CS248747B2 - 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 thereof, to pharmaceutical compositions containing said compounds, to a process for their preparation and to their use as α-lactamase inhibitors and as intermediates for their production.

One of the most well known classes of antibacterial agents that is widely used is the class of substances known as β-actam antibiotics. These compounds are characterized by the presence of a core containing a 2-azetidinone (/ lactam) ring unfused 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 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 cerbenicillin, typical examples of common cephalosporins are cephalothin, cephalexin and cephaloline.

Despite the widespread use and generally acceptance of / Mactam 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 numerous cases this resistance of a particular microorganism to a given / Mactam antibiotic is due to the microorganism producing β-actamase. Β-Lactamases are enzymes that cleave the β-actam ring of penicillins and cephalosporins to produce products lacking antibacterial activity. However, some substances have the ability to inhibit [alpha] -lactamases and when used in combination with penicillin or cephalosporin, this may increase the antibacterial activity of that penicillin or cephalosporin against certain microorganisms. An increase in antibacterial activity is reported when the antibacterial activity of the combination of a β-lactamase inhibitor and a β-actam antibiotic is significantly higher than the sum of the antibacterial activities of the individual components.

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

In European published patent application

No. 50,805 discloses compounds of formula III

phi //) in which n is 0, 1 or 2,

R 1 is cyano or a certain carbonyl radical,

R2 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. The same application describes 6-oxopenicillanic acid esters, the corresponding sulfoxides and sulfones, as well as a process for their use in the preparation of compounds of formula III by reaction with a phosphorane of formula R 1 R 2 C = P (C 6 H 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

OR3

R4-CH wherein R3 is hydrogen or alkanoyl and R4 is hydrogen, C1-C4alkyl, phenyl, benzyl or pyridyl, which are useful as β-lactamase inhibitors.

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

where n is 0 or 2,

Хз means a hydrogen or bromine atom,

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 the formula -C-R

IC c '' tr * f-COCOR ^{6 l} R *

© COCOQR

and -chocor in which

--CH (R ⁴ ) NR ¹⁶ R ¹⁷ , each of R ⁴ and R ⁵ is hydrogen or methyl, R ⁶ is C 1 -C 5 alkyl and R ¹⁴ is a radical of formula

- CN ⁸ R ⁹ II with - CN ⁸ R ⁹ II NH or

wherein X2 is a substituent in the 3-lactam -antibiotika known cephalosporin and R ¹⁵ is a substituent in position 6 or 7 of the known / .beta.-lactam antibiotics of penicillin or cephalosporin type, being especially preferred groups represented by R ¹⁴ are the aforementioned penicillin residues in which R ¹⁵ represents

- phenylacetamido group,

- phenox y, c-thiazolidine, D-2-aminoH2-phenylaceto; miido, D-2-aminoimino-2- (4-hydroxyphenyl) acetamido,

2-carboxy-2-phenylacetamido, 2-carbioxy-2- (2-thienyl) acetamido, 2-carboxy-2- (3-thienyl) acetamido, D-2- (4-ethyl-2,3-) dioxopiperidine- _1- zinccarbonyl-amino) -2-phenylacetamido-group,

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

2,2-dime ^| a thyl-4-phenyl-5-imidazolidinon-1-yl group,

R ¹⁸ is hydrogen, C 2 -C 5 alkanoyl, C 2 -C 5 alkoxycarboinyl, pyrazinecarboinyl, benzyl, CF ₃ CO or CONR ⁸ R ⁹ , one of R ¹² and R ¹³ is hydrogen and the other of these denotes a vinyl group, an alkylsulfonyl group having from 1 to 4 carbon atoms, a furyl, a phenyl group, an N-methyl-1-ol or a N-and cetylpyrrolyl group, a residue

ЛТ. Ж (OF cP- ± 'l ... /

аеЬо

with the limitation that R ¹² or

R ^{13 is a} radical of formula

- ·?

and R < ¹ > together with the nitrogen atom. which are bound to form pyrrolidino, piperidino, marine olino, thlomorpholino or 4-meithylpiperazino, and their pharmaceutically acceptable salts and salts on the kairbaxyl group.

The compounds of formula (II) are generally useful as chemical intermediates for the preparation of the corresponding 6- (subst.) Methylein-11,1-dioxopeinicilianates described in our patent applications. No. PV 6,932—85 and PV 6,934—85. Additionally, however, those compounds of formula II wherein R ¹ represents a hydrogen voidíku or Shoria defined ester residue easily · hydrolysovateliný vivo ^Rb are acceptable because of their inhibitory activity on / Maktamasu particular Palk j: soiui when used in conjunction with a .beta.-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-l, 3-hydroxy-2-pyridyl, 4-methoxy-2-pyridyl, the radical of the formula <ap is 0, then R ^{7 is} not hydrogen or methyl, in which m is 2 or 3, p is 0 or, 1, i is 0, 1 or ^ 2,

Xj represents sulfur, oxygen or a radical NR ^11,

R ⁷ is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, lallyloxy, hydroxy, hydroxy, carboxyl, C 2 -C 5 alkoxy, C 1 -C 5 alkylcarbonyl, phenynyl benzyl, naphthyl, pyrldyl, NR ⁸ R ⁹ , CONR ⁸ R ⁹ , NH.COR ¹⁰ , nitro, chloro, bromo, trifluoromethyl or 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,

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 ¹⁸ represents a hydrogen atom or an acetyl group.

Particularly preferred plays c / cz destroys upinaim and carboxy for R ^and are allyl, benzyl, tert-butyl and 2, 2,2-trichIiorethylová group being especially preferred is a dorsal fin relative к relatively easy · deployment and removal.

Particularly preferred groups are those ester residues readily hydrolyzable in vivo, i.e., the radicals R ^b defined above

C Η CIX

X v

II

O

-C0C0R ⁶

I <

-COCOOR and especially those ·· v- wherein R ^z 'and R ⁵ are hydrogen and R · ⁶ has the meaning given above.

The present invention also provides a method of treating a bacterial infection in a mammal, including a human, by administering an antibiotic-effective amount of a compound of the formula wherein R 1 is a radical R ^b to a mammal in need thereof.

Further, the invention provides pharmaceutical compositions for treating bacterial infections in mammals. including a human, -R which contain an antibacterially effective amount of a compound of formula II wherein R 1 is R ^b .

Compounds of formula (II) wherein R 1 is Rb as defined above are useful as inhibitors of α-lactarnase enzymes. In this way, the compounds increase the efficacy of Stettem antibiotics (penicillins and cephalosporins), in particular against those microorganisms which are resistant or partially resistant to β-lactam antibiotics due to the production of enzymes (Jlaktamiais) decomposing or partially decomposing, β In this way, the spectrum of activity / Miaktalmoactive antibiotic is increased.

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 a non-bacterially effective amount of penicillin or cefatosporin, in particular any of the following, and a compound of formula II tamiasu.

While the compounds of the present invention effectively enhance activity (Maadtam antibiotics in an oral manner, they are preferably combined with penicillin or cephalosporin already established in the art, such as laimpicillin, apalcilin, iazlocilin, azihireonam, bacampicillin, carbenicinilicillin, carbenicillin, orairbenicillin. -feinyl, cefaclor, cefadroxil, cefaloram, cefarnandol, cefamaindole n-sodium, cefaparol, cef.atrizine, cefazoline, cefbuperazone, cefonicide, cefmenoxim, cefodizime, cefoperazone, cefororim, cefotaxime, cefotaxime, cefotaxime, cefotaxime, cefotaxime, , cefiri ^ axon, cefuiroxime, cefacetril, cefaexine, cephaloglycine, cefialoridine, cephalothine, cefapirin, cefradiin, cyclacilin, ep-cillin, furazlocilin, hefacillin, lenampicillin, levopropylcillin, linecillin, fecilicin, penilhicin, ipersicillin, pirbenicillin, pivampicillin, sarmoxicillin, sarpicillin, suncilin, thalampicillin -and ticarcilin, including their pharmaceutically acceptable of useful salts.

The invention further provides the inhibitor / Maktalmas combinations of the invention

7--2- (2-amino-44-thiazolyl) -2-methoxyminoacetamido] -3- (5,6-pyridin-4-ylpyrrolidine) methyl-3-cephem-4-carboxylate,

7- [: 2- (2-omino- + thtazolyll-p-methoxyimino) acetamido] -3- (N-methylpyrrolidinium) methyl-3-cephem-tha-ta-carboxylate and

7- (D- (2-t-carboxy-5-imidazolecarboxamido) -2-phenylacetamido) -3- [4- (2-sulfonatoethyl) -1-pyridinium] 3-cephem-4 -carboxylic acid.

Although the compounds of the present invention may be administered separately from the antitumor antibiotic, combination dosage forms are preferred.

The pharmaceutical composition, whether oral or parenteral, comprises the inhibitor / lactamisins of the present invention and the mactiamic antibiotic in a weight ratio of 1: 3 to 3: 1, wherein the total amounts of these substances in the composition are sufficient to successfully control the bacterial infection of the mammal. single or, more usually, multiple administrations.

The compounds of the invention in which any of the radicals R ¹² and R ¹³ contain a basic nitrogen atom may form acid addition salts. The invention includes such salts with pharmaceutically acceptable acids. Examples of these acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, malic acid, tartaric acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, sugar acid, beinzensufoonic acid, p-Ooluenul acid, p-chlorobenzenesulfonic acid · -a ·, 2-naphthalenesulfonic acid.

Further, 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 include sodium, drastic, ammonium, calcium, magnesium, and zinc cations, and ammonium cations derived from amines such as diethanolamine, chlorine, ethyl eindiamine, ethianoianin, N-methylglucamine and procaine.

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

The molar moieties are those with 1 to 4 carbon atoms in the alkyl moiety or alkyl lithium. -s 1 to 4 carbon atoms in alkylové- portion -a -aldehydu- -obecného formula R ¹ CO 2 R ^13, wherein the housing top. said halide is the corresponding chloride, bromide or iodide, R 13 - and R ¹³ are as defined above, in the presence of an inert solvent at a temperature of from -100 to 100 ° C. + 25 ° C, to form a compound of formula (XI). In peinclicanoic acid derivatives, the attachment of a substituent by a dotted line (imi) to the cyclic nucleus means that the substituent is below the plane of the nucleus and of such a substituent. is said to be in atkonfigunacl. In contrast, attachment of a substituent to a bicyclic nucleus by a reinforced line [b] means that the substituent is above the plane of the nucleus. This latter arrangement is referred to as the -configuration. Binding of the substituent to the bicyclic nucleus by the normal -line line [-----] herein means that the substituent may be either in the -α-kenfguracl or in the -configuration.

The present invention provides a process for the preparation of compounds of formula (II) and salts thereof, characterized in that the compound of formula (X)

л i

in which fx / j in which

R @ 1, R @ 12, R @ 13 and R @ 11 are as defined above, and optionally, to produce compounds of formula (II) wherein R @ ⁸ is other than hydrogen and X @ 1 is bromo. a derivative having a K1-protected group wherein R @ 1 is a radical as defined above, and is acylated with an acyl chloride or an acyl bromide having the general formula R @ 18 Cl or R @ 18 Br or the corresponding acid anhydride in the presence of an eiquimolar amount of tertiary amine. and in the presence of an inert organic solvent, and / or for the preparation of compounds of formula II wherein X 3 is hydrogen, a compound of formula II wherein - X 3 is -bromine, hydrogenolyses in the presence of an inert solvent with organotin hydride, or hydrogen in the presence of a noble metal catalyst, whereupon the resulting compound (II) optionally converts to its pharmaceutically acceptable acid addition salt or acid salt.

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

R1 is - other than hydrogen and n is 0 or 2, reacts with equi248747

Br

Diagram

The starting esters of the general formula (X) used in the process according to the invention are known (see, for example, U.S. Pat. No. 4,234,579). Typically, the starting ester of formula (X) in an inert solvent such as toluene, xylene, pentane, tetrahydooturcin, ethyl ether, or ¹ mixture of these solvents is contacted with an equimolar solution at low temperature. An amount of ladkyllithium, for example n-butyllithium, tert-butyllithium or methyllithium, to form the intermediate lithium derivative of penicillin. This intermediate is immediately mixed with an equimolar amount of an aldehyde of the formula R ¹² -R ¹³ CO, where R ¹² and R ¹³ are as defined above, and the mixture is stirred at a temperature of from -100 dio to -50 ° C for about 1-4 hours. , preferably at a temperature of about -78 degrees Celsius.

The reaction is then discontinued and the intermediate bromohydrin of formula XI is isolated, for example, by shaking between water and solvent, and optionally purified by chromatography of the extract obtained (and silica gel or magnesium silicainine).

Alternatively, the aforementioned starting dibromester of formula X is reacted with an equimolar amount of a low molecular weight Grignardo reagent to form the bromohydrin of formula XI.

The bromohydrin of formula XI can then be acylated to give the corresponding compound of formula XII wherein R18 is as defined above except for hydrogen. The acylation is typically carried out by reacting equimolar amounts of the acid chloride, acyl bromide or anhydride of the appropriate acid, an intermediate bromohydrin of formula XI and a tertiary aimin such as pyridine, N-methylmetaphthalin, and pcid in the presence of an inert organic solvent, preferably methylene chloride, tetrachloride. ethyl acetate, at room temperature or below. The desired diester of formula (XII) is then isolated by known methods, such as solvent extraction and evaporation, and optionally purified, for example by column chromatography.

The bromide hydride ester of formula XI or the bromo-diester of formula XII can be hydrogenolysed to remove the bromine atom. The hydrogenolysis is carried out using any of a variety of known reducing agents and conditions, for example, that bromohydrin is treated with hydrogen in the presence of a noble metal catalysis or that the broimhydrin is subjected to reduction with certain oirgunoic anhydrides.

Preferred orgainocin hydride reducing agents are dialkyldihydrides, trialkyltin hydrides having 1 to 6 carbon atoms in each alkyl moiety, and triaryltin hydrides in which the aryl is phenyl, optionally substituted by nitro or an alkyl or alkoxy group having 1 to 3 carbon atoms. Particularly preferred reducing agents are triphenyltin hydride and tri-n-tin hydride, for economic reasons and the efficiency is especially advantageous latter ^one substance.

The reaction using these tin hydrides is usually carried out in the presence of an inert solvent. Suitable solvents for use to reduce organocínhycdrídy are those solvents which ^one substantially completely. they dissolve the starting compounds of formula (XI) or (XII) but do not react with the reducing agent itself. Examples of such solvents include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and naphthalein, and ethers such as ethyl ether, isopropyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane. From an economic and efficiency point of view, benzene and toluene are particularly preferred solvents.

Theoretically, equimolar amounts of bromohydrin (XI) or bromo diisier (XII) and hydride are required to conduct hydrogenolysis using orgainocin hydride reducing agents. In practice, to ensure a complete reaction. often uses an excess of hydride, for example from 5 to 50 mole%.

Hydrogenolysis of the organotin hydrides under the preferred conditions described above proceeds virtually completely without the use of a catalyst, however, it is accelerated by the use of a radical source such as ultraviolet radiation or by the addition of a catalytic amount of azobisisoibutyronitrile or peroxides such as benzoyliperoxide. A preferred source of free radicals for this reaction is a catalytic amount of azobisiisobutyrioinitrile.

Typically, the compound of formula (XI) or (II) is used. XII is dissolved in an inert solvent and the solution is dissolved in an inert atmosphere, for example an atmosphere. nitrogen or argon, add an appropriate amount of organocmihydride and optionally a source of free radicals, for example azobisisobutyronitrile. The resulting mixture is then stirred at a temperature of preferably about 0 ° C to the boiling point of the solvent. The reaction is. typically terminated within a few minutes to several hours, for example from 5 minutes (when operating at the boiling point of benzene) to about 20 hours (when operating at 0 ° C). The product of formula II (X 3 = H) is. it is then isolated by methods known in the art, for example by evaporation of the solvent and chromatography of the residue on silica gel.

It has been found that the compounds of formula II (X 3 - H) formed by the above-described organotin hydrideim debromination are predominantly the β-isomers, i.e., the compounds in which the 6-R 12 R 13 C (OR 18) substituent is in the figur configuration.

If the hydrogenolytic reaction is carried out by the action of hydrogen in the presence of a noble metal catalyst, it is expedient to work by stirring or shaking the solution of the compound of formula (XI) or (XII) under a hydrogen atmosphere. mixture of hydrogen and inert. a diluent, such as nitrogen or argon, in the presence of a noble metal hydrogenolysis catalyst. Suitable solvents for this hydroganolytic reaction are those which substantially dissolve the starting material of general formula (I). of formula (XI) or (XII), but they are not themselves subject to hydrogenolysis or hydrogenolysis. Examples of such solvents are ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, low molecular weight esters such as ethyl acetate and butyllilate, tertiary amides such as N, N-dimethylformmiamide, Ν, Ν-dimethylacetamide and N-: methylpyrrolidolidine, water. and mixtures thereof. Further, it is often desirable to buffer the reaction mixture such that the reaction proceeds at a pH in the range of about 4 to about 9, preferably about 6 to about 6. 8. To this end, usually; using boiritan, bicarbonate and phosphate buffers. Putting hydrogen gas into. reaction. environment with. usually carried out by carrying out the reaction in a closed vessel containing a compound of formula XI or XII, a solvent, a catalyst and hydrogen.

The pressure inside the reaction vessel may be. from about 0.1 to 10 MPa. The preferred pressure range when the atmosphere inside the reaction vessel is. of substantially pure hydrogen, is about 0.2 to 0.5 MPa. The hydrogenenoilysis is generally carried out at a temperature of about 0 ° C to 60 ° C, preferably about 20 ° C. from 25 ° C to 50 ° C. Using preferred reaction temperatures and pressures, hydrogenolysis generally takes several hours, for example about 2 to 20 hours. Preferred noble metal catalysts used. for this hydrogenolytic reaction, reagents known in the art for this kind of transformations are, for example, catalysts based on nickel, palladium, platinum and rhodium. Palladium is particularly preferred in this respect. Catalyst with. usually used in an 'amount of about' from about 0.01 to about 0.1%. 25% by weight, preferably from about 0.1 to 10% by weight, based on the compound of formula XI. It is often expedient to apply the catalyst to an inert support. A particularly preferred catalyst is palladium on an inert support such as carbon.

After virtually complete hydrogenolysis, the desired product of formula II (X → H) is then isolated by standard methods, for example by filtering the catalyst ol by evaporation of the solvent, and, optionally, purified in known manner, such as by crystallization or chimimatography. .

If the starting material of formula XI or XII beinzyleisteir (R 1 = R ^a - benzyl] may, when catalytic hydrogenolysis described above also result in cleavage of the benzyl group and give a compound of Formula II wherein X 3 and R 1 are hydrogen.

6- (Subb.t) R 1 - (R 1) xroyir (1-methylenediaryl) -carboxylic acid or ester of formula (XII) or (II) (X 1 = H), where n is 0, oxidize using any of the methods known to convert sulfides to sulfones, e.g. using S-chilo (R) -benzenesulfonic acid to give the corresponding sulfone of formula (XII) or II (X3 = H), wherein n is 2. A preferred method for obtaining sulfones of formula (XI), XII or II, however, consists in the use of the corresponding 6,6-dibroim-1,1-dioyl-opicilian of formula X, wherein n has a value of 2 as the starting material in the process according to the invention.

Oxidation of sulfides to sulfones can be accomplished using any of a wide variety of oxidizing agents known in the art for oxidizing sulfoxides to sulfones.

Particularly preferred agents of this type are horse permanganates, such as alkali metal peristates and alkaline earth metal permanganates, and organic peroxyacids. Suitable individual agents include sodium permanganate, potassium permanganate, potassium permanganate, 5-chloro-perbenzoic acid, and peracetic acid.

A particularly preferred group ⁵ consisting of organic oxidizing -činidel .penoixykyseltay being preferred organic peroxyacid is 3-čhliorpprbenzcová -acid.

Thus, an ester of formula II [R ¹ = R ^a ], where R a is a carboxy protecting group as defined above, can be converted to the corresponding acid or ester of formula II wherein R b is a hydrogen lathe or ester The opening moiety readily hydrolysable in vinzole Typically, one proceeds by removing the carboxyl function protecting group from the compound of formula II (R1 = R ^and J) to form the corresponding carboxylic acid. The choice of suitable method, however, will not cause problems for those skilled in the art.

As mentioned above, a particularly preferred carboxyl-protecting group is Ra allylive. Although this group can be cleaved with a mild acidic or alkaline hydrolysis with a satisfactory result, a particularly preferred method for cleaving is the use of a soluble palladium (O) complex, namely tetraklylphosphine palladium (II) as a catalyst. Method J., described by Jeffery and Mc Coimbie in J. Org. Ohiem., 47, 587-590 (1982), according to a typical embodiment of the method, wherein the iallylesrteir is inert. in ethylenedichtaride, chloroform or ethyl acetate, under a nitrogen atmosphere, mixed with a catalytic amount of: tetrakis (triphenylphosphine) palladium (0), for example, about 1 to 5 molar of this complex relative to the α-ethyl ester and roughly equivalent To this mixture is added the sodium or potassium salt of 2-methyl-hexanoate in an equimolar amount based on the starting ethyl ester, and the resulting mixture. was stirred at room temperature until, - termination of the precipitation of the desired salt, such as salts of sodium vzorce- II in which R1 is sodium or potassium. Ι.ι ^ ιΖ ^^^ is usually terminated roughly. from 2 to 20 hours. The resulting salt is then isolated, for example, by filtration.

Compounds of formula (II), where R ¹ is an ester-thiotic 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 problems to the skilled person. When that- R1 represents a radical selected from the group consisting of 3-phthalidyl radical, 4-kriotonoilaktoinylový residue / -buii5 ^ i ^ r ^] ^ <^ _{(lactons-4-yl} radical, and radicals of the formulas

R4

I —COCOR6

R5 a

R ⁴

I —COCOOR6

R5 where

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

RbQ i.e. 3-phthalide-halide, 4-knoitonolocithonylhialilogelideide, γ-butyrolacton-4-yl haligenigen, or a compound of the general formula i

QCOCOR ⁶ Rebo

R

I 6

QCOCOOK

I5

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 II in which R ¹ is hydrogen in a suitable polar organic solvent, for example N, N -dimethylformamide, and adding about one mole equivalent of the corresponding halide of formula R to the solution. ^b) After practically complete reaction, the product is isolated by standard techniques. A simple dilution of the reaction mixture with excess is sufficient. water, extracting the product with a water-immiscible organic solvent and then evaporating the solvent. Commonly used salts of the starting material are certain salts. with alkali metals such as sodium and potassium salts, salts with tertiary amines such as triethylamine, N-ethylpiperidines, Ν, dim-dimethylanilineim, and. The salts of the salts are formed. The reaction is carried out at a temperature of 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 far as the halogen derivatives are concerned, the iodide reacts faster than the bromide, which in turn reacts faster than the chloride. When using ailine, it is present. sometimes advantageous in practice. added up to one mole equivalent of an alkali metal (iodide (1, 1, 2, 4, 4, 4, 10, 10, 10) metal to accelerate the reaction. Se. In view of the above factors, reaction times varying are generally used. about 1 to 24 hours.

The starting aldehydes of formula R12R13CQ, wherein R12 and R13 ₍ as hereinbefore defined) are either commercially available or can be readily prepared from 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, such oxidizing agents as e.g. are 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 with, for example, selenium dioxide.

3. Reduction of the corresponding C 1-4 alkoxycarbonyl derivatives in the alkoxylated portion with a metal hydride at low temperature in the presence of an ethereal or solvent. As. examples of suitable metal hydrides include lithium aluminum hydride and diisobutyl luminiurnihydride.

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

As it was already. as indicated above, the compounds of formula II, wherein R 1 is hydrogen, and salts thereof, in combination with antibiotic antibiotics, exhibit synergistic activity in antibacterial tests in vitro. This efficacy is demonstrated by the measurement of the minimum inhibitory concentrations [MIC] in ₄ ag / imil against a number of microorganisms. In the following section, it is described: ptoistiuíi) recommended Iinteriniational Collaborative Study on Anitibiotic Sensitivity Testing [Ericcson and Sherris, Acta, Pathalogica and Microblologla Scandinav, Supp. 217, section. B: 64-68 (19: 1)], in which brain and heart infusion agar is used, and a device allowing repeated innoculation. Overnight culture in test tubes. is diluted 100-fold. and is used as a standard inoculum (20,000-20,000 cells in about 0.002 ml are applied to the surface of the agar; each plate contains 20 mils of brain and heart infusion agar ¹ ). It is used . 12-fold dilutions of the test substance,. taking the initial. the concentration of the test compound is 200 µg / ml. The experiment is evaluated after incubation for one hour at 37 ° C, the individual colonies not being taken into account. The sensitivity (MIC) of the test organism is considered. lowest conc. test compounds or a combination of compounds capable of rendering complete to the naked eye. inhibiting the growth of the organism.

Those compounds of formula II wherein

R 1 represents an atom. hydrogen, their salts, in combination with known antibiotics are useful as industrial and chemical agents, for example in water treatment, waste water and sludge treatment, paint and wood preservation. as well as for topical application as disinfectants .. when using the disclosed compounds for these, applications, it is often advantageous to mix the active ingredient with Netolický carrier such as vegetable or mineral oil or an emollient cream. it is likewise possible ^tyt'o: substances or .rozpustit Disperse in liquid diluents or solvents, such as water, alpha-alcohols, 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, based on the total mixture.

As already mentioned above, the compounds of formula (II) in which R1 is a radical of R @ ^{b are} more important as potent inhibitors of microbial .beta.-laictarnias. In this way, they increase the aliphatic activity of the O-lactam antibiotics (penicillins and cephalospoirins) against a number of microorganisms, in particular against microorganisms producing n / M actamase. The ability of the compounds of the invention to enhance the activity of β-lactaline antibiotics can be demonstrated by experiments in which the MIC values of the antibiotic itself and the compounds of formula II, where R 1 is hydrogen, are compared and compared with MICs determined for the combination of a given antibiotic with a compound of formula (II) wherein R '1 is hydrogen. If the antibacterial efficacy of this combination is significantly higher than would be expected based on the efficacy of the individual components, this is considered an increase in efficacy.

The MIC values of said combinations are measured for. using the method described by Barry-and Saba-th in "Maniual, of C lineal Microbioogy", ed. Lenette, Spaulding and Truant, 2nd edition, 1974, American Society foir Microbiology.

Compounds of formula (II) wherein R 1 represents a hydrogen atom or an ester moiety readily hydrolysable in vivo, enhances the antibacterial activity of the .beta.-lactam antibiotics in vivo, i.e., reduces the amount of antibiotics required to protect test mice from otherwise deadly inoculum of a particular bacterium. producing? -? -? litt? and? i? isu. To determine such activity, acute experimental infections are induced in mice by intraperitoneal inotulary with a standardized culture of the test organism suspended in 5% of the gastric mucin of the pig.

The severity of the infection is standardized so that the mouse receives a lethal dose of the organism (lethal dose means the minimum inolkull of the organism required to reliably kill 100% of the infected untreated control mice). Groups of infected mice are then administered orally or intraperitoneally at various high doses of the test compound in combination with an anilbiolttic. At the end of the timeout, the efficacy of this combination is determined by counting the surviving animals in the combination-treated group. Efficacy is expressed as a percentage of survival of animals at a given dose, or calculated as a PD 50 value (dose of 50% of the test animals prior to infection).

The ability of said compounds of formula (II) to enhance the efficacy of anti-antibiotic antibiotics against the bacteria they produce (Haikttamias) makes these compounds suitable for concomitant administration with microbial antibiotics in the treatment of bacterial infections in mammals, particularly humans. Юг ^ Ы · infection may be a compound of the invention admixed SJ ^ - ^ and ^ c and _amovým; ni ^: ^ iblo Jťikem if Z e Rb represents CH (R ⁴⁾ OCOR ^u wherein R 4 and R ^{As used} hereinbefore, the β-lactam antagonists bind to the compounds of the present invention, whereby both compounds are applied simultaneously, alternatively the compound of the present invention may be applied as a separate agent during treatment. In some instances, it is advantageous to pre-medicate a patient with a compound of the invention prior to initiating treatment with an actamic antibiotic.

When a compound of formula (II) is used in which R1 represents the radical R ^b as defined above for enhancing the activity of a lactam antibiotic, the mixture of this compound with the + 11 lactlaam antibiotic ern or the compound according to the invention itself when R b represents a radical CH (R 4) OC ⁶ R 14 is preferably applied in the form of a composition comprising. standard pharmaceutical carriers or diluents. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, an antibiotic. and / or from above. said compound of formula II normally containing approximately; 5 to 80% by weight of a pharmaceutically acceptable diluent.

By combining the aforementioned compounds of the present invention with another (lactam) compound, the compounds may be administered orally or parenterally, i.e., muscularly, subcutaneously or intraperitoneally. Although the dosage used in human medicine is ultimately determined by the attending physician, it will normally be of formula II, wherein R ¹ is a residue of R b, and ranges from about 1: 3 to 3: 1. in combination with the Mactam antibiotic, the daily oral dose for each component normally ranges from about 10 to 200 mg per kilogram of body weight, and, the daily dose, each parenteral administration normally ranges from about 10 to 200 mg per kilogram of body weight. up to 40 mg / kg. 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 to be understood that some / Mactamous Compounds are effective in the. oral or parenteral. administration, while others are effective only when administered parenterally. Thus, if a compound of the invention is to be used. concomitantly (i.e., in a mixture) with a / a antibiotic antibiotic effective only when administered parenterally, it will be desirable to prepare a combination formulation suitable for parenteral administration. If he has. If the compound of the invention is used concurrently (in admixture) ¹ with a β-laikitamia antibiotic active, both oral and parenteral, a combination formulation 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 the [beta] -antictam antibiotic parenterally. It is also. it is possible to parenterally administer the compositions comprising the aforementioned compounds of the invention and at the same time orally administer the mactaim antibiotic.

The invention is illustrated by the following non-limiting examples. Proton, and C ¹³ nuclear magnetic resonance spectra in the following-examples were measured at 60, 90, 250 or 300 MHz using the product solution in deuterochlioroformu, deuterium oxide, perideuteroaceitionu or · DMSOd and position signals · are expressed in ppm versus Tett [eta] &lt; b &gt; The shape of the signals is indicated by the following abbreviations:

s .singlet d. · Doublet idid doublet doublet t triplet q quartet m. has a wide signal.

Example 1

Benzyl-6- (1,2-pyridyl) -hydroxymethylpenicilate

A. Benzyl 6-bromo-6- (2-pyridyl) hydroxymethylpenicilate

A solution of 9.0 g (0.02 mol) of benzyl 6,6-dibroimpenicilianite in 200 ml of freshly distilled toluene was cooled to -78 ° C and 9 ml of 2.2 M β-β-pentane in pentane was added dropwise. . The resulting mixture was stirred for 30 minutes, then stirred at room temperature. The reaction was quenched by dropwise addition of acetic acid in toluene to the reaction mixture. Warm to -10 ° C, dilute with 200 ml of toluene, wash five times with water and dry. sodium sulfate. The toluene solution is applied to a 1 kg column of Florisil adsorbent and the column is eluted with 2: 1 toluene / ethyl acetate. The product containing fractions are combined and evaporated in vacuo. . 4.2 g of brown are obtained. of the syrup product used in the next step.

B.. 4.2 g of the brown scab product from part A are dissolved in 50 ml of benzene and 2.65 g of tributyltin hydride are added to the solution. Mixture. is heated to boiling for 2 hours. It is then treated with an additional 1.65 g of itolbutyltin hydride and refluxed overnight. The solvent is evaporated off under vacuum, the residue is washed with hexane and applied. per column 500 g 5Ι1ΙΚι®θ1π ·. Elution with a 2: 1 mixture of toluene and ethyl acetate gave 42-5 mg of the title compound.

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

1.35 (s, 3H);

1.7 (is, 3H), 4.0 (dd, 1 H),

4.5 (s, 1 H),

5.1 (s. 2H);

5.2 (d, 1 H,

5.4 (d, 1H), 7 (0-7.8 (im, 3H)),

8.5 (m. 1H).

Example 2

1,1-Doxide-O - (2-pyridyl [hydnoxymethyl peinicillanic acid)

A Benzyl-6- (2-pyridyl) hydroxymethyl-1,1-dioixopropylinic acid

To the solution 0.40 g. of benzyl 6- (2-pyridyl) hydropylacetyl / penicillanate 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. By thin layer chromaiography. the reaction mixture contains some sulfoxide. An additional 0.2 g of m-chloro-tert-butyric acid was added and the mixture was stirred overnight. The reaction mixture was diluted and washed successively with saturated sodium thiosulfate solution, water and saturated sodium bicarbonate solution. and an organic layer. is concentrated in vacuo. The residue is taken up in ethyl acetate, washed with sodium bicarbonate solution, water and brine, dried. sodium sulfate and the solvent was evaporated. 330 mg of the desired benzyl ester is obtained in the form of a brown olematerial which is purified by chromatography on silica gel. Elution with a 11: 9 mixture of methyl, hexane and hexane yields 60 mg. yellow oily product.

6 ,, ^ - ^ 6, 6 · (m,

6.6-7.4 (lim ·,

¹ H-NMR (CDCl 3, δ ppm):

2H),

2H).

1.25 (s, 3H).

1.52 (es, 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 (nm, 1 H).

The procedure of the preceding example is followed by. using 1.98 mmol of allyl-6-Oenylhydroxymethyl-11-dioxopanil nitrate, 4.2 mmol of aceylthyl chloride and 0.4 ml of pyridine gave 0.7 grams (84%) of allyl-6-phenylacetoxyimethyl-1,1- ^diol. Oxopenediolinate in the form of a yellowish gum.

B. Suspension 118 mg of 10% palladium. in 10 ml of tetrahydrofuran and 4 ml of defect were prehydrogenated for 20 minutes under a hydrogen pressure of 50 bar. To the resulting suspension was added 130 mg of the benzyl ester, prepared in Part A above, in 4 mL of the same tetrahydrofuran / water mixture. The mixture was hydrogenated at 50 psi for 30 minutes, then an additional 129 mg of 10% palladium on is added. at a pressure of 0.35 MPa. continue 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.

UV-NMR (deuterium oxide, δ in ppm):

1.3 (with 3H),

1.5 (s, 3H),

4.4 (s. 1H).

5.0 - 5.35 (m, 2H),

5.9 (d, 1 H).

IR (KB.r-tecbmik, a.):

620, 1731, 3 407 cm ¹ .

He did

Allyl-6- (N-acetylpyrroil-2-yl jacetoxymethyl-1,1-detoxoipenic lactate)

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

1 H-NMR (CDCl 3, δ in ppm):

1.3 and 1.4 (is, 3H),

1.62 (s, 3H);

2.08 and 2.2 (s, 3H),

4.2 (dd, 1 H),

4.4 (s, 1Ή)

4.5 (d, 1 H),

4.65 (dd, 2H),

6.25 (m, IH);

7.3 (im, 5 H).

Example 5

A. Allyl-6-bromo-6- (2-thiazolyl) hydroxymethyl-1,1-dioxoipeniline

A solution of 8.84 g (20 mmol) of allyl-6,6-dibromo-1,2-dexopenicillanate in 100 mL of dry tetrahydrofuran is cooled to -78 ° C, and 7.02 mL (20 mmol) of methylmagnesiuimbroimide is added, a mixture of stirred for 5 minutes, then the others at -78 ° C was added a solution of 2.26 g (20 mmol) thia.zo ⁱ _l-2-l ka rboxaiidehydui same in 10 ml of the solvent, and the resulting mixture was stirred for 20 minutes · . After addition of 1.2 ml of acetic acid, the reaction mixture was poured into water and extracted with ethyl acetate and chloroform. The combined organic layers were dried over sodium sulfate and the solvent was evaporated in vacuo. 8.5 g of crude product are obtained in the form of a glassy mass. This raw vitreous material provides after purification by chromatography on. Silica gel column using chloroform: ethyl acetate (89: 11). 6.2 g (72%) of pure product identified as a single isomer.

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

@ ¹ H-NMR (CDCl3) .delta .:

1.4 (s. 3H),

1.6 (s, 3H); 2.15 (s, 3H);

2.55 (s, 3H3,

4.15-4.3 (dd, 1H),

4.4 (s. 1H).

4.6-4.8 (m, 3H);

5.1-6.0 (m, 3H);

1.4 (s, 3 H),

1.6 (is, 3H)

4.0 · (bs, 1H),

4.42 (is, 1H);

4.6 (d, 2H).

5.3 (s, 1H);

5.55 (s, 1 H),

5.1-6.3 (m, 3H);

7.35 (d, IH);

7.75 (d, IH).

В. Benzyl-6-bromo-6- (2-thiazolyl) hydroxymethyl-1,1-dioixioipeinicanilate

The procedure described above was repeated using benzyl-6,6-dibromo-1,1-dioxenpenic ilainate instead of allylestew. The title compound is obtained in quantitative yield as an oiranza-colored foam.

@ 1 H-NMR (CDCl3, < 5 in pipm):

1.32 (is, 3H);

1.60 (а, 3H)

4.5 (is, 2H);

5.2-5.8 (m, 4H).

R * R ¹³

7.3 (d. 1H).

7.4 (s. 5H);

7.8 (d, 1 H).

C. The following compounds are prepared in an analogous manner to Part A:

yield (%) ¹ H-NM R (deuteroc chloride, values of δ in ppm) 100 (yellow foam) 1.25 (s, 3H), 1.54 (s, 3H), 4.5 (s, 1H), 5.02 (s, 2H), 5.43 (s, 1H), 5.68 (is (1H), 7.32 (m, 7H); 8.00 (m, 2; H); 88 ('yellow solid product) 1.4 (2S, 3H), 1.6 (s, 3H), 4.0 (s, 1H), 4.9 (2s, 1H), 518 (m, 2H), 5.5-5.8 (im, 2 H), 7.5 (s. 5H); 8.0 and 8.5 (2s, 1H), 100 ALIGN! 1.25 (s, 3H), 1.52 (s, 3H), 4.45 (p, 0.75H), 4.52 (s, 0.25H), 5.1-5.4 (m, 4H); 7.3 (s, 5Ή), 8.6 (m, 2H), 9.0 (m, 1H); 38 1.38 (s, 3H), 1.60 (s, 3H), 4.38-4.73 (m, ЭН), 5.0-6.0 (m, 5H); 7.10 (s, 1H), 8.51 (s, 1H).

Example 6

A. Acylation of the compounds obtained in the preceding example, with. Using the procedure described in Example 3, the following compounds were prepared in an analogous manner:

A. When R ^a is an allyl group and R ¹⁸ is a CH 3 CO group

R13

2-thiazolyl yield (colorless crystals by 1 H-NMR (CDCl 3, δ values in ppm)

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

2.25 (s, 3H); 4.45 (s, 1H);

4.65 (m, 2H); 5.4 (s, 1H);

5.2-6.3 (tm, 3H),

6.7 (s, 1H), 7.4 (d, 1H),

7.8 (d. 1H);

i ³ C-NMR (deuterohitaroforani, δ values in ppm):

18.4 19.8, 20.4, 60.7, 63.1, 64.4,

66.5, 66.9, 73.3, 120.3, 120.4,

130.6, 143.6, 163.7, 165.5, 166.2,

168.6,

1.40 (is, 3H), 1.60 (s, 3H), (+ 21% isomeric product) 2.25 (s, 3H),

4.48-4.70 (m, 3H),

5.2-6.2 (m, 5H);

6.92 (s, 1 H), 8.83 (s, 1 H),

B. When R a is a benzyl group and R ^{18 is a} group

2-thtazalyl

100 (9: 1 glass isomer mixture)

1.25 - (is, 3H), 1.55 (is, 3H),

4.50 (s, O ⁽ 9H), 4.55 (s, O, 1H),

5.2 (tm, 2H); 5.40 (s, 0.9H);

5.57 (s, 0.1H), 6.40 '(s, 0.1H),

6.60 (s, 0.9H), 7.3 (tm, 6H),

7.75 (d, 1 H),

100 (yellowKXHaMag foam)

1.3 (s, 3H), 1.52 (s, 3H),

2.25 (s, 3H), 4.54 (s, 1H), 5.02 (s, 2H), 5.52 (s, 1H),

6.8 (s, 1H); 7.3 (m. 7H);

7.9 (tm, 2 H),

1.25 (ts, 3H), 1.5 (s, 3H),

2.19 (s, 3H), 3.95 (s, 3H), (s, 1H), 5.15 (s, 2H),

5.45 (s, 1 H), 6.3 (s, 1 H),

7.35 (s, 5H); 7.73 (s, 1H);

1.25 (s, 2.25 H), 1.35 (s, 0.75H), (3: 1 mixture of isomers) 1.4 (s, 2.2H), 1.42 (s, 0.75H) )

2.2 ( _f s, 2.25H), 2.3 (s, 0.75H), 4.45 (s, 0.75H), 4.55 (s, O.25H), 5.1-5.3 (m, 2H)

5.3 (s, 0.75H), 5.6 (s, 0.25H),

6.25 (s, 0.25H), 6.4 (s, 0.75H),

7.3 (m, 5H), 8.67 (m, 2H), 9.67 (6, 1H),

C. Alternatively, the compounds of the above formula are prepared by acylating the reaction mixture prior to product isolation as follows:

To a solution of 1.0 equivalent of 6,6-dibroimpenicillanic acid ester in tetrahydrofuran at -78 ° C was added 1.3 equivalents of methylmaginesulfurimide dissolved in the same solvent, and the mixture was stirred for 5-10 minutes at -78 ° C. -68 cc is added 1.3 equivalents of the appropriate aldehyde (R 13 CHO) in the same solvent and the reaction is stirred for 30-60 minutes. The reaction product is isolated by pouring the mixture into ice / water, extracting with ethyl acetate, drying the extract and removing the solvent under vacuum.

When R ^{18 is} confused with sikuptus CH _{: i} CO _R a

R13 benzyl allyl allyl

benisyl benzyl benzyl

allyl

yield (%) * H-NMR (deutemochlarophores, hiodinates δ in ppm) 100 ALIGN! light yellow foam 77 ('yellow alley) 1.35 (is, 3H), 1.56 (s, 3H), 2.22 (s, 3H), 4.42 (br, 1H), 4.60-4.74 (m, 2H), 5 24-5.4-2 [m, 3H], 5.79-5.96 (m, 1H), 6.52 (s, 1H), 8.70-8.74 (d, 1H); IR: 1,810, 1,760 cm ^-1 59 (yellow oil) 1.42 (s, 3H), 1.62 (s, 3H), 2.28 (1s, 3H), <2.48 (S, 3H), 4.5 (s, 1H), 4.6- 4.8 (m, 2H), 5.28-5.47 (; m, 2H), 5.82-6.0 (m, 1H), 6.3 (s, 1H), 6.97 (s (1H); ID: 1,810 1,760, 1,730 cm ^-1 59 1.6 (s, 3H); 1.8 (s, 3H); 2.2 (s, ZNЪ 2.3 (s, 6H)), 4.4 (is 1H), 5.2 (d, 2H), 5.3 (is, 1H); 6.4 (d, 1H); 7.3 (s. 5H); 22nd 1.22 (is, 3H); 1.5 (s, 3H); 2.18 (s, 1H), 2.42 (s, 3H), 4.5 (s, 1H); 5.16-5.36 (m, 3H); 6.18 (1H, 1H), 6.48 (s, 1H), 7.4 (is, 5H); 44 (yellow foam) 1.26 (s, 3H), 1.5 (s, 3H), 2.2 (s, 3H); 2.4 (s, 3H); 4.4 (s, 1H); 5.16 (d, 2H); 5.3 (is, 1H); 6.6 (s, 1H); 6.8 (s, 1H); 7.3 (s, 5H); 36 (ipina) 1.40 (s, 3H), 1.60 (s, 3H), 2.27 (s, 3H), 2.65 (s, 3H), 4.20-4.8 (та, 3H), 5.1 -6.2 (im, 4H); 6.41 (s. 1H); IR: 1815, 1760 cm ¹

Example?

-1,11- (dio-molpeinjin) other

To the roll · 74.6 g (134 mmol) of benzyl-6- .....

-bromo-6- (thiazol-2-yl) acetoxymethyl-11,1-diioixopeinililate In 850 ml of benzene, 43.99 g (151.2%) of triethylmethylenediamine is added. cícícícíEEtrtrtr.. The mixture was heated at reflux for 5.5 hours and allowed to stand overnight. The solvent is evaporated in vacuo, the residue is taken up in hexane and the solution is extracted twice with 250 ml of acetonitrile each time. Aceto-. The nitrile layer is evaporated, the residue is stirred in ether, the suspension is filtered and the filter cake is washed with ether. 33.28 g of colorless crystals are obtained. An additional 2.8 grams of product is obtained after evaporation of the filtrate to dryness. The residue is taken up in benzene and after addition of 10 g of tri-n-butylamine hydride, 1 point is heated to reflux. The reaction mixture is then worked up as in the first crop. The total yield of the product was 56.3%.

The first crop of product obtained above was purified by chromatography on a column of silica gel, eluting with a mixture of chloroform and ethyl acetate (9: 1). Fractions. The product-containing product is concentrated, the residue is suspended in a mixture of ethyl ether and ethyl acetate (4: 1), the suspension is filtered and the residue is filtered. The filter was washed with ether. 22.6 g of white solid are obtained.

R ^and R13

@ 4 H-NMR (CDCl3, .delta., Ppm):

1.25 (s, 3H).

1.53 (s, 3H);

2.1 (s. 3H),

4.58 (s, 1H).

4.80 (d, IH);

5.2 (dd, 1 H),

5.22 (quartet, 2H),

6.75 (d, IH);

7.35 (s, 5H);

7.4 (d, 1H).

7.8 (d, 1 H).

¹³ C-NMR (CDCl 3, DMSO):

17.7, 19.9, 20.5, 54.5 63.06, 63.6, 63.8,

64.5, 58.1, 121.8, 128.8, 128.9, 134.3, 142.6, 164.6, 166.5, 169.2, 170.5.

B. By analogous procedure, the following products were obtained by debrolidation of the other compounds of Example 6 ^; ' ^OCOCW O ^Q

R - С Ηχ, XX ^{е H} 3 'cocT Ή-NMr yield (- ^^^ vetcococo ^ ^ <^ ^ vet vetco ((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((,

(yellow solid product)

(dlej)

1.3 (s, 3H), 1.5 (s, 3H),

2.19 (s, 3H); 4.5 (s, 1H);

4.79 (d, 1 H), 5.2 (m, 3 H),

6.79 (d, 1H), 7.32 (m, 7H),

7.9 (m, 2H)

1.29 (s, 3H), 1.55 (s, 3H),

2.10 (ss, 3H); 4.03 (s, 3H);

4.5 (s, 1H); 4.78 (d, 1H);

4.87 (dd, IH),

5.25 (quartet, 2H), 6.53 (d, 1H),

7.38 (s, 5H); 7.89 (s, 1H);

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

4.45 (s, 1 H),

4.6-5.1 (bp, 2H),

5.2 (m, 2H).

6.6 (dd, 1 H), 7.35 (s, 5H),

8.6 (m, 2H); 8.83 (m, 1H);

1.44 (s, 3H), 1.62 (s, 3H),

2.10 (pcs, 3Ή), 4.51 (s, 1H), 4.60-4.80 (m, 2H), 4.89-4.91 (d, 1H), 5.26-5.42 ( mi, 3H), 5.86-5.99, (jmi, 1H), 6.88-6.92 (d, 1H),

8.82 (s, 1 H);

IC: 1795.1750 cm’1

R13

R ^and allyl

allyl

tek-NMR (CDCl 3, δ in ppm) benzyl benzyl benzyl allyl

51 (more polar) + 11 (less polar) Polar isomer: 5.84—6.00 (im, 1Ή), 6.28-6.42 (ra, 2H), 6.62-6.77 (d, 1H); 7.38-7.48 (d, 1H). 8.161-8.70 (d, 1H); white crystalline product; Company ID (KBrr-teclimka): 1 807, 1760 cm @ -1 31 (yellow oil) 1.46 (s, 3H), 1.64 (s, 3H), 2.14 (s, 3H), 2.48 (s, 3H), 4.5 (S, 1H), 4.6-4.9 (m, 3H); 5.2 - 5.26 (dd, IH), 5.3-5.6 (m, 2H); 5.86-6.1 (m, 1H); 6.7 (d, 1H); 7.0 (s, 1H); IR: 1810, 1760 cm @ -1 43, mp 194.5-195.5 ° C 1.3 (s, 3H), 1.58 (s, 3H), 2.12 (δ 5, 3H), 2.36 (d, 6H), 4.4 (s, 1H), 4.75 (d, 1H), 5.2-6.4 (dd, 3H), 6.6 (d, 1H); 7.4 (s, 5H); 16 (colorless solid; one isomer) 1.28 (s, 3H); 1.55 (s, 3H); 2.1 (s, 3H), 2.4 (s, 3HJ, 4.5 (s, 1 H), 4.8 (dd, 1 H), 5.25 (quartet, 1H), 6.15 (s, 1H), 6.5 (d, 1H); 7.4 (s, 5H), 43 1.3 (s, 3H), 1.58 (s, 3H), 2.14 (s, 3H), 2.48 (s, 3H), 4.52 (s, 1H); 4.8 (d, 1H); 5.16—5.36 (АВ quartet and dd, 3H), 6.7 (d, 1H); 7.0 (s, 1H); 7.4 (s. 5H); 44 (3: 1 mixture of isomers) 1.37-1.40 (: d, 3H), 1.58-1.60 (d, 3H), 2.12-2.14 (d, 3H), 2.58 · (s, 3H), 4, 48 (s, 1H), 4.58-4.88 (rn, 4H), 5.24-5.46 (m, 2H), 5.82-6.00 (im, 1H), 6.64-6, 67 (d, 0.75H), 7.05-7.08 (d, O.25H); IR: 1,810 1,765 cm ¹

Example 9

A. (6a, 8R) -6- (thiazol-2-yl) propionyloxymethyl-1 H -dioxopenicillinic acid

A mixture of 1.89 g of 10% palladium carbon as 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) of beinzyl- (6a, 8R) was added. -6- (thiaisol-2-yl) pinoipioinyloxy. of ethyl 1,1-dioxopiperidium in 13 ml of tetrahydrofuran and 7 ml of water. The resulting mixture was hydrogenated at 100 psi for 20 minutes, the catalyst was filtered off and the filtrate was extracted three times with 200 ml of ethyl acetate each time. The extracts were dried (MgSO4) and the solvent was evaporated in vacuo. 330 mg of a yellow solid are obtained.

B. (6R, 8R) -6- (Thiazol-4-yl) benzoyloxymethyl-11-dihydro-piperidinic acid

The title compound was obtained as described above in a yield of 57% of 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, 1HJ,

7.58 (d, 1 H),

7.7 (d, 1 H),

7.95 (d, IH);

iC (KBr technology):

473, 1,782, 1,729, 1,622 cm ^-1 .

Example 9a

A. The benzyl esters obtained above were converted to the corresponding carboxylic acids of the following general formula ⁽ Rb) by hydrogenation according to Example 8 using palladium on carbon catalyst.

R ¹³ R ¹⁸ Yield (%) ¹ Η - NMR p ^ e ^ id ^ ^^ te ^ Teita ODI ^ m ^ ^ l itthl sllOot ddлeO ^ ^ι ^ huffy et шoX ^ i ^) and ^ id value 5 ppm ')

O

II

2-thiazollyl CH3C

1.45 (s, 3H), 1.53 (js, 3H), (white solid of 2.10 (s, 3H), 4.48 (s, 1H), with decomposition at 145 5.0 (dd) 1 H, 5.41 (d, 1H), up to 155 ° C) 6.59 (d, 1H), 7.91 (m, 2H);

13 C-NMR: 17.1036, 19.3736,

20.771, 53.2954, 62.5971, 62.8347, 63.3676.64.5698.1220881, 142.4252, 164.3975, 167.8111, 168.7027.170.8035,

1.53 (is, 3H), 1.65 (s, 3H),

2.17- (δ, 3H), - 4.54 '(s, 1H), 4.87 (d, 1H), 5.13 - (dd, 1H), 6 82 (d, 2H); 7.88 (d, 1H); 8.07 (d 1H); 9.20 (bs, 1H); 13 C-NMR: 17.6, 20.09, - 20.5, 54.4,

63.2, 63.2, 63.9, -65.5, 121.9, 123.4,

126.1, 126.6, 135.3, 151.6, 166.6,

169.2, 169.3, 170.6,

R ¹³

^R18 yield Ή NMR (perdeuteTOdtaiethyl _(%) deuterimmoyid sulfoxide or, in ppm)

II

CH ₃ C

II CH ₃ C

CH ₃

O

II CH ₃ C

Q

II

CH3C (deuteriumoyide):

1.45 (s, 3H), 1.57 (s, 3H),

2.15 (s, 3H); 4.33 (s, 1H);

5.24 (s, 1H).

4.75-5.2 (1H masked by deuiterium oxide signal),

6.55 (d, IH);

8.65-8.8 (1m, 2H);

IR (KBr-techin.ifca):

416, 1785, 1618 cm ^-1 ; 13 C-NMR: 17.6, 19.8, 20.4, 54.4, 64.1, 65.7, 68.1, 144.2, 145.2, 145.5, 151.2, 172, 7 172,8,

1.48 (s, 3H), 1.55 (s, 3H),

2.15 (1H, 3H), 2.28 (s, 3H),

2.32 '(s 3H), 4.3 (s, 1H),

4.85 (dd, 1 H), 5.2 (d, 1 H),

Δ _L 6 (d, 1H);

IR (KBr-iteGhinika):

787, 1626, 1618 cm -1

1.48 (s, 3H), 1.6 (s, 3H),

2.2 (s, 3H), 2.46 (s, 3H),

4.35 (s, 1H); 5.2 (d, 1H);

6.4 (s, 1H); 6.55 (d, 1H);

IC (KBr-teohinic):

791, 1692, 1631 cm ¹

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

2.2 (s, 3H), 2.45 (s, 3H),

4.35 (s, 1H); 4.9 (idid, 1H);

5.25 (d, 1 H), 6.7 (d, 1 H),

7.3 (s. 1H);

IC (KBr):

1787, 1657, 1626 cm ^-1

The B, 6 (H-TMhizole-221) acetylmethyl-1,1,1-dioyopenilcinia acid prepared in Part A above was converted to the corresponding potassium salt by converting to a defective acid suspension. with an aqueous solution of an equivalent amount of potassium hydrogen carbonate. The product is purified by medium pressure liquid chromatography on a C18 column (C18 = olecadlylsilyl silicate), using a mixture of water and water. acetonitrile (9: 1) as the eluent. The yield of the corresponding potassium salt is 60%.

1 H-NMR (% dithiomethylsulfoxide, δ in ppm):

1.37 (s, 3H);

1.48 (s, 3H);

2.07 (is, 3H);

3.80 (s, 1 H),

4.92 (dd, IH),

5.12. (d, 1 H),

6.55 (d, IH);

7.89 (m, 2 H);

IC КБМесЬтка.):

454, 1,788, 1,630 от “!

Example 10

Potassium 4- (imidazol-2-yl) oxymethyl-11-dloxioperiicilate

A mixture of 141 mg (0.38 mmol) of allyl-6- (imidazol-2-yl) butyroyylmethyl-1,1-dioxopenicillanate (isomer mixture), 12 mg of tetrakis (triphenylphosphine) plasmid (O), 12 mg of triphenylphosphine, 0.76 (0.38 mmol) of potassium 2-ethylheyanoate and 2 ml of ethyl acetate are stirred under nitrogen for 1 hour. The precipitated product is filtered off to give 143 mg (100%) of a yellow solid which contains two isomers according to HPLC.

IC (KBr):

3,382, 1,780, 1,728 and 1,615 cm ” ¹ ·

Example 11

Ш и и от от от от от it it it it it it it ia ia ia ia ia ia ia ia ia ia ia l ia l l l l ,1 ,1 ,1 ,1 ,1 ,1 yl) ac ethoxymethyl-1,1-dioxo-einicilate was reacted for 10 minutes as described in Example 10, and the reaction mixture was treated as described in this example. 46 mg (48%) of a yellow solid are obtained.

1 H-NMR (deuterium oxide, δ in ppm):

1.45 (s. 3H);

1.6 (s, 3H);

4.4 (s. 1H).

5.55 (s, 1 H),

6.85 (s, 1 H),

7.72 (d, 1 H),

7.86 (d, IH).

B. Calcium-6-bromo-6- (thiazol-2-yl) hydroxymethyl-11-dioxoxeniliconate

Similarly dvacetimiiiniutovou reacting 220 mg of allyl-6-bromo-6- (thiazo.l-2-yl) lhydroxymethyl-l, l-dioxopenicilanátu, performed as described above, in a yield of 52 ^IO / ol title salt in the form pale yellow solid.

Ή-NMR (peroxide dimethyldimethyl oxide, δ in ppm):

1.35 (s, 3H);

1.47 (s, 3H);

375 (s, 0.4H);

3.83 (s, 0.6H),

5.3 (s, 0.4H),

5.32 (d, 0.6H),

5.45 (s, 0.6H);

5.5 (s, 0.4H);

7.6-8.0 (m, 2 H).

IC (KBir-Techtóka):

442, 1794, 1633 cm ¹ .

Example 12

Potassium (6R, 8S) -6- (thiiazoil-2-yl) hydroxyimethylipenilicillainate

A. Allyl-6-broim-6- (thiazol-2-yl) Hydroxymethylpeinicilate

To a solution of 9.971 g (24.99 mmol) of allyl-6,6-dibrompenicilianate in 150 mL of dry tetrahydinofurainium cooled to -78 ° C was added 8.77 mL of 2.85M (24.99 mimol) miethytoaginesium bromide in nitrogen under nitrogen. tetrahydrofuran and the mixture was stirred for 15 minutes. After addition of a solution of 2.824 g (24.99 mimol) of thiazole-2-carboxialdehyde in 5 mL of tetrahydrofuran, the mixture was stirred at -78 ° C for 20 min before quenching with 1.43 mL (24.99 mmol) of ice. of acetic acid. The mixture was stirred for 10 minutes and then allowed to warm to room temperature. The resulting mixture was poured into water and extracted twice with 250 ml of ethyl acetate each time. The extracts are washed twice with 250 ml of water each time, dried over magnesium sulphate and the solvent is evaporated under vacuum. 10.36 g of an orange oil are obtained which, after purification by chromatography on a silica gel column using chloroform / ethyl acetate (9: 1) as the eluent, yields 4.54 g of yellow solid (simes isomeiri) and 0.443 g. yellow foamy substance consisting only of the more polar isomer. The total yield is 46%.

Ή-NMR (deuterochloroform., Δ values in ppim) of a yellow foam:

1.56 (s, 3H);

1.76 (s, 3H).

4.60 (s, 1 H),

4.7 (m, 2H).

4.9-6.4 (im, 6H);

7.45 (im, 1 H),

7.8 (m. 1H).

B. Ally 1-6 / 3- (thiazol-2-yl) hydroxyimethylpenicilate

200 mg (0.462 mmol) of the more polar isorner prepared in Part A are dissolved in 1 ml of benzene and 0.183 ml (0.693 mimol; 1.5 equivalents) of tri-n-butylicin hydride in benzene is added. The mixture was refluxed for 3 hours then allowed to stand at room temperature overnight, then the solvent was evaporated in vacuo. The residue is taken up in acetonitrile, the solution is washed with hexane and evaporated to a small volume. This concentrate was applied to a silica gel column from which 73 mg (45%) of the desired product was eluted with chloroform.

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

1.65 (s. 3H);

1.87 (s, 3H);

3.8-4.4 (m, J = H), 4.05-4.3 (dd, 1H),

4.65 (s, 1 H),

4.78 (m, 2H).

5.3-5.6 (m, 2Ή),

5.6-6.3 (m, 3H);

7.45 (m. 1H);

7.85 (im, 1 H).

C. 73 mg (0.206 mmol) of the product obtained in Part V were converted to the potassium salt by the procedure of Example 10. Obtained mg (80%) of the title compound.

Ή-NMR (300 MHz, deuifcerium oxide, δ values in ppm):

1.36 (s, 3H);

1.55 (s. 3H);

4.13 (dld, 1 H),

4.18 (is, 1H).

5.32 (d, IH);

5.41 (d, IH);

7.56 (d, 1 H),

7.60 (d, 1H).

Example 1 to 13 in part A of the example! 12 with the proviso that the corresponding aldehyde R ¹³ CHO is used instead of thiazol-2-carbonyl dioxidyl. The corresponding compounds of the general formula are obtained

OH _e cg ^{3 0} COOCH ₂ CH-CH ₂

A. The procedure is as follows: a-

yield (%) isomer A (white crystals) isomer В (yellow oil)

(isomer A, 8S) (isomer B, 8R) (foam)

NMR-NMR (deuterochloroform, δ in ppm) isomer A:

1.46 (s, 3H), 1.64 (s, 3H),

4.42 (d, 1 H), 4.50 (s, 1 H),

4.64 (m, 2 H),

5.26-5.50 (m, 3H)

5.84 (s, 1 H),

5.8-6.0 (m, 1 H),

8.58 (d, 2H); 8.9 (s, 1H);

¹³ C-NMR (CDCl3):

26.4, 32.5, 64.4, 66.1, 69.8, 70.9,

73.7, 74.9, 119.6, 131.0, 143.0,

144.3, 144.6, 152.1, 166.8, 167.8 PPm isomer B:

1.45 (s, 3H), 1.63 (s, 3H),

4.56 (s, 1 H), 4.65 (m, 2 H),

5.1-5.5 (m, 4H);

5.6-6.0 (m, 1 H),

5.91 (s, 1H); 8.57 (m, 2H);

7.87 (m, IH);

^{1 :!} C-NMR (CDCl3): 26.27, 32.57, 64.30, 66.19, 69.94, 70.77, 72.38, 74.73, 119.70, 130.98, 143.30 , 144.57, 144.70, 152.04, 166.99, 167.99 ppm

1.52 (s, 3H), 1.70 (s, 3H),

4.64 (s, 1 H), 4.72 (m, 2 H),

4.86 (d, 1 H),

5.34-5.48 (m, 3H);

5.91 (s, 1 H),

5.92-6.05 (m, 1 H),

7.39 (t, IH);

8.87 (d, 2H).

1.52 (s, 3H), 1.71 (s, 3H),

4.61 (s, 1 H), 4.72 (m, 2 H),

4.98 (d, IH);

5.30-5.52 (m, 3H);

5.90-6.04 (m, 1 H),

6.10 (s, 1 H), 7.40 (t, 1 H),

8.85 (d. 2H);

1.49 (s, 3H), 1.69 (s, 3H),

3.56 (d, 0.7H), 3.89 (d, 0.3H),

4.7 (m, 3H); 5.5 (m, 3H);

5.9 (m, 2H); 7.53 (m, 3H);

8.14 (m, 3H).

B. Debromination of the above compounds by the procedure of Part B of Example 12 gave the following compounds:

R ¹³

yield (%) (oil) @ 1 H-NMR (CDCl3) .delta.

1.5 (s, 3H), 1.7 (s, 3H), 4.05 (dd, 1H), 4.35 (s, 1H),

4.5 (d, 1H); 4.65 (m, 2H);

5.25-5.45 (m, 3H);

5.55 (d. 1H);

5.9-6.0 (m, 1 H),

8.6 (m, 2H); 8.85 (s. 1H);

(from isomers B, 8S)

1.5 (s, 3H), 1.8 (s, 3H),

4.15 (dd, 1H); 4.25 (bs, 1H);

4.55 (s, 1 H), 4.7 (m, 2 H),

5.2 - 6.2 (m, 5H),

8.67 (bs, 2H), 9.00 (bs, 1H),

(from A, 8S isomers)

1.51 (s, 3H), 1.7 (s, 3H),

4.01 (dd, 1 H), 4.44 (d, 1 H),

4.60 (s, 1 H), 4.70 (d, 2 H),

5.40 (m, 3H); 5.60 (d, 1H);

5.96 (m, 1 H), 7.34 (t, 1 H),

8.80 (d, 2H).

(from isomers B, 8R]

1.52 (s, 3H), 1.68 (s, 3H),

4.23 (m, 2H); 4.64 (s, 1H);

4.71 (d, 2 H),

5.30-5.46 (m, 3H);

5.53 (d, 1 H),

5.90-6.04 (m, 1 H),

7.34 (t, 1 H), 8.85 (d, 2 H),

100 ALIGN!

1.47 (s, 3H), 1.67 (s, 3H),

4.16 (m, 2H); 4.64 (m, 3H);

5.47 (m, 4H); 5.94 (m, 1H);

7.43 (m, 3H); 8.02 (m, 3H);

@ 1 H-NMR (CDCl3, .delta. In ppm) _R @ 1 and yield (%)

(8R) (no cleaning)

(after cleaning)

1.42 (s, 3H); 1.7 (s, 3H);

4.4 (doublet of doublets, J = 4 and 8, 1H),

4.5 (s, 1H); 4.65 (m, 2H);

5.2-6.3 (m, 3H);

5.6 (d, J = 4, 1 H),

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

7.8-7.6 (m. 2H);

7.8-8.1 (m, 2H);

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

4.15 (doublet of doublets, 1H),

4.5 (s, 1H); 4.65 (m, 2H);

5.2-6.4 (m, 5H);

72-7.6 (m. 2H);

7.8-8.2 (m, 2H).

(8S)

C. Using the procedure of Example 10, the following potassium salts were obtained by reaction of the above allyl esters

R ¹³

(isomer A)

(isomer B)

(isomer A)

yield (%) stereochemistry at C8 Ή-NMR (perdeuterodimethyl sulfoxide, δ values in ppm) 75 8R 1.46 (s, 3H), 1.56 (s, 3H), 3.76 (s, 1H), 4.13 (dd, 1H), 5.05 (d, 1H), 5.4 (d) 1H, 8.58 (d, 2H), 8.72 (s, 1H). IR (KBr - echnika): 3,478,1761,1607 cm ^-1 82 8S 1.42 (s, 3H), 1.65 (s, 3H), 4.25 (s, 3H); 4.27 (dd, 1H); 5.3 (d, 1 H), 5.35 (d, 1 H), 8.6-8.7 (m, 2H); 8.8 (m. 1H); 94 8S (deuterium oxide): 1.32 (s, 3H), 1.54 (s, 3H), 4.18 (s. 1H). 4.14-4.19 (m, 1H), 5.19 (d, 1 H), 5.25 (d, 1 H), 7.45 (t, 1H); 8.75 (d, 2H); 95 8R (deuterium oxide): 1.44 (s, 3H), 1.58 (s, 3H), 4.12 (s, 1H), 4.18 (m, 1H), 5.22 (d, 1 H), 5.49 (d, 1 H), 7.46 (t, 1 H), 8.75 (d, 2 H), 97 8R 1.47 (s, 3H), 1.58 (s, 3H), 3.79 (s, 1H); 4.13 (dd, 1H); 5.2 (d, 1 H), 5.4 (d, 1 H), 5.95 (bs, 1H), 7.45 (t, 1H), 7.60 (t, 2H); 8.03 (d, 2H); 8.16 (s, 1 H), 85 8S 1.48 [s, 3H], 1.67 (s, 3H), 4.27 (doublet of doublets, J = 4 and 10. 1H), 4.3 (s, 1H), 5.45 (d, J) = 4, 1H), 5.57 (d, J = 10, 1H), 7.45-7.65 [m, 2H], 8.04 (t, J = 8, 2H); IR (KBr - echnika): 3,424, 1,765, 1,746, 1,592 cm ¹ · 91 8R 1.42 (s, 3H), 1.56 (s, 3H), 4.16 (s, 1 H), 4.25 (doublet of doublets, J = 4 and 8, 1H), 5.46 (d, J = 4, 1H). 5.5 (d, J = 8, 1H). 7.4-7.6 (m, 2H); 7.8-8.05 (m, 2H).

Example 14

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

472 mg (1.23 mmol) of allyl 6- (1-methylimidazol-2-yl) hyidroxymethyl-1,1-dioxopenicillanate were acylated according to the procedure of Example 3 to give 392 mg (75%) of the desired acetoxy compound as mixtures of two isomers.

Ή-NMR (deuiteriochlorofOTm, 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 15

Allyl-6- (2-thiazolyl) acetoximethyl-1,1-dioxopenicilate

As described in Example 3, 0.5 g (1.29 mmol) of allyl 6- (2-thiazolyl) hydroxymethyl-1,1-dioxopenicillanate was acetylated with 0.396 g (3.88 mmol) of acetic anhydride and 0.307 g (3.88 mmol). 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.

Ή-NMR (dieuiteriochloirofoirim, δ in 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);

5.2-6.4 (m. 3H);

6.65 (d, IH);

7.4 (d, 1 H),

7.8 (d, 1 H).

Example 16

Following the procedure of Example 3 but starting from the appropriate ester of 1,1-dioxopenicillanate acid substituted at the 6-position by a residue R ^I3 CHOH starting material is prepared as follows acetylated esters:

QC0CH ₃ i

R- С H

COOCH 2 CH 2 Cl 2

R13

stereochemistry at C ₆ and C ₈ yield (%) NMR NMR-NMR (deuterochloroform, δ in ppm) a mixture of 6a, 8S and 6a, 8R 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); 8.20 (m, 2H). mixture 6a, 8S а 6a, 8R in a ratio 60: 40 69 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); mixture 6a, 8S а 6a, 8R in a ratio 60: 40 66 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, 1H); 6.45 (m, 1H); 8.6 (m, 2H); 8.75 (m, 1H).

Example 17

The above-prepared 8-acetoxy-3-carbonyloxyalkyl esters are reacted with tetrakis (triphenylphosphine) palladium (O), triphenylphosphine and potassium 2-ethylhexanoate to the potassium salts of the following general formula:

Λ 1

J O i—

O ‘CQQK

R13 stereochemistry at C ₆ and Cg yield (%) ^lH-NMR (deuterlumoxid, 6 values in ppm)

8a, 8S and 6a, 8R in the ratio of 65: 35

(crude product) 1.45 (s, 3H), 1.58 (s, 3H),

1.25 (s, 1.05H), 1.32 (s, 1.95H), (after purification chromium 4.25 (s, 0.65H), 4.28 (s, 0.35H), matography , mixture of isomers)

4.37 (dd, 0.65H), 4.45 (dd,),

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);

N. ť 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), 3.8 (s, 3H),

4.27 (s, 1H); 4.4 (dd, 1H);

4.96 (d, 1H); 6.45 (d, 0.15H);

6.5 (d, 0.85H), 7.07 (s, 0.15H),

7.1 (d, 0.85 H),

7.16 (s, 0.15H), 7.2 (d, 0.85H); IC (KBr technology):

409, 1,786, 1,740, 1,620 cm ¹

6a, 8S and 6a, 8R in a ratio of 30:70 (crude product)

1.3 (s, 2.1H), 1.34 (s, 0.9H),

1.42 (s, 3H), 2.13 (s, 0.9H),

2.2 (s, 2.1H), 3.66 (s, 0.7H), (after chromatography) 3.7 (s, 0.3H), 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' carried out by chromatography on a column of C ₁₈ (C ₁₈ = monooktadecylsilikát)

Example 18

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

(a) potassium (6a, 8R) -6- (2-thiazolyl) acetoxymethyl-1,1-dioxopenicillanate 1,0 (b) ampicillin trihydrate 1,0 (c) lactose0,5 (d) polyethylene glycol with an average molecular weight of 4,0003.0

The mixture (1375 mg) is filled with hard gelatin capsules of appropriate size. Capsules containing 250 mg of each active ingredient are obtained. Appropriate adjustment of the fill dose 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, 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 1,700 mg of the mixture is dispensed into each capsule. In this way, capsules containing 225 mg of component (a) and 450 mg of component (b) are obtained.

Similarly, other inhibitors / Mactamases of the invention may be combined with other conventional / Mactam antibiotics suitable for oral administration.

24Я747

Preparation А

Allyl-6a-bromo-1,1-dioxopenicillanate and allyl-6,6-dibromopenilcianate (i) 6a-Bromo-penicillanic 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) of solid sodium hydrogen carbonate. 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.

^! H-NMR (CDCl3, δ ppm):

1.4 (s. 3H),

1.6 (s, 4H),

4.4 (s. 1H).

4.6 (d, 1 H),

4.7 (d, 2 H),

5.15 (d. 1H);

5.1-5.95 (m, 3H).

(iii) Allyl-6,6-dibrompenicilate

6,6-Dibrompenicillanic acid (0.417 mol) was esterified as above to give 140 g (84%) of the corresponding allyl ester as an oil.

* H-NMR (CDCl3, δ ppm):

1.5 (s. 3H),

1.65 (s, 3H);

4.6 (s, 1 H),

4.75 (m, 2H).

5.3-5.6 (m. 2H);

5.85 (s, 1H).

5.8-6.3 (m, IH).

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 at 4 ° C overnight. 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. The second proportion of the product weighing

6.48 g is 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 selenium dioxide, and the mixture was subsequently stirred at 85 DEG C. for 5 hours. to 90 ° C, then 36 hours at room temperature, 8 hours at 85 ° C and finally 15 hours at room temperature, filtered and the solvent evaporated in vacuo. 4.81 g of crude aldehyde 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.

Preparation C

4-formylpyrimidine

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

^! H-NMR (CDCl3, δ ppm):

7.87 (dd, IH),

9.06 (d, 1H).

9.43 (d, IH);

10.0 (s, 1 H).

Preparation D

Diphenylmethyl-6a, -bromo-1,1-dioxopenicillinate

31.2 g (0.1 mol) of 6α-bromo-1,1-dioxopenicillanic acid are added portionwise to a solution of 21.557 g (0.1 mol) of diphenyldiazomethane in 400 ml of dry tetrahydrofuran over 30 minutes at 2,447,747. 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 DEG C. After 18 hours no crystals formed. thus concentrating in vacuo to give 51.2 g of a yellow solid which is chromatographed on silica gel. Elution with chloroform gives 14.86 g of a colorless glassy product. 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 'E

Benzthiazole-2-carboxaldehyde

A solution of 10 g (0.074 mol) of freshly distilled benzothiazole (boiling point 82 ° C / starting material aldehyde / 267 Pa) in 250 ml tetrahydrofuran was cooled to -78 ° C under nitrogen, stirred at this temperature for 15 minutes. 29.6 ml (0.074 mol) of 2.5M n-butyllithium are added dropwise over 15 minutes, stirring is continued for 25 minutes, then 8.6 ml (0.111 mol) of dimethylformamide are added and the mixture is stirred for 1 hour. Allow to warm to room temperature, add 200 g of ice and evaporate the solvent in vacuo. Extract the aqueous residue five times with 100 ml of ethyl acetate, dry the extracts over magnesium sulfate, concentrate to a small volume and concentrate by chromatography on a silica gel column. chloroform and ethyl acetate (96: 4) were obtained

8.4 g of the desired aldehyde, m.p. 74.5-75 ° C;

H-NMR (CDCl3, 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 also prepared analogously, yield (%)

H-NMR (CDCl₃, δ values in ppm) _CH3 / ~

Ή

Amber oil, boiling point 120-122 ° C / 3 333 Pa

CHO ^ch 3

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

1.2 ((6H)), 3, Q (quartet, 2H),

3.64 (kw, e = 22, J) 6.95 (s, 1H)

7.21 (d, H, J) ', 55 [(, HH)]

8.23 (d, d)) *> 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 ethoformate according to the procedure of Curtis et al., J, Org, Chem., 45, 4038 (1980)

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 to pH 7.5 with sodium bicarbonate. Concentration of the dried organic layer yielded 84% yield of methyl pyrazine-2-carboxylate as an off-white solid, which, after recrystallization from isopropanol / ethyl ether, gave yellow needle crystals.

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

4.1 (s, 3 H),

8.93 (m, 2H).

9.47 (m, IH).

g (0.145 mol) of this methyl ester is dissolved in 600 ml of dry tetrahydrofuran, cooled to -78 ° C and treated dropwise over 15 minutes with a solution of 5.8 g of 98% lithium aluminum hydride in tetrahydrofuran. 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. 8.53 g of crude product are obtained, which is 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.

Ή-NMR (deuterochloroform, δ values 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 (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.

(li) 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 a volume of 250 ml and cooled. 24.7 g of the desired phenylhydrazone are obtained.

Ή-NMR (perdeuteroacetone, δ values 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 acetic anhydride 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 (= NNH H · _U,) CH = NOCOCH3 as 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 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 heated under reflux 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 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. Evaporation of the solvent in vacuo gave a yellow liquid material which, after distillation, afforded 14.68 g of the product, b.p. 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 with 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 ppm):

2.4 (s, 3H).

6.3 (d, 1 H),

Claims (7)

I will invent the object A process for the preparation of 6- (substituted hydroxymethylpenicillanic acids of the general formula II (II)) in which n has the value 0 or 2, Я _я means a hydrogen or bromine atom, 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 3-phthalidyl, 4-crotonolactonyl, γ-butyrolacton-4-yl, a radical of formula - ^с н ₂ - ^ = с_ _я »v 4 - CHOCOR ¹ * -COCOR * L R ^T 6, -COCOOR in which each of R ⁴ and R ⁵ represents a hydrogen atom or a methyl group, R ⁶ represents an alkyl group having 1-5 carbon atoms and R ¹⁴ represents a radical of formula wherein R ¹⁵ is 2-phenylacetamido, 2-phenoxyacetamido, D-2-amino-2-phenylacetamido, D-2-amino-2- (4-hydroxyphenyl) acetamido, 2-carboxy-2-phenylacetamido, 2-carboxy-2- (2-thlenyl) acetamido, 2-carboxy-2- (3-thienyl) acetamido, D-2- (4-ethyl-2,3-dioxopiperazinocarbonylamino) -2-phenylacetamido or 2,2-dimethyl-4-phenyl-5-imidazolidinon-1-yl, R ¹⁸ is hydrogen, C 2 -C 5 alkanoyl, C 2 -C 5 alkoxycarbonyl, pyrazinecarboxylic acid, benzoyl, CF ₃ CO or CONR ⁸ R ⁹ , one of R ¹² and R ¹³ is 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-p zbytefcCH acetylpyrroylovou group R ^{Z ') NR ¹⁶ R ^17, CNR ⁸ R ⁹ With the proviso that R ¹² or R ^{13 is a} radical of formula R ⁷ and p are 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 a residue 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, phenyl a group, benzyl, naphthyl, pyridyl, NR ⁸ R ⁹ , CONR ⁸ R ⁹ , NHCOR ¹⁰ , nitro, chloro, bromo, trifluoromethyl or NR ⁸ , R ⁸ and R ⁹ are each independently hydrogen, C 1 -C 4 alkyl, phenyl or benzyl, R1 ⁽⁾ is C1-C4alkyl, 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 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 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 the radicals R ¹² or R ¹³ contain a carboxyl group, characterized in that the compound of formula X (*) in which: R ¹ is other than hydrogen and n is 0 or 2, reacted with equimolar amounts of C 1-4 alkyl halide or C 1-4 alkyl lithium, and an aldehyde of the formula R 12r 13co, from above said respective halide is chloride, bromide or iodide and R ⁱ² and R @ ¹³ have the abovementioned meaning, in the presence of an inert solvent at a temperature from -100 to 4-25 ° C, to give a compound of formula XI R ^{@ 1} , R @ ¹² , R @ ¹³ and n are as defined above, and optionally, to produce compounds of formula II wherein R @ ¹⁸ is other than hydrogen and X @ 3 is bromo, is converted to carboxy protected derivative. group, wherein R ¹ means the above-defined radical R ^a, and acylated with an acyl chloride or acyl bromide of the formula R ¹⁸ C 1 or R ¹⁸ Br, wherein R ^lTI is as defined above, except a hydrogen atom 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 / or to produce compounds of formula II wherein X ₃ is hydrogen, a compound of formula II wherein X ₃ is bromo is hydrogenolysed in the presence of an inert solvent with organotin hydride or hydrogen in the presence of a catalyst based a noble metal, whereupon the resulting compound is optionally added of Formula II 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 compounds of formula (II) in which R @ ¹ , X @ ₃ , R @ ^{18 and} n are as in point 1, one of R @ ¹² and R @ ¹² . ¹³ represents a hydrogen atom and the other of these represents vinyl, furyl, thienyl, N-methylpyrrolyl or N-acetylpyrrolyl, the remainder CH (R ^4], NR ¹⁶ R ¹⁷ CNR ⁸ R ⁹ II p CNR ⁸ R ⁹ II NH 7, with the restriction that when R is ^three or R13 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 1 or 2 X is 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, NR ⁸ R ⁹ , CONR ⁸ R ⁹ , NHCOR ¹⁰ , nitro, chloro, bromo, trifluoromethyl or 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; 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 17 and R 17 together with the nitrogen atom to which they are attached form pyrrolidino, 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 ¹³ contains a carboxyl group. 3. A process according to claim 1 wherein the reaction with an aldehyde of the formula R @ 13 R @ 13 CO is carried out at -78 DEG C. in the presence of tetrahydrofuran or ethyl ether. 4. A process according to claim 3, wherein the starting aldehyde of the formula R1 ' 2R &lt; ¹³ &gt; CO is one in which R &lt; 12 &gt; 2-thiazolyl, 3-isothiazolyl, 5-methyl-o-oxazylol, 1,3,4-thiadiazol-2'-yl, pyridazin-3-yl, 1,2.3-thiadiazin-4-yl, A 1.2.4-axadiazin-3-ylava group; A 1.2.4-axadiazin-5-ylava group; 1,3,4-oxadiazin-2-yl group, 1-phenyl-5-methyl-1,2,3-triazin-4-yl, N-methyl-1,2,3,4-tetrazin-5-yl , 1-methyl-1,2-diazin-3-ylava, 4-pyrimidinyl, 4,5-dimethylthiazol-2-yl, benzothiazal-2-yl or 1-benzylbenzimidazol-2-yl, 5 Process according to claim 1 or 4, characterized in that a compound of formula X, wherein R ^l represents aHylovou or benzyl, is reacted with methylmagnesium bromide and an aldehyde of formula R ^ R ^ CO, and the product of formula II wherein X 3 represents a hydrogen atom is obtained by hydrogenolysis of tri-n-butyltin hydride in benzene or toluene as the solvent, at a temperature of from 0 ° C to the boiling point of the solvent, 6 Process according to claim 4, characterized in that used as starting material aldehyde of the above formula wherein one of R ⁿ and R ¹³ represents. and the other represents 2248747 -thiazolyl or benzothiazol-2-yl. 7. A method according to any of claims 1 to 6, characterized in that starting materials are used wherein R ¹ is allyl, which are converted to the corresponding product wherein R ¹ represents hydrogen, sodium potassium, no bo, treating the resulting an allyl ester product with catalytic amounts of tetrakis (triphenylphosphine) palladium (0) and triphenylphosphine, and an equimolar amount of sodium or potassium salt of 2-ethylhexanoic acid in the presence of an Inert solvent.