmagnesium bromide in tetrahydrofuran and the mixture was stirred at -78 ° C for 5 min. After addition of 162 mg (0.16 ml) of N-methylpyrrole-2-carboxaldehyde, stirring was continued at -78 ° C for 20 minutes, then the mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo. 466 mg of crude product is obtained, which is purified by chromatography on silica gel using a 9: 1 mixture of chloroform and ethyl acetate as eluent. This gave 180 mg (32%) of the pure title compound.

Ή-NMR (deuterochloroform, δ values in ppm):

1.4 (s, 3 H),

1.62 (s, 3H);

3.68 (s, 3H);

4.0-4.4 (s, 1 H),

4.42 (s, 1 H),

4.5-4.8 (m, 3H);

4 8 7 4 8

5.0-6.0 (m, 4H),

6.0-6.7 (m, 2H).

Example 1 and 2

The procedure described in Example 1 was repeated using the corresponding aldehyde of the general formula

R ¹³ CHO

The corresponding compounds of general formula are obtained

R ^j3 yield _______________________ (%} _________

30 ......... П ³⁰

4 ..-, u ·

Cl í

COGl · ^

C ₆ H ₅ 78

22nd CH 73 i «’ -СН N ^: ' ⁴ ......—- /> ^{Z <} C ../ CCH ₂ №CH ₂ elution ¹ H-NMR (CDCl 3, reagent *> values of δ in ppm) AND 6 «- isomer: 1.4 (s, 0.39H), 1.5 (s, 2.61H), 1.62 (s, 0.39H), 1.7 (s, 2.61H), 3.0 (bs, 1H), 4.0-4.4 (m, 1 H), 4.45 (s, 1 H), 4.5-4.9 (m. 2H); 5.1-6.1 (m, 4H). 6.3-6.6 (m. 2H); 7.45 (m, cm), AND Mixture of 6a1, 8R- and 6a, 8S-isomers AND 1.4 (s, 3H); 1.60 (s, 3H); 2.50 and 2.60 (s, 3H), 4.1-4.4 (m, IH), 4.4 and 4.5 (s, 1H); 4.6-5.0 (m, 3H); 5.1-6.0 (m, 4H); 6.0-7.2 (m. 4H); AND 1.4 (s, 3H); 1.6 (s, 3H); 3.28 (bs, 1H), 3.8-4.2 (m, 1H), 4.35 (s, 1 H), 4.45-4.8 (m, 3H), 5.0-6.1 (m, 4H). 7.3 (s, 5H). В 1.3 (s, 3H), 1.55 (s, 3H), 4.04 (bs, 1H), 4.35 (s, 1H), 4.5-4.85 (m, 3H), 5.1-6.1 (m. 4H); 7.1-7.4 (m. 1H); 7.6 - 8.0 (m, 1H); 8.2- 8.7 (m, 2H); В 1.3 (s, 3H), 1.55 (s, 3H), 4.0 (m, 1 H), 4.35 (s, 1 H), 4. 4-6.8 (m, 3 H), 5.1 - 6.2 (m, 4H); 7.2-7.5 (m, 2H); 8.2-8.6 (m, 2H).

yield (%) eluent * '

Ή-NMR (deuterochloroform, δ values in ppm)

S0

1.25 (s, 0.75H), 1.35 (s, 2.25H),

1.55 (s, 3H), 3.3 (bs, 1H),

4.05 (dd, 1 H), 4.3 (s, 1 H),

4.3-4.8 (m, 3H);

5.0 - 6.2 (m, 4H)

6.8-7.4 (m, 3H),

CHa = CH

21 1.4 (s, 3H); 1.6 (s, 3H); 3.0 (bs, 1H), 3.7-4.0 (m, 1 H), 4.4-4.8 (m, 4H); 5.0, 6.3 (m, 6H); 25 D 1.36 (s, 1.5H), 1.40 (s, 1.5H), 1.60 (s, 1.5H), 1.65 (s, 1.5H), 3.7 (s. 3H), 4.0-4.5 (m, 2H). 4.4 (s, 1 H), 4.1-4.4.8 (m, 2H), 6.7 (s, 1H); 6.85 (s, 1H); 52 D 6a, 8S-isomer: 1.4 (s, 3H), 1.6 (s, 3H), 4.38 (dd, 1H), 4.43 (s, 1H), 4.67-4.75 (m, 2H), 4.76 (d, 1 H), 5.3-5.5 (m. 2H); 5.63 (d, IH); 5.85-6.05 (m, 1H); 7.4 (d, 1H); 7.8 (d, 1H); 6o, 8R isomer: 1.36 (s, 3H), 1.60 (s, 3H), 4.22 (d, 1H); 4.4 (s, 1H); 4.65 (m, 2H), 4.88 (s, 1H), 5.25-5.5 (m, 2H), 5.55 (d, 1 H), 5.8-6.0 (m, 1 H), 7.35 (d, 1 H), 7.75 (d, 1 H), 42 E 6a, 8S-isomer: 1.44 (s, 3H, 1.62 (s, 3H), 3.68 (bs, 1H), 4.31 (dd, 1H), 4.5 (s, 1H), 4.74 (d, 2H), 4.86 (d, 1H), 5.4 (m 3H), 5.9 (m, 1H), 7.5 (m, 3H), 8.02 (s, 1H), 8.14 (m, 2H); IC: 3,482, 1880 cm -1 57 AND Less polar 6a, 88 - somer: crude product (less polar 1.41 (s, 3H), 1.6 (s, 3H), 9 isomer) 4.45 (s, 1 H), less polar F 4.4-4.8 (m, 4H); isomer (more polar isomer) 5.2-5.6 (m. 3H); 8 5.7 - 6.3 (m, 1H), the more polar isomer 7.35 (t, 1 H), 8.85 (d, 2 H); More polar 6A, 8R isomer: 1.45 (s, 3H); 1.6 (s, 3H); 4.4 (s, 1H); 4.45 (dd, 1H); 4.7-4.9 (m, 2H); 4.95 (d, IH); 5.2-5.6 (m. 3H); 5.7-6.3 (m, 1H); 7.35 (t, 1 H), 8.85 (d, IH);

yield (%) eluent * '

R ¹³

1 H-NMR (deuterochloroform, δ in ppm)

N

W Kb)

Legend:

%, first fraction (one isomer),% second fraction (mixture of two isomers) 70: 30 isomer mixture first fraction:

1.4 (s, 3H); 1.6 (s, 3H);

42-4.4 (m, 2H),

4.5-5.0 (m, 3H);

5.1-6.1 (m, 6H);

7.6 (d, 1 H), 8.87 (d, 1 H),

9.23 (s, 1 H),

1.4 (s, 3H), 1.57 (s, 3H),

4.25 (m, 1H); 4.37 (s, 0.7H);

4.42 (s, 0.3H), 4.75 (m, 2H),

4.8 (d, 0.3H), 4.85 (d, 0.7H), 5.25-5.5 (m, 3H),

5.9 (m, 1 H), 8.52 (m, 2 H),

8.84 (m, IH),

1.4 (s, 1 H), 1.46 (s, 2 H),

1.6 (s, 1 H), 1.63 (s, 2 H),

4.12 (m, 1 H), 4.22 (m, 1 H),

4.41 and 4.46 (s, 1H),

4.6-4.8 (m, 2H);

4.95 (d, IH);

5.2-5.5 (m, 3H);

5.9 (m, IH)

6.95 and 7.05 (s, 1H);

7.28 and 7.36 (s, 1H),

1.38-1.40 (d, 3H), 1.56-1.57 (d, 3H). 4.20-4.40 (m, 2H), 4.59-4.72 (m, 2H), 4.86-4.88 (d, 0.5H), 5.04-5.06 (d) (0.5H), 5.26-5.42 5.55-5.62 5.82-6.00 7.50-7.86 7.90-8.08 (m, 1H), 9.02 - 9.10 (m, IH); IC: 1800 cm &^lt; -1 ^&gt; (m, 2H), (m, 1H), (m, 1H), (m, 1H), * eluents used in silica gel chromatography:

A - chloroform - ethyl acetate (9: 1)

B - ethyl acetate - chloroform (7: 3)

C - chloroform - ethyl acetate (19: 1)

D - Chloroform - methanol (19: 1)

E - chloroform

F - chloroform - ethyl acetate (1

G - ethyl acetate

1) ** '1-Diethoxymethylimidazole-2-carboxaldehyde was used as the starting aldehyde.

Example 3 dried and concentrated to give 171 mg (75 why) of a yellow crystalline product, Allyl-6- (N-acetylpyrrol-2-yl) acetoxymethyl-1,1-dioxopenicilate @ 1 H-NMR (CDCl3) .delta in ppm): 210 mg (0.51 mmol) of allyl-6- (N-acetylpyrrol-2-yl) hydroxymethyl-1,1-dioxopenicillanate are dissolved in 3 ml of tetrahydrofuran, 0.16 ml of acetic anhydride and 0.2 ml of pyridine are added, and The reaction mixture was diluted with water, extracted with methylene chloride, extracts 1.4 (s. 3H), 1.6 (s, 3H); 2.15 (s, 3H). 2.55 (s, 3H); 4.15-4.3 (dd, 1H), 4.4 (s. 1H).

46-4.8 (m, 3H),

5.1 - 6.0 (m, 3H);

6.1-6.6 (m, 2H);

6.6-7.4 (m, 2H).

Example 4

Using the procedure of the previous example, using 1.98 mmol of allyl-6-phenylhydroxy-4- (1,1,6-dihydro-1,1-dioxopenicillanate, 4.2 mmol of acetyl chloride and 0.4 ml of pyridine), 0.7 g (84%) of allyl-6-phenylacetoxymethyl-1,1-dioxopenicillanate as a yellowish gum.

Ή-NMR (deuterochloroform, δ in ppm):

1.3 and 1.4 (s, 3H),

1.62 (s, 3H);

2.08 and 2.2 (s, 3H),

4.2 (dd, 1 H),

4.4 (s. 1H).

4.5 (d, 1 H),

4.65 (d, 2 H),

6.25 (m, IH);

7.3 (m. 5H).

Example 5

Allyl-6- (1-methylimidazol-2-yl) acetoxymethyl-1,1-dioxopenicillanate

472 mg (1.23 mmol) of allyl 6- (1-methylimidazol-2-yl) hydroxymethyl-1,1-dioxopenicillanate are acetylated according to Example 3 to give 392 mg (75%) of the desired acetoxy compound as a mixture of two isomers.

Ή-NMR (deuterochloroform, δ values in ppm):

1.4 (s, 1.5H)

1.5 (s, 1.5H);

1.6 (s, 1.5H)

1.7 (s, 1 H),

2.2 (s. 3H),

3.7 (s, 1.5H);

3.75 (s, 1.5H), 4.0-6.0 (m, 8H),

6.3-6.5 (m. 1H);

6.8 (m, 1 H),

7.0 (m, IH).

Example 6

6- (2-Pyridyl) hydroxymethylpentilicanoic acid 1,1-dioxide

A. Benzyl-6- (2-pyrrolidinyl-hydroxymethyl-1,1-dlox openicllanate at room temperature) According to thin layer chromatography, the reaction mixture contained some sulfoxide, an additional 0.2 g of m-chloroperbenzoic acid was added and the mixture was stirred at room temperature. The reaction mixture was diluted with methylene chloride, washed sequentially with saturated sodium thiosulfate solution, water and saturated sodium bicarbonate solution, and the organic layer was concentrated in vacuo, the residue was taken up in ethyl acetate, washed with sodium bicarbonate solution, water and brine. The organic layer was dried over sodium sulfate and evaporated to give 330 mg of the desired benzyl ester as a brown oil which was purified by silica gel column chromatography to give 60 mg of a yellow oil, eluting with a 11: 9 mixture of ethyl acetate and hexane.

Ή-NMR (deuterochloroform, δ values in ppm):

1.25 (s, 3H).

1.52 (s, 3H);

4.1 (dd, 1 H),

4.5 (s, 1 H),

4.72 (d, IH);

5.5 (d, 2H).

5.8 (d, 1 H),

7.1-8.0 (m. 3H);

8.5 (m. 1H).

B. A suspension of 118 mg of 10% palladium on carbon catalyst in 10 ml of tetrahydrofuran and 4 ml of water was prehydrogenated under 20 psi of hydrogen for 20 minutes. To the resulting suspension was added 130 mg of the benzyl ester prepared above in Part A in 4 mL of the same mixture of tetrahydrofuran and water. The mixture was hydrogenated at 50 psi for 30 minutes, then an additional 129 mg of 10% palladium on carbon was added and hydrogenation at 50 psi was continued for 2 hours. The catalyst was filtered off, the solvent was evaporated in vacuo and the residue was partitioned between water and ethyl acetate. Lyophilization of the aqueous layer gave 85 mg of the desired acid.

Ή-NMR (deuterium oxide, δ values in ppm):

1.3 (s. 3H),

1.5 (s. 3H),

4.4 (s. 1H).

5.0 - 5.35 (m, 2H),

5.9 (d, 1 H).

IC (КВМесЬтка):

620, 1731, 3 407 cm ^-1 .

Example 7

Allyl-6- (2-thlazolyl) acetoxymethyl-1,1-1-dioxopenicilate

To a solution of 0.40 g of benzyl 6- (2-pyridyl) hydroxymethylpenicilate in 5 ml of methylene chloride was added 0.20 g of m-chloroperbenzoic acid, and the mixture was stirred at room temperature for 1 hour.

28

Using the procedure described in Example 3, 0.5 g (1.29 mmol) of allyl 6- (2-thiazolyl) hydroxymethyl-1,1-dioxopenicillanate (prepared in Example 2) was acetylated with 0.396 g (3.88 mmol) of acetic anhydride and 0.307. g (3.88 mmol) of pyridine in 5 mL of tetrahydrofuran. The reaction mixture was stirred at room temperature for 4 hours, then diluted with methylene chloride and washed with water until neutral (pH 6.0-6.5). The organic phase was dried over sodium sulfate and the solvent was evaporated. 0.688 g of the desired acetate is obtained.

1 H-NMR (CDCl 3, δ ppm):

1.52 (s, 3H);

1.70 (s, 3H);

2.35 (s. 3H);

4.4-4.6 (m, 2H);

4.6-5.0 (m, 3H);

6.2-6.4 (m, 3H);

6.65 (d, IH);

7.4 (d, 1 H),

7.8 (d, 1 H).

Example 8

Tetrabutylammonium 6- [D- (2- (1-methyl-2-methoxycarbonylvinylamino) -2-phenylacetamido)] penicillanate

To 300 ml of chloroform was added 39.3 g of 6- [D- (2-amino-2-enylenedioido) -penicillanic acid trihydrate, 50 ml of water was added, and the pH of the mixture was adjusted to 40% aqueous tetrabutylammonium hydroxide solution. value 8.5. The layers were separated, the aqueous layer was saturated with sodium sulfate and extracted with fresh chloroform. The extracts were combined with the original backsheet and concentrated to a total volume of 250 mL by evaporation of the solvent.

To this concentrate was added 150 ml of methyl acetoacetate and 30 g of anhydrous magnesium sulfate, the mixture was heated under reflux for 3 hours, then allowed to settle and the warm organic layer was decanted off. The clear chloroform solution was allowed to cool, yielding 52% yield crystals of the title compound, melting at 182-184 ° C with decomposition.

@ 1 H-NMR. (deuterochloroform, δ values in ppm):

(m, 4H)

1.88 (s, 3H);

3.1-3.6 (m, 8H);

3.6 (s, 3 H),

4.17 (s, 1 H),

4.58 (s, 1 H),

5.05 (d, IH);

5.38-5.6 (m, 2H);

6.78 (d, IH);

7.35 (s. 5H);

9.4 (d, 1 H).

Example 9

Tetrabutylammonium-5- [D- (2- (1-methyl-2-methoxycarbonylvinylamino) -2- (4-hydroxyphenyl) acetamido)] penicillanate

To 300 mL of dichloromethane was added 41.9 g of 6- (2-amino-2- (4-hydroxyphenyl) acetamido) penicillanic acid trihydrate and 50 mL of water, and the pH of the mixture was adjusted to 8.5 with 40% aqueous tetrabutylammonium hydroxide.

The mixture was divided into three layers. The upper layer was separated, saturated with sodium sulfate, and extracted with dichloromethane. The extracts were combined with the original middle layer and the bottom layer, and the resulting mixture was evaporated in vacuo to an oily residue which crystallized upon trituration with acetone. 44.6 g of tetrabutylammonium-5- (2-amino-2- (4-hydroxyphenyl) acetamido) penicillanate are obtained.

The above prepared salt was added to 150 ml of methyl acetoacetate and the suspension was heated to about 65 ° C until it became clear (8 minutes). The mixture was allowed to cool and the precipitated solid material was filtered off. This solid material, after washing, first with methyl acetoacetate and then with diethyl ether, gave 49.25 g of crystalline tetrabutylammonium-5- [2- (1-methyl-2-methoxycarbonylvinylamino) -2- (4-hydroxyphenyl) acetamido] penicillanate.

Example 10

A. Potassium (6ka, 8S) -6- (pyrimidin-2-yl) hydroxymethyl-1,1-dioxopenicilate

To a solution of 300 mg (0.79 mmol) of the first eluted isomer of allyl-5α- (pyrimidin-2-yl) hydroxymethyl-1-dioxopenicillanate (see Example 2) in 4 mL of ethyl acetate was added 30 mg of tetrakis (triphenylphosphine) palladium (0). and 30 mg triphenylphosphine. The mixture was stirred under nitrogen until the reagents dissolved (5-10 minutes) and then treated with 1.57 ml (0.79 mmol) of potassium 2-ethylhexanoate in ethyl acetate. The reaction mixture was stirred at room temperature for 20 minutes, then filtered, the filter cake was washed with ethyl acetate and dried. 53 mg of a yellow solid are obtained. An additional 152 mg of product precipitated from the filtrate with ethyl ether. The total yield is 69 why.

1 H-NMR (250 MHz, perdeuterodimethylsulfoxide, δ in ppm):

1.33 (s. 3H);

1.44 (s, 3H);

3.77 (s, 1 H),

3.95 (doublet of doublets, J = 2, J = 6, 1H),

4.89 (d, J = 2, 1 H),

5.1 (d, J = 6, 1 H),

6.33 (s, 1 H),

7.48 (t, J = 4, 1H).

8.84 (d, J = 4, 2H).

30

B. Potassium (6a, 8R) -6- (pyrimidin-2-yl) hydroxymethyl-1,1-dioxopenicilate

A solution of 300 mg (0.79 mmol) of the second eluted isomer of allyl-6α- (pyrimidin-2-yl) hydroxymethyl-1,1-dioxopenicillanate (see Example 2) was converted to the corresponding potassium salt as described above. Yield: 236 mg (79%).

¹ H-NMR (250 MHz, perdeuterodimethylsulfoxide, δ in ppm):

1.30 (s, 3H);

1.42 (s, 3H);

3.65 (s, 1 H),

4.60 (dd, K = 2, J = 8, 1H);

4.75 (d, J = 2, 1 H),

5.15 (d, J = 8, 1H).

7.47 (t, J = 4, 1H).

8.85 (d, J = 4.2, 2H).

Example 11

A. Allyl- (6a, 8S) -6- (pyrimidin-2-yl) acetoxymethyl-1,1-dioxopenicillanate

To a solution of 785 mg (2.1 mmol) of the first eluted isomer of allyl-6α- (pyrimidin-2-yl) hydroxymethylil, 1-dioxopenicillanate (see Example 2) in 4 mL of methylene chloride was added 0.45 mL (5.6 mmol). pyridine and 0.53 ml (5.6 mmol) of acetic anhydride, the mixture is stirred at room temperature for 2.5 hours, then diluted with 30 ml of methylene chloride and extracted seven times with 60 ml of water each. The organic phase was dried over anhydrous magnesium sulfate and filtered. Evaporation in vacuo gave 813 mg (92%) of the title compound.

* H-NMR (CDCl3, δ ppm):

M (s, 3 H),

1.6 (s, 3H);

2.2 (s. 3H),

4.45 (s. 3H);

4.45 (dd, 1 H),

4.75 (m, 2H).

4.95 (d, IH);

5.2-5.6 (m. 2H);

5.7-6.3 (m, 1 H),

6.45 (d, 1 H),

7.35 (t, 1 H),

8.85 (d, IH).

B. Allyl- (6a, 8R) -6- (pyrimidin-2-yl) acetoxymethyl-1,1-dioxopenicillanate

Acetylation of the isomer (N, N-pyrimidin-4-yl) hydroxymethyl-1,1-dioxopenicillanate, which was eluted second (see Example 2) using the method described above, gave the title compound in 88% yield.

Ή-NMR (deuterochloroform, δ values in ppm):

1.4 (s. 3H),

1.6 (s, 3H);

4.45 (s, 1 H),

4.50 (dd, J = 1, J = 8, 1 H),

4.75 (m, 2H).

4.8 (d, J = 1, 1 H),

5.25-5.6 (m, 2H);

5.7-6.3 (m, 1 H),

6.4 (d, J = 8, 1 H),

7.35 (t, J = 6, 1 H),

8.8 (d, J = 6, 1 H).

Example 12

A. Potassium (6a, 8S) -6- (pyrimidin-2-yl) acetoxymethylil, 1-dioxopenicillanate

A solution of 789 mg (1.86 mmol) of allyl- (6a, 8S) -6- (pyrimidin-2-yl) acetoxymethyl-1,1-dioxopenicillanate in 4 mL of ethyl acetate was subjected to the reaction described in Example 10 to give 342 mg ( 43% of the desired potassium salt which was purified by preparative medium pressure liquid chromatography using a 9: 1 mixture of water and acetonitrile as eluent. 105 mg of product are obtained, which is 85% pure by HPLC.

B. Potassium (6R, 8R) -6- (pyrimidin-2-yl) acetoxymethyl-1,1-dioxopenicillanate

A solution of 666 mg (1.57 mmol) of allyl- (6α, 8R) - (pyrimidin-2-yl) acetoxymethyl-1,1-dioxopenicillanate is reacted in an analogous manner to give 339 mg (51%) of the crude product which, after purification Preparative medium pressure liquid chromatography, eluting with water: acetonitrile (9: 1) gave 162 mg of pure isomer.

NMR-NMR (250 MHz, perdeuterodimethylsulfoxide, δ in ppm):

1.34 (s, 3H);

1.44 (s, 3H);

2.17 (s, 3H).

3.65 (s, 1 H),

4.15 (dd, J = 2, J = 8, 1H);

4.97 (d, J = 2, 1H).

6.27 (J = 8, 1H).

7.50 (t, J = 5, 1 H),

8.85 (d, J = 5, 2H).

ri

The following acetylated esters were prepared as described in Example 3 or 11 using the corresponding 1,1-dioxopenicillanic acid ester substituted at the R ¹³ position with CHOH as starting material:

CCOCH? n

Zr — N — i> ch ₃ '' С00СН ₂ СН = СН ₂

O'

R13 stereochemistry at Cg and Cg a mixture of 6a, 8S and 6a, 8R

yield (%) ⁴ H-NMR (deuterochloroform, δ values in ppm)

100 ALIGN!

1.43 (s, 3H), 1.63 (s, 3H),

2.25 (s, 3H); 4.51 (m, 2H);

4.79 (m, 2H); 5.43 (m, 2H);

5.98 (m, 1 H), 6.65 (d, 1 H),

7.5 (m, 3H); 7.98 (s, 1H);

8.30 (m, 2H).

a mixture of 6a, 8S and

6a, 8R at a ratio of 60:40

1.4 (s, 1.8H), 1.43 (s, 1.2H),

1.56 (s, 1.2H), 1.62 (s, 1.8H),

2.2 (s, 1.2H), 2.3 (s, 1.8H),

4.35 (m, 1H); 4.4 (s, 0.6H);

4.43 (s, 0.4H), 4.78 (d, 0.6H),

4.8 (d, 0.4H);

5.3-5.5 (m. 2H);

5.8-6.05 (m, 1 H),

6.3 (m, 1H); 7.45 (d, 1H);

8.82 (d, 1H), 9.25 (m, 1H), 6a, 8Sa mixture

6a, 8R ratio: 40

1.4 (s, 1.8H), 1.5 (s, 1.2H),

1.6 (s, 1.8H, 1.65 (s, 1.2H),

2.2 (s, 1.2H), 2.26 (s, 1.8H), 4.23 (dd, 0.4H), 4.35 (dd, 0.6H),

4.4 (s, 0.6H), 4.45 (s, 0.4H), 4.68 (m, 2H), 4.74 (d, 0.6H), 5.0 (d, 0.4H) 5.35 (m, 2H).

5.9 (m, 1 H), 6.45 (m, 1 H),

8.6 (m, 2H); 8.75 (m, 1H).

Example 14

Using the procedure of Example 10, the following procedure was followed:

The 8-acetoxy-3-carbonyloxyallyl esters of Examples 5 and 13 are converted to the potassium salts of the following formula

R1.3 Сб stereochemistry and yield of Ca (%) ^* H-NMR (deuterium oxide, 6 values in ppm)

6a, 8S and 6a, 8R in a ratio of 65:35 57 (crude product) 21 (after purification by chromatography, mixture of isomers) ^M purified product: 1.45 (s, 3H), 1.58 (s, 3H), 1.25 (s, 1.05H), 1.32 (s, 1.95H), 4.25 (s, 0.65H), 4.28 (s, 0.35H), 4.37 (dd, 0.65H), 4.45 (dd, 0.35H); 5.15 (d, 0.65H), 5.2 (d, 0.35H), 6.25 (d, 0.65H); 6.35 (d, 0.35H), 7.73 (m, 1 H), 8.85 (m, 1 H), 9.15 (m. 1H); 6a, 8S and 6a, 8R in a 6: 1 ratio 64 1.44 (s, 3H), 1.5 (s, 3H), 1.62 (s, 3H), 2.2 (s, 0.4H), 2.24 (s, 2.6H), 3 Δ (s, 3H), 4.27 (s, 1 H), 4.4 (dd, 1 H), 4.96 (d, 1 H), 6.45 (d, 0.15 H), 6.5 (d, 1 H) d, 0.85H), 7.07 (s, 0.15H), 7.1 (d, 0.85H), 7.16 (s, 0.15H), 7.2 (d, 0.85H); IR (KBr): 3409, 1786, 1740 1620 ¹ СИГ 6a, 8S and 6a, 8R in a ratio of 30:70 84 1.3 (s, 2.1H), 1.34 (s, 0.9H), (crude product) 1.42 (s, 3H), 2.13 (s, 0.9H), 43 2.2 (s, 2.1H), 3.66 (s, 0.7H), (after chromatography) 3.7 (s, 0.3), 4.1 (dd, 0.3H), 4.95 (d, 0.7H), 5.07 (d, 0.3H),

6.24 (d, 0.3H), 6.36 (d, 0.7H),

8.7 (s, 2H); 8.8 (s, 0.7H);

8.83 (s, 0.3H);

IC (KBr technology):

468, 1781, 1746, 1623 cm ^'1' chromatography performed on silica with ₁₈ С (C == monooktadecylsilikát ₁₈₎

Example 15

Potassium 6- (imidazol-2-yl) hydroxymethyl-1,1-dioxopenicilate

A mixture of 141 mg (0.38 mmol) of allyl 6- (imidazol-2-yl) hydroxymethyl-1,1-dioxopenicillanate (mixture of isomers retained in Example 2), 12 mg of tetrakis (triphenylphosphine) palladium (0), 12 mg of triphenylphosphine 0.72 ml (0.38 mmol) of potassium 2-ethylhexanoate and 2 ml of ethyl acetate were stirred under nitrogen for 1 hour. Filtration of the precipitated product gave 143 mg (100%) of a yellow solid which contained two isomers according to HPLC.

IC (KBr technology):

382, 1 780, 1 728 and 1 615 cnr ‘.

Example 16

A. Benzyl 6- (2-thiazonyl) hydroxymethyl-1,1-dioxopenicilate

A solution of 17.79 g (44 mmol) of benzyl 6α-bromo-1,1-dioxopenicillanate in 250 mL of dry tetrahydrofuran at -78 ° C was treated with an equimolar amount of methylmagneslumbromide, after stirring for one minute equimolar amount of thla248749 zol-2 -carboxaldehyde and stirring was continued for 10 minutes. An equimolar amount of acetic acid was added, the reaction mixture was stirred for 5 minutes and then poured into 500 ml of water. The aqueous mixture was extracted with ethyl acetate, the extracts were washed with water and, after drying over magnesium sulfate, the solvent was evaporated in vacuo. 16.93 g (89%) of crude product are obtained, which gives two spots in the thin layer chromatogram. This crude product was purified by silica gel column chromatography using a 96: 4 mixture of chloroform and ethyl acetate as eluent.

4.72 g of the more polar isomer, 2.98 g of the less polar isomer and 0.5 g of a mixture of isomers are obtained (total yield 43%).

Silica gel column chromatography using chloroform / ethyl acetate (9: 1) as eluent gave 2.444 g of the less polar isomer and 3.029 g of the more polar isomer.

Polar isomer:

Ή-NMR (deuterochloroform, ppm values):

Polar isomer:

1 H-NMR (CDCl 3, δ ppm):

1.25 (s, 3H).

1.55 (s. 3H);

4.3 (dd, 1 H),

4.45 (s, 1 H),

4.65 - (bs, 1H),

4.9 (d, 1 H),

5.2 (m, 2H).

5.55 (d. 1H);

7.35 (m. 6H);

7.75 (d, IH).

Less polar isomer:

Ή-NMR '(deuterochloroform, δ in ppm):

1.2 (s. 3H),

1.5 (s. 3H),

4.35 (m, 2Ή)

4.75 (d, 1 H),

5.1 (m. 2H);

5.55 (d, 1 H),

7.2 (m, 6H).

7.6 (d, 1 H).

B. Diphenylmethyl-6- (2-thiazolyl) hydroxymethyl-1,1-dioxopenicilate

The above procedure was repeated using 20 mmol of diphenylmethyl-6α

-bromo-1,1-dioxopenicillanate and corresponding amounts of the other reactants. From the reaction product, after purification of the chroma, 1.06 (s, 3H),

1.52 (s, 3H);

4.1-4.3 (m, 1 H),

4.42 (s, 1 H),

4.76 (d, 1 H),

5.45 (d, IH);

6.82 i (s, 1 H),

7.05 - 7.3 (m, 11H),

7.56 (d, IH).

Less polar isomer:

1 H-NMR (CDCl 3, ppm):

1.2 (s, 3H);

1.65 (s. 3H);

4.35 (dd, IH),

4.55 (s, 1 H),

4.83 (d, 1 H),

5.65 (dd, IH),

6.95 (s, 1 H),

[Delta] -7.4 (m, 11H),

7.75 (d, IH).

r

The following compounds were prepared according to the procedure of Part A of Example 3 using the appropriate acid chloride of the formula R 1 Cl or the corresponding acid anhydride and the corresponding 1,1-dioxo-enicillanic acid ester substituted with the R ¹³ CHOH moiety obtained above. :

^CH 3

COOR *

R ^and R ¹³ r ¹⁸ stereochemistry at C 8 Ή-NMR (deuterochloroform, δ ppm) O 1.3 (t, 3H), 1.4 (s, 1H),

II 1.65 (s, 1H).

2-thiazolyl C2H5C- (R) 2.55 (quartet, 2H),

~ x bU CO , —Ζ X X CM X rH rH ~ cT WHAT ~ _r . ел Й 'Ό cn 4-Γ Гх LO '-' or CM CM ^IO CM ^ CO what S ' ^H 0 LO (x? r-i . г Я Ю "

г-1

XX ¹ what what «5 and HH CN tf IS ^ r _{ω ό} к® Sk - ¹ - | - - ι> - Ό unin m οηω I in cmcx cq co lo · φ r-ι tx r-Γ r-Γ

T what tx øx

ο — ω

O m X

CM

O

TO O u a '>> 4- »> o Д> ф P <

'> Д> ω P <

'>>

> o> N

Pi

O — O o IO K CM O

S rno * - '' n - 'I in tx 00 CO t \ N rH © CO tx СП r-T r-T CT m LO LO cc tx

° ~ x

O

CM

Kl X o

ř— < ""AND f-4 г — 1 >? >> > » - 0 O O 0 N N N N WITH .2 with 2 ² Ξ WITH Λ 4- » + - » +> • w CM CM CM CM

> aT ^N ti>. д ча χ; u 2 X > 5? о Ё 2’1 ._____ f-i > CD ^Λ 'what 0 § Qoo tí N 0 4D Λ N 2 2 N u—, O Г-Н N СЛ *

r-1 r-I CO stereochemistry at C ₈ ^{X 1} H-NMR (deuterochloroform, δ ppm) (R) 1.18 (m, 3H), 1.28 (m, 3H), more polar yield 1.33 ( s, 3H), 1.52 (s, 1 H),% 2.6 (m, 1 H),

X τ — 1 2 ^ ~ Д rc X CM E Д Днем τί what CM what - Ό ω Ό oo CM σΓ ~ СЛ z — í σΤ Ό <- / '-' > -> '-' ж 'CM 27 Mar: ю r-4 £ CM ^ uo CM tH CO CD ю r-Γ - Ж CD r-i ^ 00

it

Pi

487 49;

Example 18

A. (6as, 8R) -6- (thiazol-2-yl) propionyloylmethyl-1,1-dioxopenicillanic acid

A mixture of 1.89 g of 10% palladium on carbon catalyst and 20 ml of a 9: 7 mixture of tetrahydrofuran and water was saturated with hydrogen and a solution of 689 mg (1.4 mmol) was added. benzyl- (6a, 8R) -6-thiazol-2-yl) propionyloxymethyl-1,1-dioxopenicillanate in 13 ml tetrahydrofuran and 7 ml water. The resulting mixture was hydrogenated for 20 minutes. The catalyst is filtered off and the filtrate is extracted three times with 200 ml of ethyl acetate each time. The extracts were dried over magnesium sulfate and the solvent was evaporated in vacuo. 330 mg of a yellow solid are obtained.

Β. (6a, 8R) -6- (thiazol-2-yl) benzoyloxymethyl-1,1-dioxopenicillanic acid

The title compound is obtained as described above in a yield of 57 why, from the corresponding benzyl ester.

NMR-NMR (deuterium oxide, δ in ppm):

1.38 (s, 3H);

1.55 (s. 3H);

4.25 (s, 1 H),

4.44 (dd, IH),

5.05 (d, IH);

6.68 (d, IH);

7.4 (t. 7H);

7.55 (t, 1 H),

7.58 (d, 1 H),

7.7 (d, 1 H),

7.95 (d, IH);

IR (K 2 H 2 -) (K 2 H 2):

473, 1782, 1729, 1622 ^cm-first

Example d 19

A. (6a, 8S) -6- (thiazol-2-yl) ethoxycarbonylrxymethyl-1,1-dirprenicilanic acid

To a solution of 557 mg (0.954 mmol) of diphenylmethyl- (6a, 8S) -6- (thiazol-2-yl) ethoxycarbilliliter methylene chloride was added 0.62 mL (5.72 mmol) of anisole, cooled to -5 ° C and a mixture of anhydrous aluminum chloride (382 mg, 2.86 mmol) and nitromethane (2 mL) was added over 15 minutes. The reaction mixture was diluted with 50 mL of ethyl acetate, water was added and the pH was adjusted to 7.5. The aqueous layer was separated, acidified to pH 3 and extracted with ethyl acetate. After evaporation of the solvent, a glassy residue is obtained which is dissolved. ^; in ethyl ether. The solution was filtered and filtered ^. Hexar was added to the filtrate to precipitate the product. Filtration of the solid and dehydration yielded 211 mg (53%) of the desired product.

Ή-NMR · (300 MHz, d + iBatlorochloride, δ ppm) :,

1.40 (t, · · 3H ·) ,:

1-53 · (s, 3H)

1,674š; 3H),

4.28--4.42. ·. (m, 3H -), 1 ·

4.50 '(s, 1H).

4.92 (s, 1 H),

6.58 (d, IH);

7.53 (d, 1 H-),

7.93 (d, IH). .

IC (КВа ^ ескйгКа):

443, 1797, 1754 cm.

B. The above procedure was followed using the (6a, 8R) -isomer of the starting diphenylmethyl ester prepared in Example 17. The corresponding 6 (thiazol-2-yl) ethoxycarbonyloxymethyl ester was obtained. -1,1-dioxopenicillanic acid.

NMR-NMR (300 MHz, deuterrlo -loofram, δ in ppm):

1.34 (t, 3H);

1.53 (s, 3H);

1.65 (s, 3H);

4.2-4.4 (m, 3H);

4.44 (s, 1 H),

5.04 (s, 1 H),

6.67 (d, 1 H),

7.53 (d, 1 H),

7.90 (d, IH).

Company ID (КВа ^ есЬтка):

418, 1803.51750 cm @ -1

Example 2 0 '

Following the procedure of Example 15, using the appropriate allyl ester prepared in Example 17 as the starting material, the following potassium salts were obtained:

stereochemistry at C ₈

R13

R18 ^f H-NMR (deuterium oxide, δ in ppm)

2-thiazolyl

(S) 1.46 (s, 3H), 1.65 (s, 3H), + 4.35 (2s, 1H), 5.2 (d, 1H), (R) 7.05 (d, 1H) )

7.7-8.0 (m, 2H).

8.7-9.5 (m, 3H);

2-thiazolyl

O

II _{(CH3) 2} CHC

1.13 (d, 3H), 1.16 (d, 3H), (S) 1.33 (s, 3H), 1.45 (s, 3H), 90% yield 2.65 (m, 1H) 3.73 (s, 1H).

4.23 (dd, 1 H), 4.93 (d, 1 H), 6/50 (d, 1 H), 7.85 (m, 2 H); IC (KBr technology):

777, 3,472, 3,447, 3,342, 3,270, 1783, 1746, 1621 cm @ ^-1 (R) 1.17 (d, 3H), 1.20 (d, 3H), 27% yield 1.44 (s) 3H), 2.69 (m, 1 H),

3.68 (s, 1H); 4.12 (dd, 1H); 7.84 (m, 2H);

IC (KBr technology):

543, 3,498, 3,437, 3,348.3,415, 3,270, 3,119, 1,917, 1,783, 1,745, 1718, 1619 cm ' ¹

Example 21

The following ingredients are mixed in the following proportions until a homogeneous powder mixture is formed:

component parts (and) potassium (6 #, 8R) -6- (2-thiazolyl) acetoxymethyl-1,1-dioxopenicilate 1.0 (b) ampicillin trihydrate 1.0 (O) lactose 0.5 (d) polyethylene glycol o medium molecular weight 4 000 3.0

Mixtures (1,375 mg) are filled with hard gelatin capsules of appropriate size. Capsules containing 250 mg of active ingredient are obtained. Appropriate dose adjustment during filling and selection of a suitable capsule yields capsules with higher or lower doses of the active ingredients. In order to obtain capsules in which the weight ratio of the active substances is different from one, the weights of the active substances used vary accordingly. For example, the above ingredients are mixed in a weight ratio of 0.75, 1.5, 0.5 and 3.0 and 1700 mg of the mixture is dispensed into each capsule. In this way, capsules containing 225 milligrams of component (a) and 450 mg of component (b) are obtained.

Similarly, other [beta] -lactamase inhibitors of the invention may be combined with other conventional [beta] -lactam antibiotics suitable for oral administration.

Preparation

Allyl-6α-bromo-1,1-dioxopenicillanate (i) 6α-Bromo-penicillanic acid 1,1-dioxide

To a suspension of 20.66 g (0.0517 mmol) of 6,6-dibromopenicillanic acid 1,1-dioxide in 80 ml of water was added portionwise 13 g (0.155 mol) of solid sodium bicarbonate. The vigorous gas evolution is controlled by the addition of ethyl acetate. 6.76 g (0.062 mol) of solid sodium bisulfite was then added portionwise to the reaction mixture, stirred for 35 minutes and then acidified to pH 1.0 with concentrated hydrochloric acid. The acidified mixture was diluted with ethyl acetate, the organic phase was washed with brine, dried over sodium sulfate and the solvent was evaporated in vacuo.

The residue was triturated with chloroform and the mixture was filtered. 6.72 g of a pale yellow solid are obtained. An additional 3.2 g of product is obtained by concentrating the filtrate and treating the residue with chloroform.

(ii) To 6.352 g of the material first isolated above in 20 ml of dimethylformamide was added 1.76 ml (20.3 mmol) of allyl bromide, 2.83 ml (20.3 mmol) of triethylamine and 0.2 g of bicarbonate The mixture was stirred at room temperature under nitrogen for 15 hours. After addition of water, the mixture is extracted with ethyl ether, the extracts are washed with water, dried over sodium sulfate and the solvent is evaporated off under vacuum. 4.60 g (64%) of the desired ester are obtained in the form of an oil.

⁴ H-NMR (CDCl3, δ ppm):

1.4 (s. 3H),

1.6 (s, 3H);

4.4 (s. 1H).

4.6 (d, 1 H),

4.7 (d, 2 H),

5.15 (d. 1H);

5.1-5.95 (m, 3H).

Preparation В

2-formyl-1-methylimidazole (i) 2-hydroxymethyl-1-methylimidazole

A mixture of 50 g of 1-methylimidazole and 100 ml of 37% formaldehyde (density 1.08) was placed in a 300 ml stainless steel autoclave and heated at 150 ° C (bath temperature) for 17 hours. The autoclave was cooled in ice, the mixture was removed, concentrated in vacuo and the residue stored overnight at 4 ° C. The resulting mixture of crystals and oil was filtered, the colorless crystalline product was washed with ethyl acetate and dried in vacuo. 14.60 g of the desired product are obtained. A second crop of 6.48 g was obtained by treating the mother liquors. The overall yield was 21.08 g (31%).

(ii) 4.90 g (44.1 mmol) of selenium dioxide are added to a solution of 4.96 g (43.9 mmol) of 2-hydroxymethyl-1-methylimidazole in 50 ml of dioxane, and the mixture is subsequently stirred at 85 DEG C. for 5 hours. to 90 ° C, then 36 hours at a temperature. at room temperature, 8 hours at 85 degrees Celsius and finally 15 hours at room temperature, filtered and the solvent was evaporated in vacuo to give 4.81 g of crude aldehyde which, by distillation, yielded 2.11 grams of the product as colorless crystals. Boiling point 65 ° C / 373 Pa.

Preparation C

4-formylpyriinidine

To a solution of 10 g (0.106 mol) of 4-methylpyrimidine in 100 ml of dioxane at room temperature was added 11.8 g of selenium dioxide and the mixture was heated to 100 ° C for 15 hours. After the addition of an additional 2.5 g of selenium dioxide, heating is continued for 1 hour, then the mixture is cooled, filtered and the filter cake washed with ethyl acetate. The filtrate was combined with the washings and evaporated in vacuo to dryness. The remaining dark oil was taken up in methylene chloride, the solution was filtered and the solvent was evaporated. The residue was crystallized from a small amount of methylene chloride to give the title aldehyde.

@ 1 H-NMR (CDCl3, .delta. in ppm):

7.87 (dd, IH),

9.06 (d, 1 H),

9.43 (d, IH);

10.0 (s, 1 H).

Preparation D

Diphenylmethyl-6α-bromo-1,1-dioxopenicilate

To a solution of 21.557 g (0.1 mol) of diphenyldiazomethane in 400 ml of dry tetrahydrofuran was added portionwise 31.2 g (0.1 mol) of 6-bromo-1,1-dioxopenicillanic acid over 30 minutes. The reaction in progress is slightly exothermic. The reaction mixture was stirred for 1 hour, then the solvent was evaporated and the residue was dissolved in 50 ml of ethyl acetate. After addition of 400 ml of ethyl ether, the resulting mixture was stored at 4 ° C. After 18 hours no crystals formed. The mixture was then concentrated in vacuo to give 51.2 g of a yellow solid which was chromatographed on silica gel. Elution with chloroform gave 14.86 g of a colorless glass.

¹ H-NMR (CDCl 3, δ in ppm):

1.26 (s. 3H);

1.57 (s, 3H);

4.55 (s, 1 H),

4.70 (d, IH),

5.13 (d, IH);

6.9 (s, 1 H),

7.27 (s, 10H).

Preparation

Benzthiazole-2-carboxaldehyde

A solution of 10 g (0.074 mol) of freshly distilled benzothiazole (bp 82 ° C / 0.2 mm Hg) in 250 ml of tetrahydrofuran was cooled to -78 ° C under nitrogen, stirred at this temperature for 15 minutes, then stirred for 15 minutes. 29.6 ml (0.074 mol), 2.5 M n-butyl lithium are added dropwise. Stirring was continued for 25 minutes, then dimethylformamide (8.6 ml, 0.111 mol) was added and the mixture was stirred for 1 hour. The reaction mixture was allowed to warm to room temperature, 200 g of ice was added and the solvent was evaporated in vacuo. The aqueous residue is extracted five times with 100 ml of ethyl acetate each time, the extracts are dried over magnesium sulfate, concentrated to a small volume and the concentrate is chromatographed on a silica gel column. Elution with a 96: 4 mixture of chloroform and ethyl acetate gave 8.4 g of the desired aldehyde, m.p. 74.5-75 ° C.

βI-NMR (deuterochloroform, δ in ppm):

7.54 (m, 2H).

7.97 (m, IH),

8.21 (m, IH),

10.1 (s, 1 H).

Using the above procedure, the following aldehydes are prepared analogously.

starting material

X) aldehyde

CX

CH ..

/ 5 \ _...... of * / - .A /

T cwo

CX

I -...... Al)

AND

Ч ^ - 'СН Q Yield (%) of an amber oil, boiling point 120–122 ° C / / 3 333 Pa

Ή-NMR (deuterochloroform, V values in ppm)

4.2 (s, 3H); 8.05 (s, 1H);

10.00 (s, 1H);

1.2 (t, 6H);

3.6 (quartet, 2H),

3.64 (quartet, 2H),

6.95 (s, 1H); 7.21 (d, 1H);

7.55 (d, 1 H), 8.23 (d, 1 H).

prepared in solid form in didem yield in ethanolic sodium ethoxide ** prepared from imidazole and ethyl orthoformate as described by Curtis et al., J. Org. Chem. 45, 4038 (1980).

1 H-1,2,4-triazine with methyl. Preparation F

Pyrazine-2-carboxaldehyde

The pyrazine-2-carboxylic acid is esterified by refluxing with methanolic sulfuric acid for 5 hours. Methanol was evaporated. in vacuo the residue was diluted with methylene chloride and neutralized with sodium bicarbonate to pH 7.5. Concentration of the dried organic layer afforded methyl pyrazine-2-carboxylate (84% yield) as an off-white solid, which was recrystallized from isopropanol / ethyl ether to give yellow needle crystals.

Ή-NMR (deuterochloroform, δ values in ppm):

4.1 (s, 3 H),

8.93 (m, 2H).

9.47 (m, IH).

g (0.145 mol) of this methyl ester was dissolved in 600 ml of dry tetrahydrofuran, cooled to -78 ° C, and a solution of 5.8 g of 98% lithium aluminum hydride in tetrahydrofuran was added dropwise over 15 minutes. The mixture was stirred at -78 ° C for 30 minutes, then 20 mL of acetic acid was added and the resulting mixture was concentrated under reduced pressure. The residue was partitioned between 2N hydrochloric acid (30 ml) and chloroform, the combined organic layers were washed with water and evaporated to dryness. It is obtained

8.53 g of crude material, which was chromatographed on a silica gel column. Elution with a 4: 1 mixture of methylene chloride and ethyl acetate yielded 5.02 g of the product as pale yellow needle crystals.

Ή-NMR (CDCl 3, δ in ppm):

8.38 (m, 2H).

8.7 (bs, 1H),

9.7 (s, 1 H).

Preparation G

2-phenyl-1,2,3-triazole-4-carboxaldehyde

0.34 mol of acetic dicarboxylic acid is reacted with 100 ml of water at 0 ° C with 0.58 mol of sodium nitrite. The reaction mixture is then precipitated up to 10 ml.

dilute nitric acid was added to the product. The desired dioxime, i.e. 1,3-xioximino-x-oxopropane, was obtained in 46% yield as red-yellow colored crystals.

(ii) 0.158 mol of this didxime was treated with equimolar amounts of phenylhydrazine hydrochloride and sodium acetate for 30 minutes at 70 ° C in 170 ml of ethanol. After addition of 170 ml of water, the mixture is heated to 85 ° C, concentrated to a volume of 250 ml and cooled. 24.7 g of the desired phenylhydrazone are obtained.

NMR-NMR (perdeuteroacetone, δ in ppm):

7.3 (m. 5H);

7.9 (s. 1H).

8.6 (s, 1 H),

10.5 (bs, 1H),

11.4 (bs, 1H),

12.3 (s, 1 H).

(iii) 24.7 g · (0.119 mol of the dioxime-phenylhydrazone prepared above) was stirred with 500 ml of acetic anhydride at room temperature for 30 minutes, the mixture was poured into water, stirred for 20 minutes and then filtered. and ethyl acetate to give 15.47 g (52%) of the monoacetate of formula

HON CH-C (= NNHC _(; H5) CH · NOCOClT;

in the form of a yellow powder,

Ή-NMR (deuterochloroform, acetone, δ in ppm):

1.85 (s, 3H);

7.09 (m, 5H);

7.95 (s, 1H).

8.3 (s. 1H).

10.9 (bs, 1H),

12.25 (s, 1 H).

(iv) A solution of 15.40 g (0.062 mol) of the above monoacetate and 22.16 g (0.068 mol) of cesium carbonate in 400 ml of tetrahydrofuran was stirred at room temperature for 1 hour, then filtered and the filtrate was concentrated. The yellow colored residue was dissolved in 700 mL of hot isopropyl ether-cyclohexane (1: 2) and concentrated to 200 mL to give 9.41 g (80%) of 2-phenyl-1,2,3- triazole-4-carboxaldehyde oxime as a yellow powder, which is used in the next step.

(v) A mixture of 9.41 g (0.0497 mol) of the above oxime, 4.48 g of s-trioxane and 300 ml of 2N hydrochloric acid was refluxed for 3.5 hours. The aqueous phase was extracted with ethyl ether, the combined ether layers were washed with water, dried over magnesium sulfate and the ether was evaporated in vacuo to give 6 g of crystalline aldehyde.

Ή-NMR (deuterochloroform, δ v · ppm):

7.6 (m. 3H);

8.25 (m. 3H);

10.25 (s, 1 H).

Mp 66-67 ° C.

Preparation H

5-Methylisoxazole-3-carboxaldehyde (i) Ethyl 5-methylisoxazole-3-carboxylate

A mixture of 0.16 mol of ethyl 2,4-dioxovalerate and 0.08 mol of hydroxylamine isulfate was stirred at 40 ° C in 50 ml of ethanol and 70 ml of toluene for 4 hours. The resulting mixture was cooled to 15-20 ° C, 1.8 g of concentrated ammonium hydroxide was added and stirring was continued at room temperature for 60 hours. The reaction mixture was poured into a mixture of toluene and water, and the aqueous layer was extracted with toluene after separation. The organic layers were combined, washed with brine and dried over sodium sulfate After evaporation of the solvent in vacuo a yellow liquid material was obtained which, by distillation, yielded 14.68 g of the product with a boiling point of 120 ° to 124 ° C / 4 kPa, which crystallizes on standing.

(ii) 2.0 g (14.4 mmol) of the above ethyl ester in 75 ml of toluene was reduced under nitrogen at -75 to -70 ° C by an equimolar amount of 1M dlisobutylaluminum hydride in hexane. After stirring for 30 minutes, the reaction is quenched by the addition of an ammonium chloride solution. The reaction mixture is allowed to warm to room temperature and the solvent is evaporated off under vacuum. The residue was triturated with · hot · methanol. After evaporation of the solution, 0.85 g of product is obtained in the form of a colorless oil.

Ή-NMR (deuterochloroform, δ values in ppm):

2.4 (s, 3H).

6.3 (d, 1 H),

9.0 (s, 1 H).

Claims (6)

A process for the preparation of 6- (substituted hydroxymethylpenicillanic acids of the general formula II) in which R 1 represents a radical R ^a or R b, wherein R ^a represents a carboxyl function protecting group selected from the group consisting of tetrahydropyranyl, allyl, benzyl, 4-nitrobenzyl, benzhydryl, 2,2,2-trichloroethyl, tert-butyl and phenacyl radicals and R ^b represents a hydrogen atom or an ester residue readily hydrolyzable in vivo, selected from the group consisting of a 3-phthalidyl residue, a 4-crotonolactOnyl residue, a γ-butyrclactol-4-yl residue, a residue of the formula -CH-g-C-- R 1 -V II o t -COCOR ^rS R * I 6 QOQOOR is _Ra -CHOCOR14 R4 wherein each R4 and ^R5 represents a hydrogen atom or a methyl group, R ⁶ represents an alkyl group having 1-5 carbon atoms and R 4 ^J is a radical of formula wherein R 15 represents 2-phenyiacetamido, 2-phenoxyacetamido, D-2-amino-2-phenylacetamido, D-2-amino-2- (4-hydroxyphenyl) acetamido, 2-Cacoxy-2- (2-thienyl) acetamido, k-1-oxo-2- (2-thienyl) acetamido, D-2- (4-ethyl-2,3) -dioxopiperazinocarbonolamino) -Z 2 - ((R 1) -) - (ethoxy) -amino or,,--dimethyl-4-phenylimidazolazol-1-yl, R 15 represents a hydrogen atom, an alkanoyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms. to 5 carbon atoms, porazlnkarbcnolovou, benzo-nominal group, CF 3 CO or CONR ⁸ R ^9, one of R ^u and R ¹³ is hydrogen and the other of the symbols represents a vinyl group, alkylsulfonylovcu group having 1 to 4 carbon atoms, furyl, thienyl, N-methylpyrrolyl or N-acetolpyrrole group * residue CH (R 4) NR ¹⁶ R 17 CNR8R9 II p CNR8R9 NH 2 4 8 7 4 9d b with the restriction that when R ¹² or R ^{13 is a} radical of formula (O) _p (I *) and p is 0, then R ^{7 is} not hydrogen or methyl, in which formulas m is 2 or 2, p is 0 or 1, t is 0, 1 or 2, Xj represents sulfur, oxygen. or NR11, R 7 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, allyloxy, hydroxyl, carboxyl, C 2 -C 5 alkoxycarbonyl, C 1 -C 5 alkylcarbonyl, phenyl , benzyl, naphthyl, pyridyl, NR ⁸ R ⁹ , CONR ⁸ R ⁹ , NHCOR ^W , nitro, chloro, bromo, trifluoromethyl or NR ⁸ , R8. and R9 are each independently hydrogen, C1-C4alkyl, phenyl or benzyl, R ^w represents a C 1 -C 4 alkyl group, a trifluoromethyl group or a phenyl group, R ¹¹ is hydrogen, methyl, ethyl or acetyl group and R 16 and R 17 are each independently hydrogen, C 1 -C 4 alkyl or C 2 -C 4 hydroxyalkyl, or R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a pyrrolidino group, piperidino, morpholino, thiomorpholino or 4-methylpiperazino, and pharmaceutically acceptable acid addition salts of those compounds wherein R 12 or R 13 contains a basic nitrogen atom or pharmaceutically acceptable cationic salts of those compounds wherein R ¹ is hydrogen or residues R ¹² or R 3 contain a carboxyl group, characterized in that the compound of the general formula (IX) in which: R ¹ has the above meanings except hydrogen, is reacted with an equimolar amount of alkylmagnesium halide having 1 to 4 carbon atoms and an aldehyde of formula R ¹² R ⁿ CO, wherein the aforementioned halide is appropriate chloride, bromide or iodide, and R12 and R13 are as defined above meaning, in an ether solvent at a temperature of from -80 to 25 ° C, to give the product of formula (II) " (JI) in which R 1, R ¹² · and R13 are as defined above, then, to produce a compound of formula II 'wherein R ¹⁸ is other · than hydrogen this product with an acyl chloride or acyl bromide of the formula R18C1 or R18Br wherein R * ⁸ is as defined above, or the corresponding acid anhydride, in the presence of an equimolar amount of a tertiary amine and in the presence of an inert organic solvent, and the resulting compound is optionally converted to its pharmaceutically acceptable acid addition salt or cationic salt. 2. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula H &apos; wherein R &apos; and R &lt; ¹⁸ &gt; are as defined in 1, R &lt; 12 &gt; hydrogen and the second of these symbols represents 248,749 as vinyl, furyl, thienyl, N-methylpyrrolyl or N-acetylpyrrolyl, the remainder CNR ⁸ R ⁹ II WITH CH (R ⁴⁾ NR ¹⁶ R ¹⁷ CNR ⁸ R ⁹ NH N — N 44 II -HR Or with the restriction that when R ¹ · ² or R 1 · ^{3 is a} radical of formula (0) with from 1 to 4 carbon atoms, allyloxy, hydroxyl, carboxyl, alkoxycarbonyl of 2 to 5 carbon atoms, alkylcarbonyl with 1 to 5 carbon atoms, NR ⁸ R ⁹ , CONR ⁸ R ⁹ , NHCOR ^{1, O} , nitro, chloro, bromo, trifluoromethyl or NR 8, R8 and ^R9 independently are hydrogen, alkyl having 1 to 4 carbon atoms, phenyl or benzyl, R 10 is C 1 -C 4 alkyl, trifluoromethyl or phenyl; R ¹¹ is hydrogen, methyl, ethyl or acetyl group and R 16 and R 17 are each independently hydrogen, C 1 -C 4 alkyl or C 2 -C 4 hydroxyalkyl, or R, 6 and R 17 together with the nitrogen atom to which they are attached form a pyrrolidino group having a value of 0, then R ^{7 is} not a hydrogen atom or a methyl group, in which m has a value of 2 or 3, p has a value of 0 or 1; 1 or 2 X. _f represents sulfur or oxygen, R 7 represents a hydrogen atom, a C 1 -C 4 alkyl group, a pin alkoxy group, a piperidino group, a morpholino group, a thiomorpholino group or a 4-methylpiperazino group, and pharmaceutically acceptable acid addition salts of those compounds wherein R ¹² or R ¹³ contain a basic nitrogen atom; pharmaceutically usable cationic salts of those compounds in which R @ 1 is hydrogen or the radicals R @ ¹² or R @ 13 contain a carboxyl group, 3. A process according to claim 1 wherein the reaction with an aldehyde of the formula R @ ¹² R @ ¹³ CO is carried out at a temperature of -78 DEG C. in the presence of tetrahydrofuran or ethyl ether. 4 Process according to claim 3, characterized in that a starting aldehyde R12R13CO wherein one of R 13 and R ¹³ 'is hydrogen and the other is A 2-thiazolyl group, 3-isothiazolyl, 5-methyl-3-oxazolyl, 1,3,4-thiodiazol-2-yl, pyridazin-3-yl, 1,2.3-thiadiazin-4-yl, 1,2.4-oxadiazin-3-yl, 1,2,4-oxadiazin-5-yl, 1,3,4-oxadiazin-2-yl, 1-phenyl-5-methyl-1,2,3-triazin-4-yl, N-methyl-1,2 ', 3,4-tetrazin-5-yl, 1-methyl-1H-diazin-4-yl, A 4-pyrimidinol group, 4,5-dimethylthiaxol-2-yl, benzothiazol-2-yl or 1-benzylbenximidazol-2-ylo2Ou; 5 Process according to claim 4, characterized in that used as starting material aldehyde of the above formula wherein one of R ¹² and R ¹³ is hydrogen and the other is 2-thiazolyl or benzothiaxol-2-yl group , 6. A process according to any one of Claims 1 to 5, wherein starting materials in which R1 is an allyl group are converted to the corresponding products wherein R1 is hydrogen, sodium or potassium by reacting the resulting allyl ester product with catalytic amounts of tetrakis (triphenylphosphine palladium) and triphenylphosphine, and an equimolar amount of sodium or potassium salt of 2-ethylhexanoic acid in the presence of an inert solvent.