CS248748B2 - Production method of the 6-(subst.)methylenpenicilan acids - Google Patents

Description

The present invention relates to novel 6- (subst.) Methylenepenicillanic acids, their esters and pharmaceutically acceptable salts, to pharmaceutical compositions containing said compounds, to a process for their preparation and to their use as inhibitors / actamases 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 (Mactam antibiotics. These compounds are characterized by the presence of a core containing a 2-azetidinone (1-lactam) ring fused to either a thiazolidine or dihydrola, a 3thiazine ring. the core contains a thiazolidine ring, the corresponding compounds are generally referred to as penicillins, while when the core contains a dihydrothiazine ring, such compounds are referred to as cephalosporins.

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

Despite the widespread use and general acceptance of / Mactam antibiotics as valuable chemotherapeutic agents, however, these substances have a major disadvantage in that some of them are not effective against certain microorganisms. It's supposed, that - . in many cases this resistence of the particular microorganism is desired. Mactam antibiotic caused by - that the microorganism produces β-lactamas.

[Beta] -Lacamases are enzymes that cleave the > -lactam ring of penicillins and cephalosporins to produce non-showing antibacterial activity. However, some substances have the ability to inhibit - / Mactamases and, when used in combination with penicillin or - cephalosporin, may - increase the antibacterial - activity of this penicillin or cephalosporins against certain microorganisms. G enhancement of antibacterial efficacy is said to be when the antibacterial activity of the combination of [alpha] -lactamase inhibitor and [beta] -mactic antibiotic is significantly higher than the sum of the antibacterial activities of the individual components.

Accordingly, the invention describes new ones

6- (Substituted methylene penicillanic acid) 1,1-dioxides and their esters readily hydrolyzable in vivo These novel penicillanic acids and their esters readily hydrolyzable in vivo are potent inhibitors of microbial / Maktamas. also a method of increasing the efficacy of β-lactam antibiotics using these novel acids, their salts and certain readily hydrolyzable esters.

The invention further provides a carboxyl-protected 1,1-dioxide derivative of 6- (subst.) Methylenepenicillanic acid, which compounds are useful as intermediates.

In European patent publication no. 50805 there are described compounds of formula III <0), when ^R < ^«я с ^'3

O ' ^FROM COOR ₃

where n is 0, 1 or 2,

R ₍ represents cyano or a certain carbonyl radical,

R ₃ represents a hydrogen atom, a lower alkyl group or a halogen atom and

R ₃ represents a hydrogen atom or an easily hydrolyzable group which are useful as β-lactamase inhibitors. In the same application, 6-oxopenicillanic acid esters, corresponding sulfoxides and sulfones, as well as a process for their use in the preparation of compounds of the formula III by reaction with a hypophosphite of the formula Rt R ₂ C = P (C ₆ H ₅ ) ₃ are described.

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 ₍ and R ₃ 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 ₃

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 inhibitors of? lactamases.

The present invention describes novel 6- (substituted) methylenepenicillanic acid derivatives of formula VIII

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 1 ^b represents a hydrogen atom or an ester residue readily hydrolyzable in vivo, selected from the group consisting of 3-phthalidyl, 4-crotonolactonyl, γ-butyrolacton-4-yl, a radical of formula

-CH ^ C — C-Fť 'v

II o

/ -coccé.-сосоог / h ·

Rí

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

(OF

wherein X ₂ represents a substituent at the 3-position of the known cephalosporin-type β-lactam antibiotic and R ¹⁵ represents a substituent at the 6 or 7 position of the known (3-actam penicillin or cephalosporin type antibiotic), particularly preferred groups for R14 are penicillin residues in which R 15 represents

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

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

D-2- (4-ethyl-2,3-dioxo piperazinocarbonylamino) -2- [4-hydroxyphenyl) acetamido or

2,2-dimethylr4'-phenyl-5iimidazolidinon-l-yl group, one of R ⁿ and Ri represents hydrogen and the other of the symbols represents a vinyl group, an alkylsulfonyl group having 1 to 4 carbon atoms, furyl, thienyl, N -methylpyrrolyl or N-acetylpyrrolyl, the residue

CH (R ⁴ ) NR 16 R 17

CNR ⁸ R ⁹

II p

CNR8R9

II

NH ε

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

Where R is / ap X 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,

Xj is sulfur, oxygen or NR11,

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

R8 and R9 are each independently hydrogen, C1-C4alkyl, phenyl or benzyl,

R 10 is C 1 -C 4 alkyl, trifluoromethyl or phenyl,

R1 ¹ is hydrogen, methyl, ethyl or formyl, acetyl and R16 _and R17 _are either each independently are hydrogen, alkyl having 1 to 4 carbon atoms or a hydroxyalkyl group with 2-4 carbon atoms or R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form pyrrolidino, piperidino, morpholino, thiomorpholino or 4-methylpiperazino, and pharmaceutically acceptable addition salts with. acids of those compounds in which R ¹² or R ¹³ contain a basic nitrogen atom or pharmaceutically acceptable cationic salts of those compounds in which R ¹ is a hydrogen atom or the radicals R 12 or R 13 contain a carboxyl group.

The above compounds wherein R 1 is the radical R ^and, are useful as intermediates for the preparation of those compounds in which R ¹ represents a group R ^b. The latter are potent inhibitors of the 3-lactamase according to the invention.

Particularly preferred are those compounds of formula VIII wherein one of R2 and R3 is hydrogen and the other is furyl, thienyl, hydroxymethyl, phenyl, methylsulfonyl, N-methylpyrrolyl, the remainder of the formula

(O) p / («V

Particularly preferred carboxyl protecting groups for R a are allyl, benzyl, tert-butyl and 2,2,2-trichloroethyl, with the group being particularly preferred. allyl relative to allyl. quite easy. deployment and removal.

Especially preferred as ester radicals readily hydrolyzable in vivo, i.e. as defined above for R ^b , are the groups P, CH ₃ g * c = c. -Cocor and -cococr of I 1 '| Ir ^W Ir

II o

a. especially those in which R 4 and R ⁶ are hydrogen and R ⁶ is as defined above.

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

Compounds of formula (VIII) wherein R 1 is Rb as defined above are useful as β-lactamase inhibitors. In this way, the compounds increase the efficacy of [beta] -actam antibiotics (penicillins and cephalosporins), in particular against those microorganisms which are resistant or partially resistant to [beta] -actam antibiotics due to the production of [beta] -actames degrading or partially degrading enzymes. . In this way, the spectrum of activity / Mactam increases. antibiotics.

The invention also provides a method of treating a bacterial infection in a mammal, including a human, comprising administering to the mammal in need thereof an antibacterially effective amount of penicillin or cephalosporins, in particular any of the following, and a compound of formula VIII in an β-lactamase inhibiting amount.

I. when the compounds of the invention effectively enhance the activity of β-lactam antibiotics generally are preferably combined with penicillin or cephalosporin already established in clinical practice such as amoxicillin, ampicillin, apalcilin, azlocilin, azthreonam, bacampicillin, carbenicillin, carbenicillin-indanyl, carbenicillin-phenyl. cefaclor, cefadroxil, cefaloram, cefamandole, cefamandol-naphat, cefaparol, cefatrizine, cefazoline, cefbuperazone, cefonicide, cefmenoxim, cefodizime, cefoperazone, ceporonide, cefotiramide, cefotiin, cefotiin, , cefacetril, cephalexin, cephaloglycine, cephaloridine, cephalothin, cepapirin, cepradine, cyclacilin, epicillin, furazlocilin, hetacillin, lenampicillin, levopropylcillin, mecilinam, meslocillin, penicillin G, penilinicin, siphenicinin, feneticin, ,. talampicillin and ticarcilin, including their pharmaceutically acceptable. salts.

The invention further provides a combination of the actamate inhibitors of the invention with

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

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

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

Compounds. Although the present invention may be administered separately from the actam antibiotic, combined dosage forms are preferred. The pharmaceutical composition, whether for oral or parenteral administration, comprises the inhibitor (Mactamase) of the invention and a / Mactam 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 in a single mammal. or, more usually, multiple administrations.

Compounds of the invention wherein one of the radicals R 1 and R 13 contains a basic nitrogen atom may form acid addition salts. The invention includes such salts with pharmaceutically acceptable acids. Examples of said acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, malic acid, tartaric acid, maleic acid, fumaric acid, gliconic acid, sugar248748 acid, benzenesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic 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 cations, and 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

In penicillanic acid derivatives, the attachment of a dotted line substituent (IEIIIIISHEi) to a bicyclic nucleus means that the substituent is below the plane of the nucleus and is said to be in the α-configuration. In contrast, attachment of a substituent to a bicyclic nucleus by a reinforced line (ь-) means that the substituent is above the plane of the nucleus. This latter arrangement is referred to as the β-configuration. The attachment of a substituent to the bicyclic nucleus by the normal solid line [-----] herein means that the substituent may be in either the «-configuration or the ^-configuration.

The present invention provides a process for the preparation of compounds of the above formula (VIII) and salts thereof, characterized in that the compound of formula (IX) is prepared

Г / x?

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 ¹³ CO, the above-mentioned halide is the corresponding chloride, bromide or iodide and R ¹² and R ¹³ are as defined above, in an ethereal solvent at a temperature of from -80 to 25 ° C to give the product of formula (II ⁾

in which

R @ ¹ , R @ ¹³ and R @ ¹³ are as defined above, optionally compounded on the free hydroxyl group with acetyl chloride, acetyl bromide or acetic anhydride in the presence of an equimolar amount of tertiary amine and in the presence of an inert organic solvent;

Ol ') in which

R ¹ , R ¹² and R ¹³ are as defined above and

R ¹⁸ represents a hydrogen atom or an acetyl group, is dehydrated or deacetylated, and optionally the resulting compound of formula VIII is converted to its pharmaceutically acceptable acid addition salt or cationic salt.

The process according to the invention can be described by the following reaction scheme:

Diagram

HO O

-z ^with N / ^{CH 3} Щ-R ··.

(γ COOR (IX) R ^H)

9 ^H β r ^{, ile} 1 — A— in ^CH3 4 _л ^{, f} CQOR ° (II ^{/ f} ) R ^ H • v

Οχ <г i (vlil) R ^ H

In the process of the invention, the appropriate 6'-bromo-1,1-dioxo-penicillanic acid starting ester of formula IX is converted to the corresponding Grignard reagents by reaction with an equimolar amount of a 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 -78 ° C. After stirring for several minutes, an equimolar amount of the corresponding aldehyde of formula (I) is added

R ¹² R ¹³ CO and stirring is continued until the reaction is virtually complete, which usually takes about 10 minutes to 4 hours (at the same temperature). The desired ester of formula (II) is then isolated by standard methods. For example, an aqueous ammonium chloride solution is added to the reaction mixture, and the product is extracted with a water-immiscible solvent. The resulting product of formula (II) is then further purified, for example by chromatography on silica gel.

The alcohol of formula (II) is then dehydrated to give the corresponding 6- (substituted) methylene-1,1-dioxopenicilate (VIII). Although a variety of methods known in the art for dehydrating secondary alcohols to olefins can be used to perform this reaction step, the preferred method is to convert the alcohol by reacting with at least equimolar amounts of acetic anhydride and pyridine to acetate and subsequently stirring at room temperature for 1 within 10 hours to produce a large amount of the desired olefin. Water is usually added to the reaction mixture and the desired product is isolated by extraction and purified if necessary.

The products of formula (1Г) or (VIII) 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 denotes a group R ^and, if desired, converted to the corresponding carboxylic acid (R ^b - hydrogen). If desired, however, the carboxylic acids of the formulas (VIII) and (VIII) may be converted to the corresponding compounds in which R ¹ represents an ester residue readily hydrolyzable in vivo.

Thus, an ester of formula ΙΓ or VIII (R ¹ -R ^a ), wherein R ^a represents a carboxyl function protecting group as defined above, can be converted to the corresponding acid or ester of formula IT or VIII (R ¹ -R ^b ), wherein R ^b means a hydrogen atom or an ester-forming residue readily hydrolyzable in vivo. Typically, the carboxyl function protecting group is removed from a compound of formula ΙΓ or VIII (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

^And R, the proper method, however, will not cause difficulties to those skilled.

As mentioned above, a particularly preferred carboxyl protecting group R a is an allyl group. Although this group can be cleaved with mild acidic or alkaline hydrolysis to a satisfactory result, a particularly preferred method for cleavage consists in using a soluble palladium (O) complex, namely tetrakis (triphenylphosphine) palladium (0) as a catalyst. This method has already been described by Jeffery and Mc Combie in J. Org. Chem., 47, 587-590 [1982]. 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 (0, e.g. about 1 to 5 mole%) of the complex in a nitrogen atmosphere. To this mixture is added the sodium or potassium salt of 2-ethylhexanoate in an equimolar amount based on the starting allyl ester, and the resulting mixture is stirred at room temperature until precipitation of the desired salt, for example the salt, is complete. of formula II * or VIII, wherein R 1 is sodium or potassium The reaction is usually complete in about 2 to 20 hours, and the resulting salt is then isolated, for example by filtration.

Compounds of formula II VIII or VIII 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 γ-butyrolacton-4-yl radical and a radical of the formulas

R4 —COCOR ⁶

R ⁵ a

R4 —COCOOR ⁶

AND

R ⁵ where

R 4, R 5 and R 6 are as defined above, such compounds may be prepared by alkylation of the corresponding compound of the invention wherein R ¹ is hydrogen with a halide of formula

R ^b Q i.e. 3-phthalidyl halide, 4-crotonolactonyl halide, γ-butyrolactone-4-halide or a compound of formula

QCOCoF rj.or QCOCOOR * ¹ 5 ^L

R ^b

R ^s where

Q is halogen 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 or VIII in which R ¹ is hydrogen in a suitable polar organic solvent such as N, N-dimethylformamide and adding about one mole equivalent of the corresponding halide of formula R ^b) After practically complete reaction, the product is isolated by standard techniques. It is often sufficient to simply 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, Ν-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. With regard to

4 870 '

171/18 and the above * · factualry / generally using: eating / reaction - times · · · moving! · · Secuzhrubarnoď.č 1 until ^:: 24 / hour. ,

The starting ethers of .alpha.-bromo-11-diotrophic acid: the novel acids of general formula (IX) are usually prepared from - 6,6-dibiome-1,1-dioxopenil. - Lactic acids by reaction with ΚγάΓΓ ηηιιΙ-ιΐΊϋϋβ-, sodium ¹ and sodium bisulfite, followed by seizure. The resulting * η 6 · · - + - rom-1,1-dioxopenicillanic acid is levered; is converted to the general ester of formula (IX) by default aldehydes of the formula R12-R13cq, wherein R @ ¹ - and - R @ ¹³ are as defined above, are,. either -. commercially available,. or they can be readily prepared from available and starting materials by methods known in the art; · For example - ·

1. Oxidation of the corresponding primary alcohols described above as required by the Wi-Tig precursors; · Reagents. using, for example, - oxidizing agents such as potassium diphosphate, chromic acid mixture. and pyridine, · kae talytic · oxidation · in the presence. noble metals and manganese dioxide.

2. The reaction of the corresponding methylsubstituted aromatic hydrocarbon, for example selenium dioxide.

3. Reduction of the corresponding 'alkoxycarbonyl' derivatives of 1 to 4 carbon atoms; in the alkoxy moiety a metal hydride at a low temperature in the presence of an ether residue; Examples of suitable metal hydrides include lithium aluminum hydride and diisobutylaluminum hydride. : ·.

4. Reaction - relevant · aromatic -. hydrocarbon - precursor with n-butyllithium and dimethylformamide. ;

As already described above. ^ m-compounds exhibit substituting Compound obecnéheuvzorce 'VIII wherein, R ¹ -knows *' · Na- hydrogen. and their . - in combination '. with d-lacquer-like antibiotics; synergistic efficacy in in vitro antibacterial assays. -; . This efficiency is demonstrated by the measurement of the minimum inhibitory concentrations (MICs) in a series of microorganisms.

The following section describes the procedure recommended by the International Collaborative Study on Antibiotic Sensitivity Testing [Errccson and Sherris, Acta. Pathologica et - - Microbiologia Scandinav. Supp. 2'7, section · B: · 64-68 (1971)], using brain-heart infusion agar, and a device allowing repeated inoculation. Overnight culture in test tubes is diluted 100-fold and used as. standard inoculum (20,000-10,000 cells in about 0.002 milliliters) is applied to the surface of the agar; each ml; contains 20 ml; agarn; · From the brain - and - the heart.

It is used - 112 - double - dilutions · - tested - substances - with - initial; the concentration of the test compound is 200 - / g / ml. Attempt - -se - - -evaluates. after; Incubate at 37 ° C for 18 hours, allowing the individual to incubate; do not take into account the sensitivity (lUt; jMlGj of the experimental one) - the 'lowest' - concentration - tested - by the ele - s of the woman - or - the combination - capable of being / is capable of / - by evaluating - by merely - causing a complete inhibition of the growth of the organism.

These compounds are of the formula: wherein R 1 is a atom. - - hydrogen- ·. and their salts, in combination with known / Mactamic: tibiotics, are useful as industrial industrial antinicubial agents. -example / at -process-. · Water treatment, - / cleaning -. waste water and sludge; . the protection of - paints - and wood, as well as - in local applications - as - disinfectants. When - using the described - to these;

Felling is often - - advantageous. . mix- the active substance-> with a non-toxic. -carrier ,! -. as · © '- is a vegetable · - or' mineral oil 'or a cream softening agent

Similarly, they can be dissolved or dispersed in liquid diluents. - or - solvents, - such as: water-, alkanols, glycols - or mixtures thereof - Mostly -; falls; it is expedient to use a concentration of the active substance moving from about 0.1; up to 10 - o proC; - - - Mass - - - Based on. - - total - - mixture / ¹

Jakujjižn byto bewitched ^ o /. above, they have compounds of the general formula-VIII-wherein R 1 is. - the remainder · Rb '-many. - more meaning ·! as effective inhibitors of microbial d-lactamases. These substances increase the antibacterial effect of the lactam antibiotics. i - (peníellditů '-.a ícefalosporrnů р anti - numerous - · mikrboщ-antsmůπг ,. - especially uproti Miko t ^ i ^ J ^ ianismům ¹ - - produkujícím- - U-laktamaH su.

The ability of the compounds to increase the activity of the. - Is - - possible * - - 'no evidence - experiments; where - are - fixed. MIC values of the tamutomatic and antibiotic compounds and of the compound; - obeon-*. - the formula - - - VIII; wherein 'RC' represents a hydrogen atom; a. these values are: comparing with the MIC values found for the combination of the antibiotic with a compound of the formula VI - wherein - R ¹ represents; atom, --vodtab - If ¹ antibacterial - potency - of this - combination; it is 'significantly' higher than one would expect the effectiveness of the individual components; it is considered to: increase efficiency;

The -MIC values (of these combinations) are determined using the method described by Barry and Sabath ' s Clinical - ' Clinical - &quot; Miicrobiology &quot;, edv - Lehette; Spáulding. .Trúent, -2. -Dary, »- -1974, - American - - Society - - for '- Mič · ru-Ьi ^ 0'lx ^^^: 5. ·· ^,

Compounds of formula (VIII) wherein R ¹ represents a hydrogen atom or an ester residue. readily hydrolyzable in vivo enhances the antibacterial efficacy of the in vitro antibiotics; - i.e.; reducing the amount of antibiotic required; to protect test mice from - otherwise - 1 lethal inocfluules of certain β-actamase-producing bacteria. In determining such efficacy, the mouse is intra. peritulation - inoculation with standardized-

A suspension of the test organism suspended in 5% of the porcine gastric mucin induces an acute experimental infection. The severity of the infection is standardized so that the mouse receives a lethal dose of the organism (lethal dose means the minimum inoculum of the organism needed to reliably kill 100% of the 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 group treated with the given dose of the 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 the compounds of the invention to enhance the efficacy of β-lactam antibiotics against β-lactamase-producing bacteria makes these compounds suitable for co-administration with β-lactam antibiotics in the treatment of bacterial infections in mammals, particularly humans. In the treatment of a bacterial infection, the compound of the invention may be mixed 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 a compound of the invention, whereby both are applied simultaneously. Alternatively, the compound of the invention may be administered as a separate agent during treatment with the .beta.-lactam antibiotic.

When using a compound of formula (VIII) wherein R ¹ is a R ^b moiety as defined above to enhance the efficacy of / Mactam antibiotic, a mixture of this compound with a Mactam antibiotic, or a compound of the invention itself when R ^b is CH 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 lactam antibiotic and / or the aforementioned compound of the invention normally comprises about 5 to 80% by weight of a pharmaceutically acceptable diluent.

When the compounds of the invention are combined with another / Mactam antibiotic, the compounds may 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 (VIII), wherein R ¹ is a residue of R ^b , / a lactam antibiotic, is in the weight range of about 1: 3 to 3: 1. Furthermore, when using a compound of the invention in combination with a 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 parenterally administered is normally about from 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 i / Mactam 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 / Mactam 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 / Mactam 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 and to administer parenterally / Mactam antibiotic. It is also possible to administer parenterally the compositions comprising the above-mentioned compounds according to the invention and at the same time orally administering the 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 or 300 MHz using a solution of the product in deuterochloroform, deuterium oxide, DMSO-d₆ or acetone-d, 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, cooled to -78 ° C and 0.52 ml of a 2.85 M solution of methylmagnesium bromide in tetrahydrofuran and the mixture was stirred at -78 ° C for 5 min. After adding 162 mg (0.16 ml)

248748>

The N-methylpyrrole-2-carboxaldehyde was stirred for 20 minutes at -78 ° C and then stirred. pour into a saturated ammonium chloride solution and extract 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 silica gel chromatography. using . mixtures. chloroform and ethyl acetate (9 r) as eluent. This yields · 180 · mg · · (.32%) · pure. .subject compounds.

3.68 (s, 3H0, t)

4.0--4.4 · (m, 1Ή),

4.42 (s, 1Η),

4.5-4.8 (m, 3H);

5.0-6.0 (m, 4H).

6.0-6.7 (m, 3H).

Example 2

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

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

1.4 (s, 3 H),

1.62 (s, 3H);

R13CHO

The corresponding compounds of the general formula are obtained

R ¹³

yield (% ') eluent *'

Ή-NMR (deuterochloroform, δ values in ppm)

A 6a-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. 1H).

A A mixture of 6a, 8R- and 6α, 8S-isomers

Δ 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),

1,4 1.4 (s, 3H), 1.6 (s, 3H),

3.28 (bs, 1H),

3.8-4.2 (m, 1 H),

4.35 (s, 1 H),

4.45-4.8 (m, 3H), 5.0-6.1 (m, 4H),

7.3 (s, 5H).

B 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); 71-7.4 (m, 1H);

7.1 - 8.0 (m, 1H).

8.2 - 8.7 (m, 2H);

R ¹³ Yield (%)

eluent * H-NMR (deuterochloroform, ppm values)

W 1.3 (s, 3H), 1.55 (s, 3H),

4.0 (m, 1H); 4.35 (s, 1H); 4.4-6.8 (m, 3H);

5.1- 6.2 (m, 4H); 72-7.5 (m, 2H);

8.2 - 8.6 (m, 2H);

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

1.55 (s, 3H), 3.3 (bs, 1H), 4.05 (dd, 1H), 4.3 (s, 1H),

4.3-4.8 (m, 3H), 5.0-6.2 (m, 4H), 6.8-7.4 (m, 3H),

1.4 (s, 3H), 1.6 (s, 3H), 3.0 (bs, 1H),

3.7-4.0 (m, 1H);

4.4-4.8 (m, 4H), 5.0-6.3 (m, 6H),

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, 1H); 4.1-4.8 (m, 2H);

6.7 (s, 1H); 6.85 (s, 1H);

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, 1H), 5.3-5.5 ( _m , 2H), 5.63 (d, 1H), 5.85-6.05 (m, 1H),

7.4 (d, 1H); 7.8 (d, 1H); 6a, 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. 1H);

5.8-6.0 (m, IH),

7.35 (d, 1H), 7.75 (d, 1H), _E 6a, the 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) 11.02 (s, 1H); 8.14 (m, 2H); IR: 3482, 1802 ^cm-first

R13 yield (%) eluent * ' 1 H-NMR (CDCl 3 ppm) 57 AND Less polar · 6a:, 8S-isomer: crude product (less polar 1.41 (s, 3H), 1.6 (s, 3H), '' N ^x 9 less polar iso- isomer) 4.45 (s, 1 H), mer F 4.4-4.8 (m, 4H) 8 more polar · (more polar isomer ) 5.2-5.6 (m, 3H) isomer 5.7 - 6.3 (m, 1H), 7.35 (t, 1H), 8.85 (d, 2H); More polar: 6A, 8R4Somer: 1.45 (s, 3H), 1.6 (s, 3H), 4.4 (s, 1H), 4.45 (dd, 1H), 47-4.9 (m, 2H), 4.95 (d, IH); 5.2-5.6 (m, 3H) 5.7 - 6.3 (m, 1H), 7.35 (t, 1H); 8.85 (d, 1H); Г li 25%, first fraction D First · fraction: (one isomer) 1.4 (s, 3H); 1.6 (s, 3H); 12 · ° / o, second fraction, 42-44 (m. 2H); (mixture of · two isomers) 455-5.0 (m, 3H) 5.1 - 61 (m, 6H), 7.6 · (r, 1H), 6.87 (d, 1H), 9.23 (s, 1H). rf 56 D 1.4 (s, 3H), 1.57 (s, 3H), 70: 30 mixture of isomers · 4.25 (m, 1H), 4.37 (s, 0.7Hi), r! 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), H xx) 8.84 (m, IH), '-M 22nd D 1.4 (s, 1H), 1.46 (s, 2H), mixture of isomers 1: 2 1.6 (s, 1H), 1.63 (s, 2H), 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, 1H)

6.95 and 7.05 (s, 1H),

7.28 and 7.36 (s, 1H),

Two isomers G 1.38-1.4.0 (d, 311), 1.56-1.57 (d, 3H), 4.20-4.40 (m, 2H), 4.59-4.72 ( m, 2H).

486-4.88 · [d, 0.5H], 5.04-5.06 (d, 0.5H), 5.28-5.42 (m, 2H), 5.5 (0 5.82 (m, 1H), 5.82-8.00; (m, 1HJ, 7.50-7.86 · (m, 1H), 7.90-8.08 · (m) (1H), 9.0-9.10 (m, 1H);

Legend:

*> eluents used in silica gel chromatography:

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

E - chloroform

F - chloroform - ethyl acetate (1: 1)

G - ethyl acetate

A - chloroform - ethyl acetate (9: 1)

B - ethyl acetate - chloroform · (7: 3 ')

C - chloroform - ethyl acetate (19 ·: 1)

D - Chloroform - methanol (19: 1)

Example 3

Allyl-6 (E) - (N-methylpyrrol-2-yl) methylene-1,1-dioxopenicillanate

180 mg (0.47 mmol) of allyl-6α- (N-methylpyrrol-2-yl) hydroxymethyl-1,1-dloxopenicillanate are dissolved in 3 ml of tetrahydrofuran and 0.15 ml of acetic anhydride and 0.2 ml are added to the solution. ml of pyridine. The mixture was stirred at room temperature for 1 hour, then stirred with water and extracted with ethyl acetate. The organic layer was dried and the solvent was evaporated in vacuo to give 162 mg of product which still contained the starting material. This product is dissolved in 3 ml of methylene chloride and 0.15 ml of acetyl chloride and 0.2 ml of pyridine are added. The mixture was stirred at room temperature for 2 hours and then worked up as above. 140 mg of crude product is obtained which, after purification by silica gel column chromatography, affords 72 mg (42%) of pure product. After recrystallization from ethyl acetate, the product is obtained in the form of colorless needle crystals.

1 H-NMR (CDCl 3, δ ppm):

1.45 (s, 3H);

1.65 (s. 3H);

3.7 (s, 3 H),

4.4 (s. 3H),

4.6-4.9 (m, 2H);

5.1-6.4 (m, 4H);

6.6- 7.0 (m, 2H);

7.5 (dd, 1H).

Example 4

Sodium-6 (E) - (N-methylpyrrol-2-yl) methylene-1,1-dioxopenicillanate

A solution of 46 mg allyl-6 (E) - (N-methylpyrrol-2-yl) methylene-1,1-dioxopenicillanate, 5 mg tetrakis (triphenylphosphine) palladium (0) and 4 mg triphenylphosphine in 1 ml methylene chloride under nitrogen for 5 minutes spinal cord. The resulting mixture was diluted with 1 mL of ethyl acetate and 0.25 mL of a solution of sodium 2-ethylhexanoate in ethyl acetate was added. The reaction mixture was stirred at room temperature for 1 hour, then filtered and the filtered precipitate was washed with ethyl acetate and ethyl ether. 30 mg of a yellow solid are obtained.

NMR-NMR (deuterium oxide, δ in ppm):

1.50 (s, 3H);

1.60 (s, 3H);

3.65 (s. 3H);

4.10 (s, 1H),

5.4 (s, 1H),

6.1- 6.5 (m, 1H);

7.0 (broad s, 2H),

7.2-7.4 (m, 1H);

IR (KBr):

568, 1660, 1745, 3465 cm @ -1.

Example 5

Allyl 6- (2-furanyl) methylene-1,1-dioxopenicillanate, (E) - and (Z) -isomers

To a solution of 310 mg (0.84 mmol) of allyl-6- (2-furanyl) hydroxymethyl-1,1-dioxopenicillanate in 5 ml of methylene chloride was added 0.14 ml (1 mmol) of triethylamine and 0.1 ml (0.924 mmol). of trifluoromethylsulfonyl chloride and the mixture was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was diluted with water and extracted with methylene chloride. The extracts were dried over magnesium sulfate and the solvent was evaporated in vacuo. 330 mg of crude product is obtained, which is chromatographed on a silica gel column using chloroform as the eluent to give 130 mg of a purified product of high resolution liquid chromatography (E) and (Z) -isomers in a ratio of 4: 1.

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

1.47 (s. 3H),

1.61 (s, 3H);

4.47 (s, 1H).

4.75 (d, 2 H),

5.1-6.2 (m, 4H);

5.52 (dd, 1H);

6.8 (m, 1H);

7.17 (d, 1H);

7.6 (d, 1H).

Example 6

Allyl-6 (E) - (N-acetylpyrrol-2-yl) methylene-1,1-dioxopenicillanate

A. Allyl-6- (N-acetylpyrrol-2-yl) Jacetoxymethyl-1,1-dioxopenicillanate

210 mg (0.51 mmol) of allyl-6- (N-acetylpyrrol-2-yl) hydroxymethyl-1,1-dioxopenicinate are dissolved in 3 ml of tetrahydrofuran, 0.16 ml of acetic anhydride and 0.2 ml of pyridine are added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water, extracted with methylene chloride, dried and concentrated. 171 mg (75%) of a yellow crystalline product are obtained.

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

1.4 (s, 3 H),

1.6 (s, 4H),

2.15 (s, 3H).

2.55 (s, 3H);

4-8

4.4 (s, 1Η)

4.6-4.8 (m, 3H)

5.1 - 6.0 (m, 3H);

6.1-6.6 (m, 2H);

6.6 - 7.4 (m, 2Ή).

B. 170 mg (0.38 mmol) of the Ν, diac-diacetate prepared in Part A are dissolved in methylene chloride and · 47 mg (0,38 mmol) of 1,5-diazabicyclo [4.3.1.0 &lt; O '] non-5-ene.

The resulting mixture was stirred for 1 hour. After stirring at room temperature, water was added and the mixture was extracted with methylene chloride. The extracts were dried and concentrated. 158 mg of oily material are obtained which, after purification by chromatography on silica gel using 2% ethyl acetate in chloroform as eluent, affords 108 mg of the desired product as a pale yellow oil.

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

1.5 (s. 3H),

1.6 (s, 4H),

2.55 (s, 3H);

4.4 (s, 1 H),

4.65 (d, 2 H),

5.0 - 6.0 (m, 4H),

6.3 (t, 1 H),

6.8 (dd, 1 H),

7.2 (m, 1 H),

8.2 (d, 1 H).

Example 7

Allyl-6 (E) -phenylmethylene-1,1-dioxopenicilate and the corresponding (Z) -isomer

A. Using the procedure of Part A of the preceding example, using. 1.98 mmol of allyl-6-phenylhydroxymethyl-11-di-xenicenicilate, 4.2. mmol of acetyl chloride and 0.4 ml of pyridine gave 0.7 g (84%) of allyl-6-phenylacetoxyethyl-1,1,1-dioxopenicillanate as a yellowish gum.

@ 1 H-NMR (CDCl3, .delta. 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).

Β. To a solution of 0.7 g (1.66 mmol) of the product prepared in Part A above in methylene chloride was added 0.25 ml (1.67 mmol) of 1,5-diazabicyclo [5.4.0] undec-5- The mixture was stirred at room temperature for 10 minutes. After addition of water and methylene chloride, the layers were separated, the organic extracts were washed with 0.1N hydrochloric acid, brine and water, dried over sodium sulfate and the solvent was evaporated. 660 mg of crude product is obtained, which is purified by chromatography on a column of 100 g of silica gel, eluting with chloroform. 68 mg (11%) of the corresponding (Z) -isomer is obtained.

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

1.45 (s. 3H);

1.60 (s, 3H);

4.45 (s, 1 H),

4.68 (d, 2 H),

5.37 (d, IH);

5.1-6.05 (m, 3H),

7.35 (d, IH);

7.45 (d, IH).

From the later eluted fractions, 100 mg (16.7%) of the (E) -somer of the title compound was obtained as a colorless oil which crystallized on standing.

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

1.45 (s. 3H);

1.58 (s, 3H);

4.45 (s, 1 H),

4.75 (d, 2 H),

5.45 (d. 1H);

5.2-6.2 (m, 3H).

7.36 (d, IH);

7.45 (s. 5H).

Example 8

Following the procedure of Example 5, the following compounds were obtained using the corresponding hydroxy compound prepared in Example 2:

R CH <

R13 yield (%) eluent in silica gel chromatography ¹ H-NMR (CDCl 3, δ in ppm) ’/’ Χ. X &quot; 22 (E) 19 (Z) ethyl ether (E) -isomer: 1.5 (s, 3H); 1.7 (s, 3H); 4.5 (s, 1H); 4.7 (d, 2H); 5.5 (d, 1 H), 5.1-6.2 (m, 3H); 7.3-7.5 (m. 2H); 7.7-8.0 (m, 1H); 8.53-8.83 (m, 2H); (Z) -isomer: 1.48 (s, 3H), 1.6 (s, 3H), 4.5 (s, 1H), 4.7 (d, 2H), 5.25 (s, 1H), 5.1 - 6.2 (m, 3H); 6.88 (s, 1 H), 7.2-7.5 (m, 1H); 8.43-9.0 (m, 3H); r o '• N ·' 36 ethyl acetate / hexane (1: 1) Isomer mixture: 1.45 (s, 3H), 1.62 (s, 3H), 4.5 (s, 1H); 4.7 (d, 2H); 5.2 - 6.2 (m, 4H); 6.75 (s, 0.3H), 7.2-7.5 (m, 1.7H), 7.6-7.85 (m, 1 H), 8.5-8.83 (m, 2H). l! ll , .Л * 'X 14 chloroform 1.45 (s, 3H); 1.6 (s, 3H); 4.4 (s, 3H), 4.7 (d, 2H), 5.0-6.2 (m, 3H), 5.25 (d, IH); 7.0 - 7.65 (m, 4H), CH ₂ = CH— 18 chloroform 1.45 (s, 3H); 1.65 (s, 3H); 3.7-4.2 (m, 1 H), 4.45 (s, 0.6H), 4.5 (s, 0.4H), 4.75 (d, 2 H), 5.1-6.4 (m, 7H).

Example 9

Following the procedure of Example 4, using the appropriate allyl-6-methylene-R ¹³ l, l-dioxo penicillanate sodium salt obtained by following the corresponding potassium salt was obtained using 2-ethyl hexanoate.

R ¹³

ČOCH ·.

c ₆ H ₅

CH ₂ = CH—

isomer: 1 (E): (Z) yield (%)

IC spectrum (KBr-technology)

621, 1,678,

764, 2 979,

402.3472 (E) (Z) (E) (Z) (E) + (Z) (E)

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

1.5 (s, 3H), 1.6 (s, 3H),

4.25 (s, 1H); 5.57 (s, 0.25H);

5.9 (s, 0.75H), 6.65 (m, 1H), 7.0 (d, 1H), 7.17 (d, 0.25H),

7.36 (s, 0.75H), 7.78 (m, 1H),

622, 1,728,

764, 3438 cm @ -1

565, 1,619,

667, 1,759,

950, 3,453 cm‘1

623, 1,778,

462 cm ^_ 1

303, 1 623,

761, 3,445 cm ^-1

623, 1,778,

448 cm ^-1

619, 1773,

425 cm ⁴

620, 773,

430 cm -1 (60 MHz):

1.56 (s, 3H), 1.65 (s, 3H),

2.68 (s, 3H); 4.25 (s, 1H);

5.88 (s, 1H); 6.5 (t, 1H); 7.0 (d, 1H);

76-8.0 (m, 1 H),

8.2 (s, 1 H), (60 MHz):

1.45 (s, 3H), 1.55 (s, 3H),

4.17 (s, 1H); 5.5 (s, 1H); 7.0 (s, 1H);

7.27 - 7.6 (m, 3H),

7.6-8.1 (m, 2H);

1.55 (s, 3H), 1.62 (s, 3H),

4.23 (s, 1 H), 6.05 (s, 1 H),

7.4-8.8 (m, 5H).

1.55 (s, 3H), 1.65 (s, 3H),

4.3 (s, 1H); 5.6 (s, 1H);

6.96 (s, 1 H),

7.1-9.0 (m, 4H),

1.5 (s, 3H), 1.6 (s, 3H),

4.3 (s, 0.3H), 5.55 (s, 0.3H),

6.0 (d, 0.7H), 6.95 (s, 0.3H),

72-7.8 (m, 4.7H),

1.55 (s, 3H), 1.60 (s, 3H),

4.2 (s, 1H); 5.8 (s, 1H);

70-7.9 (m. 4H);

AND

1.59 (s, 3H), 1.60 (s, 3H),

4.22 (s, 0.6H), 4.3 (s, 0.4H),

5.53 (s, 0.4H), 5.75 (s, 0.6H),

5.5-6.2 (m, 3H);

R ¹³ isomer yield IC spectrum 1 H-NMR (deuterium oxide, (%) (KBr - echnika) δ in ppm) (E) ⁷⁷ i 1

..X,

C / s ^vr (potassium salt)

.... ¾

H 4 (E) ⁹²

-Ν 'X (potassium salt)

Example 10

6 (E) -phen-ylmethyl-penieilanic acid 1,1-dioxide

To a solution of 0.1 g (0.28 mmol) of allyl-6 (E) -phenylinethylene-1,1-dioxopenicillanate, 20 mg triphenylphosphine and 20 mg tetrakisph triphenylphosphine) palladium (0) in 3 mL ethyl acetate was added 0.57 mL 0.5 M sodium 2-ethylhexanoate, the mixture is stirred at room temperature for 1 hour and then allowed to stand in the refrigerator for 65 hours without precipitation. The mixture was diluted with ethyl acetate and water, the aqueous layer - separated with dilute hydrochloric acid, acidified to pH 1.8 and extracted with fresh ethyl acetate. The extracts were dried over sodium sulfate and the solvent was evaporated. evaporation in vacuo to give 62 mg (69%) of the desired product which, upon crystallization from acetone, resulted as yellow crystals.

¹ H-NMR (perdeuteroacetone, - δ values in ppm):

1.55 (s, 3H);

1.65 (s, 3H);

4.43 (s, 1 H),

5.93 (d, IH);

7.3-70 (m, 6H).

8.7 (bs, 1H).

IR (KBr):

327, 1685, 1737, 1772, 2 929, 2 961, 3 108, 3,477 · cm -1.

Example 11

Potassium-6 (E) - (1-methylimidazol-2-yl) methylene-1,1-dioxopenicilate

A. Allyl-6- (1-methylimidazol-2-yl) acetoxymethyl-1,1-dioxopenicillanate-1,5 (s, 3H), 1,6 (s, 3H),

2.5 (s, 3H), 4.28 (s, 1H), 6.05 (d, 1H),

7.2-7.35 (m, 2H).

7.4 (d, 1H); 7.67 (t, 1H); ¹³ C-NMR (uterine oxide, δ in ppm):

20,713. - 22.436, 26.032, 68086, 68.533, 74.489, 120.794, 128.334, 132.843, 140.670, 152.5 ^ 4 ^ 9, .. 163.012, - 174.041, 175.657,

614, 1770, (deuterium oxide + perdeute3 406 cm ^-1 rodimethylsulfoxide):

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

4.1 (s, 1H); 5.9 (d, 1H);

7.5 (d, 1H); 8.5-9.0 (m, 3H).

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

@ 1 H-NMR (CDCl3, .delta. 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);

8.8 (m, 1H); 7.0 (m, 1H).

B. Allyl-6 (E) - (1-methylimidazol-2-yl) methylene-1,1-dioxopenililate

The product prepared in Part A above (392 mg, 0.920 mmol) was converted according to Part B of Example 6 using 5 mL of methylene chloride and 0.115 mL of 1,5-diazabicyclo [4.3.0] non-5-ene in 53% yield. . the title ester.

ďH-NMR (deuterochloroform, δ in ppm):

1.5 (s. 3H),

1.6 (s, 4H),

3.7 (s. 3H),

4.35 (s, 1 H),

4.7 (m, 2H), 50-6.1 (m, 3H);

5.7 (d, 1 H),

6.9 (m. 1H);

7.1 (d. 1H).

7.2 (m, IH).

C. 163 mg (0.44 mmol) of the allyl ester prepared in Part B were converted to the potassium salt of the title example using potassium 2-ethylhexanoate instead of the corresponding sodium salt. The product consisted of 143 mg (87% yield) of the individual (E-change).

T-N ^ MR (pradeuteaodimet: hyltulfoxide, δ in ppm):

1.38 (s, 3H);

1.45 (s, 3H);

3.8 (s, 4 H),

5.68 (s, 1 H),

7.15 (s, 1 H),

7.35 (m, 2 H).

13 C-NMR (pradeuteaodimeter: hylsulfoxide, δ in ppm):

18.5, 20.2, 32.5, 64.4, 66.2, 70.55, 115.2,

124.6, 129.9, 130.6, 141.2, 167.9, 169.0.

IR (KBa-technology):

614, 1762, 3428 cm ^-1 .

Example 12

Nataium-1,1-dioxo-4 (E) - (2-piperidinyl) methylenepenicilate

0.14 g (0.4 mmol) of allyl-1,1-dioxo-3 (E) - (2-pyridyl) methylenepenilicilate, 20 mg of tetrakis (thiphenylphosphine) palladium (0) and 20 mg of triphenylphosphine are dissolved in 2 ml of g 0.8 ml (0.4 mmol) of a 0.5 M solution of sodium 2-ethylhexanoate in ethyl acetate was added to the solution under nitrogen, and the reaction mixture was stirred at room temperature for 5 minutes, then the precipitate was filtered off, washed The organic layer was washed with ethyl acetate and dried to give 0.13 g (95%) of the desired sodium salt as a yellow solid.

1 H-NMR (druteroxide, δ in ppm):

1.50 (s, 3H);

1.60 (s, 3H);

4.23 (s, 1 H),

5.90 (d, 1H, J = 1Hz);

7.1-8.0 (m, 4H).

8.57 (m, IH).

IR (K ^ i - ^ ^ ^^^):

590, 1621, 1770, 3454 cm -1.

Example 13

(E) - (E) - (2-Pyrimidinyl) methylenepenicillanic acid methyl ester and potassium salt

A. 560 mg (1.69 mmol) of α-Hyl-β-β-pyrimidinyl-methylene-penicillanate and 730 mg of 3-chloro-propyl-benzoic acid (3.38 mmol) were dissolved in 10 ml of methylene chloride, stirred for 4 hours under nitrogen, then diluted with water and extract with methylene chloride. The extracts were washed with sodium thiosulphate solution, neutralized with sodium bicarbonate and, after washing with sodium chloride solution, dried and concentrated in vacuo. 460 mg of crude oil are obtained, each purified by tilica gel column chromatography. Elution with a 9: 1 mixture of chloroform and ethyl acetate yielded 180 mg of the desired any ester as a pale yellow solid.

1 H-NMR (CDCl 3, δ ppm):

1.45 (s, 3H);

1.65 (s, 3H);

4.5 (s, 1 H),

4.75 (m, 2H).

6.2-6.3 (m, 3H);

5.75 (s, 1 H),

7.1-7.5 (m. 2H);

8.9 (d, 2 H).

B. Using the procedure of Example 12, reaction of the above allyl ester with triphenylphosphine, trtrakite (triphenylphosphine) palladium (0) and potassium 2-ethyl hexanoate afforded the desired potassium salt in 89% yield as a light pink solid.

4H-NMR (deuterium oxide, δ in ppm):

1.6 (s, 4H),

1.68 (s, 3H);

4.4 (s, 1 H),

6.1 (s, 1 H),

7.48 (s, 1H).

7.54 (t, 1 H),

8.88 (d, 2 H).

¹³ CtNMR (deuterium oxide, δ in ppm):

20.9, 22.7, 68.8, 68.9, 74.6, 124.5, 132.5,

139.9, 160.9, 163.2, 172.5, 175.5.

Company ID (КБМесЬтка):

560, 1,615, 1,771, 3,439.

Example 14

Allylt 3t (2-thiazolyl) acetoxymeryl 1,1,1-dioxopenicillanate

According to the procedure described in Example 3, 0.5 g (1.29 mmol) of allyl 3- (2-thiazolyl) -hydroxymethyl-1,1-dioxopricicilate (prepared in Example 2) is 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. It is obtained. 0.688 g of the desired acetate.

248748 33

1 H-NMR (CDCl 3, δ ppm):

1.52 (s, 3H), 1H (s, 3H), 2.35- (s, 3H), 4.4-4.6 (m, 2H), 4.6-5.0 (m, 3H), 5.2-6.4 (m, 3H), 6.65 (d, 1H), 7.4 (d, 1H), 7.8 (d, 1H).

Example 15

Allyl-6- (2-thiazolyl) methylene-α, 1-dioxole penicillanate and its hydrolysis to the potassium salt

A. 0.688 g (1.29 mmol) of the above acetoxy ester was mixed with 0.16 g (1.29 mmol) of α, 5-diazabicyclo [4.3.0] non-15-ene and 5 ml of methylene chloride. The resulting mixture was stirred at room temperature for 1 hour, then diluted with methylene chloride, washed twice with 50 ml of water each time, dried over sodium sulfate and the solvent was evaporated. The oily residue is chromatographed on a silica gel column using a mixture of equal parts of ethyl acetate and hexane as eluent. 0.189 g (39%) of a pale yellow oil is obtained.

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

1.53 (s, 3H),

1.65 (s. 3H);

4.33 - (s, 1H).

4.55 (d, 2 H),

5.0-5.4 (m, 2H).

5.45- (s, 1 H), (m, 1 H),

7.1 (m. 1H);

7.75 (m, IH);

7.65 (d, IH).

B. Hydrolysis of the above allyl ester by the procedure of Example 11, Part C, yielded a yield of 84.7%. ll166 (2-thiazolyl) methylene-1,1-dioxoipe-. nicilanate resulting in the form of a yellow solid.

NMR-NMR (250 MHz, perdeuterodimethyl sulfoxide, δ in ppm):

1.40 (s, 3H).

1.45 (s. 3H);

3.80 (s, 1 H),

5.83 (s, 1 H),

7.66 (s, 1 H), 8.04 (m, 2 H).

Example 16

The corresponding 1,1-dloxopenicillanic acid ester was used according to the procedure of Example 6. substituted in position 6. The remainder - R ¹³ CHO ¹ H as the starting material. - transports the following acetylated esters:

R ¹³

Example 17

stereochemistry at C _e and C g mixture 6a, 8S and

6a, 8R mixture of 6a, 8S and

6a, 8R in a 60:40 ratio of 6a, 8S and

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

The 8-acetoxy esters prepared in the previous examples were converted to the corresponding 6-methylenderivatives using the procedure of Part B of Example 6 and then the allyl group was removed as described above to give the corresponding potassium salt. The following compounds are obtained in this way:

Yield ^! H-NMR (CDCl3, δ in ppm)

100 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, 1H), 6.65 (d) (1H),

7.5 (m, 3H), 7.98 (s, 1H), 8.20 (m, 2H),

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, 1H),

6.3 (m, 1H); 7.45 (d, 1H); 8.82 (d, 1H); 9.25 (m, 1H);

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).

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248748 *

Example 18

Injectable preparation

Equal parts by weight of celoperazone-nalria and potassium-1,1-dioxo-6 (E) - (2-pyrazinyl) methylene penicillanate were mixed with 20 parts by weight of water. Using methods common in pharmaceutical practice, the solution is sterile filtered, filled with vials, which are loosely sealed with rubber closures and lyophilized. The filling volume is such that each vial after lyophilization, which is now sealed under vacuum, contains 500 mg of each active ingredient. Prior to injection, 10 ml of sterile water for injection is injected into the vial via a syringe piercing the rubber stopper and the vial is rubbed to dissolve all solids. The solution for injection in a volume of 1 to 10 ml is withdrawn from the vial through a rubber stopper using a syringe with a hypodermic needle.

Preparation

Allyl 6'-i-bromo-1,1-dioxopenicillanate (i) 6'-bromopenicillanic acid 1,1-dioxide.

To a suspension of 20.66 g (0.0517 mol) of 6,6-dibromopenicillanic acid 1,1-dioxide in 80 ml of water was added portionwise 13 g (0.155 mol). _; 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 is diluted with ethyl acetate, the organic phase is washed with brine, dried over sodium sulfate and the solvent is evaporated off under vacuum. 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 the product was 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.

NMR-NMR (deuterochloroform, δ in ppm):

4.4 (s, 1H);

4.6 (d, 1H);

4.7 (d, 2 H),

5.15 (d, 1H);

5.1-5.95 (m, 3H). .

Preparing В '

(I) 2-hydroxymethyl-1-methylimidazole;

A mixture of 50 g of 1-methyl-radadazole ·) and 100 µl of 37% formaldehyde (1.08p density) is introduced into a 300 ml stainless steel autoclave and heated to 150 ° C (bath temperature) for 17 hours. was removed, concentrated in vacuo and the residue stored overnight at 4 ° C. the resulting mixture of crystals and oil zfiltrhje colorless crystalline product was rinsed with ethyl acetate and dried in vacuo. ¹ to afford

14.60 g of the desired product. A second crop of 6.48 g was obtained by treating the mother liquors. The overall yield was 21.08 g (31%).

(ii) To a solution of 4.96 g (43.9 mmol) of 2-hydroxymethyl-1-methylimidazole in 50 ml of dioxane was added 4.90 g (44.1 mmol) of silica, the mixture was successively added. Stir for 5 hours at 85 to 90 ° C and then for 36 hours at temperature. room ¹ ;. 8 hours at 85 ° C and finally for 15 hours at room temperature, filtered and the solvents were removed. evaporate under vacuum. 4.81 g of crude honaldehyde are obtained, which is distilled to give 2.11. g of the product in the form of colorless crystals, boiling point 65 DEG C./373 Pa.

P Гр г a C a

4-formylpyrimidine

To a solution of 10 g (0.106 mol) of 4-methylpyrimidine in 100 ml of dioxane was added at room temperature 11.8 g of selenium dioxide and the mixture was heated to 100 DEG C. for 15 hours. 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.

7.87 (dd, 1H);

9.06 (d, 1H);

9.43 (d, 1H),

10.0 (s, 1H).

1.4 (s, 3 H),

1.6 (s, 3H);

Р г í р гаva D

Diphenylmethyl-6α-bromo-1,1-dioxopenicilianate

To a solution of 21.557 g (0.1 mol) of diphenyldiazomethane in 400 ml of dry tetrahydrofuran was added portionwise over 30 minutes

31.2 g (0.1 mol) of 6α-bromo-1,1-dioxopenicillanic acid. 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 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 benzthiazole (b.p. 82 DEG C./0.2 mm Hg) in 250 ml of tetrahydrofuran was cooled to -78 DEG C. under nitrogen, stirred at this temperature for 15 minutes, then stirred for 15 minutes. 29.6 ml (0.074 mol) of 2.5M n-butyllithium was 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.

1 H-NMR (CDCl 3, δ 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 aldehyde yield Ή-NMR (deuterochloroform, (%) values in ppm)

CH., 98 M V / ‘ amber colored boiling point oil 120 - 122 ° C / 3333 Pa cho ra and CH ₃ 50 4.2 (s, 3H), 8.05 (s, 1H) ♦ p, „......; N ---- N 10.00 (s, 1 H), 1 '.‘í O AT N CHO

1.2 (t, 6H), 3.6 (quartet, 2H),

3.64 (quartet, 2H), 6.95 (s, 1H),

7.21 (d, 1 H), 7.55 (d, 1 H),

8.23 (d, IH).

ON

Prepared in solid form in 37% yield by reaction of 1H-1,2,4-triazine with methyl iodide in ethanolic sodium ethoxide prepared from Imidazole and ethyl orthoformate as described by Curtls et al., J. Org. Chem. 45, 4,038 (1980)

Preparation F

Pyrazine-2-carboxaldehyde

The pyrazine-2-carboxylic acid is esterified by refluxing with methanolic sulfuric acid for 5 hours. The methanol was evaporated in vacuo, the residue was diluted with methylene chloride and neutralized to pH 7.5 with sodium bicarbonate. 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.

¹ H-NMR (CDCl 3, δ ppm):

E (s, 3H),

8.93 (m, 2H).

9.47 (m, IH).

g (0.145 mol) of this methyl ester is dissolved in 600 ml of dry tetrahydrofuran, the solution is cooled to -78 ° C and a solution of 5.8 g of 98% lithium aluminum hydride in tetrahydrofuran is 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 product, which was purified by silica gel column chromatography. Elution with a 4: 1 mixture of methylene chloride and ethyl acetate gave 5.02 g of the product as pale yellow needle crystals.

¹ H-NMR (CDCl 3, δ ppm):

8.38 (m, 2H).

8.7 (bs 1H),

9.7 (s, 1 H).

Preparation G

2-phenyl-1,2,3-triazole-4-carboxaldehyde (i) 0.34 mol of acetone dicarboxylic acid in 100 ml of water is reacted with 0.58 mol of sodium nitrite at 0-10 ° C. Dilute nitric acid is then added to the reaction mixture to precipitate the product. The desired dioxime, i.e. 1,3-dioximino-2-oxopropane, was obtained in 46% yield as red-yellow crystals.

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

^j H-NMR (perdeuteroaoetone, δ in ppm):

7.3 (m. 5H);

7.9 (s. 1H).

8.6 (s. 1H).

10.5 (bs, 1H),

11.4 (bs, 1H),

12.3 (s, 1 H).

(iii) 24.7 g (0.119 mol) of the above-prepared dioxime-phenylhydrazone were stirred with 500 ml of aceranhydride at room temperature for 30 minutes, poured into water, stirred for 20 minutes and then filtered. The resulting crude product was recrystallized from benzene / ethyl acetate to give 15.47 g (52%) of the monoacetate of formula

HON - CH - C (- NNHC ₆ H ₅ ) CH = NOCOCH ₃ as a yellow powder.

1 H-NMR (CDCl 3, aoetone, δ in ppm):

1.85 (s, 3H);

7.09 (m, 5H);

7.95 (s, 1H).

8.3 (s, 1 H),

10.9 (bs, 1H),

12.25 (s, III).

(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 the solution was 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. 6 g of crystalline aldehyde are obtained.

Ή-NMR (deuterochloroform, δ values in 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 sulphate was stirred at 40 ° C for 4 hours in 50 ml of ethanol and 70 ml of toluene. 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 toluene / water and the aqueous layer was extracted with toluene after separation.

The organic layers were combined, washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuo gave a yellow liquid material which, by distillation, gave 14.68 g of product, bp 120-124 ^° C / 4 kPa, which crystallized on standing.

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

1 H-NMR (CDCl 3, δ 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- (subst.) Methylenepenicillanic acids of the general formula VIII o. o COOÍ? ' (Vlil) in which R @ 1 represents a radical Ra or R @ ^b , wherein R @ 1 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 radical and R ^b represents a hydrogen atom or an ester residue readily hydrolyzable in vivo, selected from the group consisting of 3-phthalidyl, 4-crotonolactonyl, γ-butyrolacton-4-yl, formula (I) -COCOR ¹ R 5, ~ COCOQR ^f μ R4 I — CHOCOR ¹⁴ where R ¹⁵ represents 2-phenylacetamido in which: R 4 and R ⁵ are each hydrogen or methyl, R ⁶ is C 1 -C 5 alkyl and R ¹⁴ is a radical of formula 2-phenoxyacetamido, D-2-amino-2-phenylacetamido, D-2-amino-2- (4-hydroxyphenyl) acetamido, 2-carboxy-2-phenylacetamidogroup, 2-carboxy-2- (2-thienyl) acetamido, 2-carboxy-2f (3-thienyl) acetamido, D-2- (4-ethyl-2,3-dioxopiperazinocarbonyl-amino) -2-phenylacetamido, or r-2 , 2-dimethyl-4-flny-eiimldlzolidinon-l-yl group, one of R ¹² and R ¹ · ³ represents hydrogen and the other of the symbols represents a vinyl group, an alkylsulfonyl group having 1 to 4 carbon atoms, furyl, thienyl , N-methylpyrrolyl or N-acetylpyrrolyl, respectively CH (R ^{/ L] NR1} 6R17 CNR ⁸ R ⁹ II WITH CNR8R ⁹ NH (O) p (Ok * · ------ 1 "and. IN' • 1. 4-Л> ⁽ C k'-o _l > D UI x ₁ Ч Сл- ’ N - N i; r ^ř </ with the proviso that R ¹² or R13 is a radical of formula a p is 0, then R ^{7 is} not hydrogen or methyl, in which m is 2 or 3, p is 0 or 1, t is 0, 1 or 2, X 1 represents sulfur, oxygen or NR 11; 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 carbon, phenyl, benzyl, naphthyl, pyridyl, NR ⁸ R 9, COR ⁸ R 9, NHCOR 10, nitro, chloro, bromo, trifluoromethyl or NR ⁸ , R8 and R9 are each independently hydrogen, C1-C4alkyl, phenyl or benzyl, R 10 is C 1 -C 4 alkyl, trifluoromethyl or phenyl; R11 represents a hydrogen atom, a methyl, ethyl or acetyl group; R ¹⁶ and R ¹⁷ are each independently hydrogen, C 1 -C 4 alkyl or C 2 -C 4 hydroxyalkyl, or R 18 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 contain a basic nitrogen atom or pharmaceutically acceptable cationic salts of those compounds wherein R 1 is hydrogen or R12 or R'3 contain a carboxyl group, characterized in that the compound of formula IX is present H Ю o '•' what? ¹ (ix) wherein R1 is as defined above except hydrogen, reacted with an equimolar amount of C1 -C4 alkylmagnesium halide and an aldehyde of the general formula R12 R13 CO, wherein said halide is the corresponding chloride, bromide or iodide and R12 and R13 are as defined above, in an ether solvent at a temperature of from -80 to 25 ° C to give the product of formula (II) with acetyl bromide or acetic 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 of formula (II) CH ₃ CH ₃ C00R4 in which R ¹ , R '2 and R ^13' are as defined above and R ¹⁸ represents a hydrogen atom or an acetyl group, is dehydrated or deacetylated, and optionally the resulting compound of formula VIII is 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 a compound of formula (VIII) in which: R1 is defined as in claim 1, one of R 12 and R ^that represent a hydrogen atom and the other of the symbols represents a vinyl group, furyl, thienyl nominal ··, N or N-methylpyrrolyl acetylpyrrolylovou radical, radical CH (R4) NR ¹⁶ R1 · ⁷ CNR8R9 II p CNR8R9 II NH (O) p in which R1, R12 and R13 are as defined above, this compound optionally being acetylated on the free hydroxyl group with acetyl chloride; Μ — N 11 i | -ή- fj. .О> .. bo -Q ' ⁽ CHm. ^N x With the proviso that when R ¹² or R ^{1 is a} radical of formula a p is 0, then R7 is not hydrogen or methyl, in which formulas m is 2 or 3, p is 0 or 1, t is 1 or 2, X. ₍ represents sulfur or oxygen, 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, radical NR ⁸ R 9, CONR ⁸ R 9, NHCOR1- ^0, nitro, chlorine, bromine, 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 is C 1 -C 4 alkyl, trifluoromethyl or phenyl; R11 represents a hydrogen atom, a methyl, ethyl or acetyl group; R ( ¹⁶⁾ and R ( ^{17) are} either independently of one another hydrogen, C1-C4alkyl or -hydroxyalkyl-C2-C4 'or R1-a-R17 together with the nitrogen atom, to which they are attached form pyrrolidino, - piperidino, - morpholino, thiomorpholino or -4-methylpiperazino, and the pharmaceutically-acceptable acid addition salts of those compounds in which R 12 or -R 1 · ³ contain a 'basic atom' nitrogen or or pharmaceutically useful canonical compounds of the above compounds, wherein R ¹ represents a hydrogen atom or the radicals -R ¹² or RJ contain a carboxyl group. ' ^:: 3. Process according to claim 1 or 2, characterized in that 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 1-hydrofuran or of ethyl ether. 4. Method according -point 3, characterized - in that it is used - the starting aldehyde - - Formula ¹ R12r 3CO - in -němž --jeden 'that' - the symbols ^R12 and R13 is "H" and the second - represents A 2-thiazolyl group, 3-isothiazolyl, 5-methyl-1H-oxazolyl, 1,3,4-thiadiazol-2-yl, pyridazin-3-yl, 1,2,3-thiadiazin-4-yl, 1,2.4-oxadiazin-13-yl, 1.2.4-oxadiazin-S-yl, 1,3,4-oxadiazin-4-yl, f-phenyl-5-methylyl-2,1-laiaz-4-O-yl, N-methyl-1,2,3,4-tetrazin-5-yl, 1-methyl-1,2-aza-n-3-yl, d-pyrimidinyl, 4. A compound having the formula 4, methylthiazol-2-yl, benzothiazyl-2-yl or 11-benzobenzimidazol-2-yl-2-yl. 5. A method -According to claim 4, characterized in that - as a starting -material -Use aldehyde from above - mentioned - of 'the formula wherein one of R' and R ² - R m '· represents hydrogen and the other -represents '- ² ltbiazylylovou group -or -benZУtelazy-2-зlyVУu group. . 6. The method of any one of items 1 to 5, characterized in that starting materials are used in which R1 is an aryl group which is converted into the corresponding products in which R1 is hydrogen, sodium or potassium by reacting the resulting aryl ester product with catalytic amounts of lerakis (1-phosphinyl) palladium (1). O) and triphenylphosphine, and with an equimolar amount of the sodium or potassium salt of 2-ethylhexanoic acid in the presence of an inert solvent.