CS241091B2 - Method of 2-heterocycloalkylthiopenemderivatives production - Google Patents

Description

The invention relates to a class of antibacterial agents comprising a 2-azetidinone (β-lactam) ring. Chemically, the antibacterial agents of the invention may be described as 6α ^, -hydroxyethyl-2-subst-2-penem-3-car-. boxylic acids and their derivatives.

Although already. Certain derivatives of 2-subst.-2-ipenem-3-carboxylic acid have been described, but there is a continuing need for new compounds having desirable therapeutic antibacterial properties.

The present invention provides a compound of formula (I) a ethyl, 1,2,4-triazolyl or tetrazolyl group,

R 1 represents a hydrogen atom or a C 1 -C 4 alkyl group, and alk represents a C 1 -C 4 alkylene group, and pharmaceutically acceptable salts thereof.

It will be understood that the novel compounds of the invention may exist in the form of various optically active isomers, and the invention includes both the optically active isomers and mixtures thereof.

Accordingly, the compounds of formula (II) are within the scope of the invention

in which

R is - _; (alik) —X — Ri wherein

X represents an imidazolyl, 1,2,3-triazo241091 in which

R is as defined in formula I, and pharmaceutically acceptable salts thereof.

Preferred compounds of formulas I and II include those wherein X is an imidazolyl group, and particularly preferred are those wherein R is 2- (1-imidazolyl) ethyl, [1-methylimidazol-2-yl] methyl (4-imidazolyl) methyl or 1- (imidazolyl) prop-2-yl.

The invention further provides pharmaceutical compositions comprising as active ingredients a compound of Formula I or II, and a pharmaceutically acceptable diluent or carrier, and a method of treating a bacterial infection in a mammal comprising administering an antibacterially effective amount of a compound of Formula I or II.

Compounds of formulas I and II are useful as antibacterial agents, and they are derivatives of the bicyclic core of formula III

Herein, the core of formula III is designated "2-pen" and the atoms in the rings are numbered as described above. The carbon atom attached to the ring carbon in the '6' position is assigned the number 8. If the abbreviation 'PNB' appears in the text, it is a p-nitrobenzyl group.

The relative position of the hydrogen atom on the carbon at the 5-position and the remaining hydrogen atom on the carbon at the 8-position of the compounds of formula I may be either cis or trans. The invention encompasses both these isomers and mixtures thereof. For pharmaceutical applications, the trans-isomer is generally preferred, and the cis-isomer is readily converted to the trans-isomer.

According to the Prelog-Ingold R, S stereochemical notation used herein, the carbon at the 5-position generally has an absolute stereochemistry denoted by R. For example, a compound of formula II wherein R is 1- (1-imidazolyl) prop- The 2-yl group is (5R, 6S-6 - [(R) -1-hydroxyethyl] -2- [1- (1-imidazol-prop-2-yl) thio-3-carboxy-2-foam).

The present invention provides penematerials substituted at the 2-position with a radical of the formula -S- (alk) -X-R 1

The heterocyclic groups represented by X may be attached to the radical alk or R 1 through any imine or methylidene group of their five membered heterocyclic ring. Preferably, R1 and alk are each independently alkyl or alkyl, respectively. . (C 1 -C 4) alkylene and may be either straight-chain or branched.

The carboxyl group at the 3-position of the penemitters of the invention can be esterified to form a non-toxic ester moiety that hydrolyzes in vivo, i.e., in blood or tissue of a mammal, to release the corresponding penem-3-carboxylic acid or salt thereof.

Typical examples of such readily hydrolyzable ester-forming moieties are C 3 -C 6 alkanoyloxymethyl, and 4- (9-C 9 alkanoyloxy) ethyl. carbon atoms, 1-methyl-1- [alkanoyloxy) ethyl group having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl group having 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl group having 4 to 7 carbon atoms, 1-methyl-1- ( (C 5 -C 6 alkoxycarbonyloxy) ethyl, N- (C 3 -C 9) alkoxycarbonyl) 1- (N- (alkoxycarbonyl) amino) C 4 -C 10 ethyl, 3-phthalidyl, 4 -crotonolactonyl, γ-butyrolacton-4-yl, carboxyalkylcarbonyloxymethyl of 4 to 12 carbon atoms, or 5-methyl-2-oxol, 3-dioxoten-4-ylmethyl.

In order to prepare compounds bearing this ester moiety hydrolyzable in vivo, the acid of formula I or II is reacted with a base to form the corresponding anion. Suitable cations include sodium, potassium, calcium, tetraalkylammonium, and the like. The anion may be prepared by lyophilizing an aqueous solution of a compound of formula I or II, for example an aqueous solution containing tetrahydrofuran, and sodium bicarbonate or tetrabutylammonium hydroxide. .

The resulting anion of the compound of formula (I) or (II) is reacted with the appropriate chloride or bromide of the ester-forming moiety in an inert solvent, such as acetone or dlmethylformamide, at a temperature of approx. from 20 to 50 ° C, preferably at 25 ° C.

Compounds of formula (I) or (II) wherein R 1 is hydrogen or salts thereof may be synthetically prepared according to the following reaction schemes A to C.

Br

Scheme A

Scheme В

CO ^ PNB ^r 9 ~

SR ^ _o

R ₃

StO Is • 4li _

Rg ^ ΐ’υ \ · ιΐ) .__ | —s * CS-R J — N o

About CCO.PNB <XI>

(XV)

Scheme C

As shown in Scheme A, the compound of formula II can be prepared according to the procedure of Yoshida et al., Chem. Pharm. Bull., 29, 2899-2909 (1981), from the known dib-ompenam of formula IV. The dibrompenam of formula IV is reacted with tert-butyl magnesium chloride at a temperature between about -90 ° C and -40 ° C, preferably at about -76 ° C, in an inert solvent such as tetrahydrofuran, diethyl ether or toluene, preferably tetrahydrofuran.

Other organometallic reagents may also be used. The resulting reaction mixture is treated in situ with an appropriate aldehyde such as acetaldehyde to prepare the 1-hydroxyethyl derivative. The aldehyde is added at a temperature between about -80 ° C and about -60 ° C, preferably about -76 ° C for acetaldehyde.

The resulting bormhydroxypenam of formula V is hydrogenated to remove the bromine at the 6-position. A suitable hydrogenation catalyst is a noble metal catalyst such as palladium. The reaction is carried out in a protic solvent such as a mixture of equal parts of methanol and water or tetrahydrofuran and water, preferably in a mixture of equal parts of methanol and water, at a pressure of about 0.1 to 0.4 MPa, preferably 0.4 MPa. and at a temperature of about 0 to 30 ° C, preferably about 25 ° C.

The resulting alcohol of formula VI can be protected by reaction with a trialkyl halogensilane of formula

R9

R9 — Si — Q 1 '

R9 in which

R 9 represents an alkyl group having 1 to 6 carbon atoms and

Q represents chlorine, bromine or iodine.

Thus, treatment with dimethyl tert-butyl chlorosilane in the presence of an amine acceptor proton such as imidazole in a polar aprotic solvent such as N-dimethylformamide at a temperature of about 5 to 40 cc, preferably at about 25 ° C affords a trialkylsilyl protecting group. a hydroxyl function group as shown in Formula VII.

Reaction of a compound of formula VII with mercuric acetate in acetic acid at about 90 ° C affords an olefin of formula III.

To obtain the desired azetidinone of formula IX, the olefin of formula VIII is ozonized in an inert solvent such as dichloromethane at a temperature between about -80 ° C and -40 ° C, preferably about -76 ^° C, and the reaction product is treated with an alkanol such as methanol, to form azetidinone of formula IX.

As shown in Scheme B, the compound of formula IX is treated with a trithiocarbonic acid salt of formula

M + R 10 -S-C (S) -S- in which: R 10 represents an alkyl group having 1 to 4 carbon atoms, preferably ethyl and

M represents a metal, such as sodium or potassium, to form a compound of formula X.

This conversion of the compound of formula IX to the compound of formula X is carried out in an organic solvent or in water, preferably a mixture of water and dichloromethane, at a temperature in the range of about 0 to 35 ° C, preferably about 25 ° C.

The compound of formula X is condensed with p-nitrobenzyl chloroxalate in the presence of a tertiary alkylamine in which each alkyl moiety contains, for example, 1 to 4 carbon atoms, such as in the presence of ethyl diisopropylamine, to form a compound of formula XI. This condensation reaction is carried out in an inert solvent, preferably dichloromethane, at a temperature of about 5 to 25 ° C, preferably about 10 ° C.

The resulting compound of formula XI is cyclized by treatment with a trialkyl phosphite wherein each alkyl moiety contains 1 to 4 carbon atoms such as triethylphosphite in an inert solvent such as trichloromethane at a temperature of about 40-80 ° C, preferably about 60 ° ^C to penemerivative of formula XII.

The thio group of the compound of formula XII is oxidized to the sulfoxide moiety (see compound of formula XIII) by treatment with an oxidizing agent such as m-chloroperbenzoic acid in an inert solvent such as dichloromethane at a temperature in the range of about -10 ° C to -30 ° C. preferably at -20 ° C.

The sulfoxide of formula XIII is substituted with a mercaptic group R-S using, for example, the corresponding sodium or potassium salt, which is reacted with the sulfoxide of formula XIII in a polar organic solvent such as ethanol or acetonitrile at a temperature of about 35 to about 35 ° C. 50 ° C, preferably at a temperature of about -35 ° C.

. The starting mercaptans of the formula R-SH or the starting thloacetates of the formula R-S-C (O) CH 5 are either known or can be prepared by methods analogous to those known in the art. For a review of these methods, see J. L. Wardell, "Preparation of Thiols" in The Chemistry of the Thiol Group, ed. S. Patai, John Wiley and Sons, London • 1974, Chapter 4.

The requisite mercaptans or derivatives thereof may be prepared from the corresponding alcohols, halides, p-toluenesulfonates, methanesulfonates and the like. Suitable thiol derivatives which are readily converted to thiols include thioacetates (saponification) and tert-butylthioethers or p-methoxybenzylthioethers [by acid treatment]. or mercury salts).

Volante in Tetrahedron Letters, 22, 3,119 to 3,112 (19'81) describes the conversion of alcohols into thiols and thiolesters using triphenylphosphine and a dialkyl azodicarboxylate in the presence of an alcohol and the corresponding thiol acid.

Of the compounds of formula XIV, the trialkylsilyl group is preferably removed prior to hydrogenolysis to remove the carboxyl function protecting group (PNB). The trialkyl group is removed by treatment with tetraalkylammonium fluoride in an ether solvent such as tetrahydrofuran at a temperature of about 15 to 40 ° C, preferably at a temperature of about 15 ° C. 25 ° C to give the compound of formula XV.

The conversion of a compound of formula XV to a compound of formula I or II is carried out by a conventional hydrogenolytic reaction and is carried out in a manner customary for this type of reaction. Thus, a solution of a compound of formula XV may be stirred or shaken under an atmosphere of hydrogen or a mixture of hydrogen with an inert diluent such as nitrogen or argon in the presence of a catalytic amount of a noble metal hydrogenolysis catalyst such as palladium on calcium carbonate or palladium on diatomaceous earth.

Suitable solvents for this hydrogenolysis are lower alkanols such as methanol, ethers such as tetrahydrofuran and dioxane, low molecular weight esters such as ethyl acetate and butyl acetate, water and mixtures of these solvents. Typically, such solvents and conditions are chosen to dissolve the starting material.

The hydrogenolysis is generally carried out at room temperature and under a pressure of about 5 to 5 bar. The catalyst is usually present in an amount of from about 10% by weight, based on the weight of the starting material, up to the weight corresponding to the weight of the starting material, although larger amounts of catalyst may be used.

The reaction usually takes about 1 hour, after which the compound of formula (I) or (II) is isolated simply by filtration and subsequent evaporation of the solvent in vacuo.

When using palladium on calcium carbonate as a catalyst, the product is often isolated in the form of a calcium salt, and when using palladium on diatomaceous earth, the product is often isolated in the form of a sodium salt.

The compound of formula (I) or (II) may be purified by methods common to β-lactam compounds. For example, a compound of Formula I or II can be purified by column chromatography, Sephadex gel filtration, or recrystallization.

An alternative synthetic procedure is described in Reaction Scheme C. The azetidinone of formula IX is reacted with a trithiocarbonate of formula

M + R — S — C (S) —S ~ in which

Μ represents a metal, such as sodium or potassium, using the procedure described above for the preparation of a compound of formula X.

The resulting trithiocarbonate of formula XVA is treated with (p-nitrobenzyloxycarbonyl) (dihydroxy) methane in an aprotic solvent such as benzene, toluene or dimethylformamide, preferably benzene, at a temperature in the range of about 25 ° C to 110 ° C, preferably at about 80 ° C to give an alcohol of formula XVI.

The corresponding chloride of formula XVII is prepared from an alcohol of formula XVI by treatment with thionyl chloride in an inert organic solvent such as dichloromethane in the presence of a hindered amine which serves as an acid acceptor such as 2,6-lutidine at a temperature in the range of about -10 to 75 ° C, preferably at 0 ° C.

The chloride of formula XVII is reacted with a triarylphosphine such as triphenylphosphine in an inert solvent such as tetrahydrofuran in the presence of a tertiary amine such as

2,6-lutidine, at a temperature of about 25 ° C, to form a compound of formula XVIII, which is cyclized by heating to reflux in an aromatic solvent such as toluene, to give the penem-derivative of formula XIV.

Salts of trithiocarboxylic acid of formula M ⁺ R = S- (C = S) -S- are prepared from the corresponding mercaptan of formula R-SH or by reaction of the thioacetate of formula RSC (O) CH 3 with an alkali metal alkoxide and then with carbon disulphide.

Using the procedure described above by Yoshida et al., Stereochemistry at the carbon atom at the 6-position of the penem as well as the hydroxyethyl groups attached to the carbon at the 6-position correspond to the state shown in Formula II. Using cyclization according to Schemes V or C, the product has such a basic stereochemical arrangement that the hydrogen at the 5-position of the penem ring is in the trans-position to the hydrogen at the 6-position and has a d-configuration.

The compounds of formulas I and II are acidic and form salts with bases. These salts are within the scope of the invention. Said salts can be prepared by standard techniques, such as by realizing the acidic and basic components, usually in a stoichiometric ratio, in an aqueous, non-aqueous or partially aqueous medium, as appropriate for each case.

The resulting salts are then isolated by filtration, non-solvent precipitation followed by filtration, solvent evaporation or, in the case of aqueous solutions, lyophilization.

The basic agents suitable for salt formation may be both organic and inorganic and include ammonia, organic amines, hydroxides, carbonates, bicarbonates, hydrides and alkoxides of alkali metals, as well as alkaline earth metal hydroxides, carbonates, hydrides and alkoxides.

Representative examples of such bases include primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine, secondary amines such as diethylamine, morpholine, pyrrolidine and piperidine, tertiary amines such as triethylamine, N-ethylipiperidine, N - methylmorpholine and 1,5-diazabicyclo [4.3.0.0] non-5-ene hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide, alkoxides such as sodium ethoxide and potassium ethoxide, hydrides, such as calcium hydride and sodium hydride, carbonates such as potassium carbonate and sodium carbonate, bicarbonates such as sodium bicarbonate and potassium bicarbonate, and alkali metal long chain fatty acid salts such as sodium 2-ethylhexanoate.

Preferred salts of the compounds of formulas I-II are sodium, potassium and calcium salts.

The pharmaceutically acceptable salts of the compounds of formula (I) or (II) are those which do not exhibit significant adverse side effects at commonly used amounts, and include, for example, sodium, potassium or calcium salts.

The in vitro antibacterial activity of the compounds of formula (I) or (II) and their salts can be demonstrated by measuring their minimum inhibitory concentrations (МГС) in µg / ml. for many microorganisms.

The following procedure is recommended in the International Collab-orative Study on Antibiotic Sensitivity Testing [Eri-cson and Sherris, Acta. Pathologica et Microbiologia Scandinav., Supp. 217, Section B: 6,468 (1971)] using agar with cerebral infusion and multiple inoculation devices.

One hundred-fold diluted contents of tubes with culture grown over n-oc are used as standard inoculum. Plates containing in each case 20 ml of brain and heart infusion agar are inoculated by plating 20000 to 10,000 cells in a volume of about 0.002 ml on the agar surface.

A series of twelve-fold dilutions of the test compound are run, with an initial concentration of 2 µg / iril. Plates are evaluated after 18 hours incubation at 37 ° C, disregarding individual colonies.

The sensitivity (МГС) of the test organism is the lowest concentration of the test substance which, when assessed with the naked eye, is capable of completely inhibiting the growth of the organism.

The compounds of formula I or ΙΊ and their pharmaceutically acceptable salts are useful for the control of bacterial infections caused by susceptible bacteria in mammals241091

-ve mi, for example sensitive strains of Staphylococcus aureus. Mentioned substances. can also be used in human medicine.

The compounds of the invention may be administered orally or parenterally, i.e., intramuscularly, subcutaneously, intraperitoneally or intravenously, either alone or in combination with a pharmaceutically acceptable carrier. The ratio of active ingredient to carrier depends on the chemical nature, solubility and stability of the active ingredient as well as the dosage considered.

The ratio of pharmaceutically acceptable carrier to penemderivative normally ranges from about 1: 10 to 4: 1. For oral administration, the compounds of the invention may be used in the form of tablets, capsules, lozenges, troches, powders, syrups, elixirs, aqueous solutions and suspensions and the like.

In the case of tablets, the carrier can be, for example, loktose, sodium citrate and salts of phosphoric acid. Various disintegrants such as starch, and glidants such as magnesium stearate, sodium lauryl sulfate and talc are usually used in the manufacture of tablets.

Diluents useful in the preparation of capsules include lactose and high molecular weight polyethylene glycols. If aqueous suspensions are required for oral administration, the active ingredient can be combined with emulsifiers with a suspending agent, and sweeteners and / or motor additives can also be added.

For parenteral administration, sterile solutions of the active compound are suitably prepared, the pH of which is suitably adjusted and buffered. For intravenous formulations, the total concentration of dissolved components should be checked to render the formulation isotonic.

The appropriate dose for a given patient in human medicine will be determined by the attending physician. This dose may vary depending on the age, weight, and response to the preparation as well as the nature and severity of the symptoms of the disease.

The compounds of formula I or Π are normally used in doses ranging from about 10 to about 200 mg / kg body weight per day for oral administration and about 10 to about 400 mg / kg body weight per day for oral administration. .

However, it may be necessary to use doses outside this range in some cases.

The following Examples and Preparations illustrate the invention but are not intended to limit the scope of the invention in any way.

Infrared spectra (IC) were measured either in tablets with potassium bromide (KBr technique) or in suspension in nujol (nujol) or in a solution in -chloroform (chloroform), methylene chloride (methylene chloride) or dimethylsulfoxide (dimethylsulfoxide) by an diagnostic absorption bands are given either in μΐη or in wave numbers (cm-1).

Nuclear magnetic resonance spectra (NMR) were measured in solutions in deuterochloroform or perdeuterodimethylsulphoxide, or in their mixtures, by signal positions, expressed in ppm relative to tetramethylsilone. The following abbreviations are used to describe the shape of the signals:

s singlet d-doublet t triplet q quartet m multiplet w wide signal c complex

The abbreviations "ss" and "sss" mean that the respective proton appears in the form of two resp. three singlets.

Example 1

(5R, 6S) -6 - [(R) -1-hydroxy-ethyl] -2 - [(1-imidazolyl) ethylthio] -2-penem-3-carboxylate

A suspension of 38 mg of 10% palladium on diatomaceous earth in 10 ml of tetrahydrofuran and 10 ml of water is adjusted to pH 7.0 with a 0.1 N aqueous hydrochloric acid solution and a solution of 38 mg of p-nitrobenzyl- (5R, 6S) -6 - [(R) -1-imidazolyl) ethylthio-2-penem-3-carboxylate in 5 ml of tetrahydrofuran with 5 ml of distilled water, the resulting mixture is hydrogenated under a hydrogen pressure of -0.385 MPo for 75 minutes, 38 mg of 10% palladium on diatomaceous earth are added thereto, the pH of the suspension is adjusted to 7.0 with an aqueous sodium hydroxide solution of 0.02 M and the mixture is hydrogenated under a hydrogen pressure of -0.385 MPo for 75 minutes.

The catalyst is filtered off, the filtrate is concentrated in vacuo to remove the tetrahydrofurac, the resulting aqueous solution is adjusted to pH 7.0 and extracted with 25 ml of ethyl acetate. Lyophilization of the aqueous solution afforded 23 mg (80% yield) of the title compound as an amorphous solid.

IC (KBr - technology): 2.93, 5.65 at 6.28 µm.

NMR (25.0 MHz, perdeuterodimethylsulphoxide):

1.16 (d, 3H);

3.2 (m, 2H).

3.54 (m. -1H);

3.92 (m, IH);

4.18 (m, 2H).

35.54 (s, 1 H),

6.88 (s, 1 H),

7.2 (s, 1H) [delta]

7.65 (s, 1 H) ppm.

Example 2

Sodium (5R, 6S) -6 - [- (R) -1-hydroxyethyl] -2241091

[4-Imidazolyl] methylthio-2-penem-3-carboxylate

The procedure described in Example 1 was repeated using p-mtrobenzyl- (5R, 6S) -6 - [(R) -1-6a-hydroxyethyl] -2- [4-imidazolyl) methylthio-2-penem-3- carboxylate starting material. In a yield of 38%, sodium is obtained.

- [5R, 6S] -6 - [- [R] -1-hydroxyethyl] -2- (4-imidazolyl) methylthio-2-penem-3-carboxylate.

IR (KBr): 2.93, 5.65 and 6.26.

When p-nitrobenzyl- [5R, 6S) -d - [[R) -1-hydroxyethyl] -2- [1- [1-imidazolyl) prop-2-yl] thio-2- is used as starting material penem-3-carboxylate derived. % of the less polar dlastereomer, the corresponding sodium salt of the product of formula II is obtained in a yield of 97.5%.

IC [nujol suspension]: 5.65 ₍ m &lt; -1 &gt;).

Similarly, starting from a compound of formula XV wherein R is a 1- [1-imidazolyl) prop-2-yl radical derived from the more polar diastereomer, the corresponding sodium salt of the product of formula II is obtained in 60% yield. .

IC (nujol suspension): 5.66

Example 3

Kaleium- [5R, 65] -6 - [[R) -1-hydroxyethyl] -2- [1-methylimidazol-4-yl] methylthio-2-penem-3-carboxylate

To a suspension of 0.12 g of 5% palladium on calcium carbonate in 20 ml of water and 10 ml of tetrahydrofuran, which was prehydrogenated with hydrogen under pressure. A solution of 0.12 g of p-nitrobenzyl- [5R, 6S) -6 - [[R) -1-hydroxyethyl] -2- [1-methylimidazol-2-yl) methylthio-2] is added -penem-3-carboxylate in 15 ml tetrahydrofuran and 5 ml water.

The mixture was hydrogenated under 50 psi of hydrogen for 45 minutes, an additional 0.12 g of 5% palladium on calcium carbonate was added thereto, and the mixture was hydrogenated for 60 minutes under 50 psi of hydrogen.

The catalyst was filtered off and the filtrate was concentrated in vacuo to remove tetrahydrofuran. The aqueous solution was washed with ethyl acetate (3.times.25 ml) and lyophilized. 74 mg (yield 82%) of the title compound were obtained as an amorphous solid.

IC [KErdechnilka]: 2.92, 5.7 and 6.28 ₍ µm.

NMR [250 MHz, perdeuterodimethylsulfoxide]:

1.16 [d, 3H]

3.55 to 3.7 [m together with s at 3.64, total 4H),

3.94 (m, 1 H),

4.21 (q, 2H),

5.56 К 1H)

6.8 [s, 1H] and

7.1 [s, 1h] ppm.

Preparation A p - Nitrobenzyl [5R, 6S] -8 - [[R) -1-hydroxyethyl] -2- [1-imidazolyl] ethylthio-2-pentene-3-carboxylate

To a solution of 152 mg [0.258 mmol] of p-nitrobenzyl- (5R, 6S) -6 - [[R) -1-tert-butyldimethylsilyloxyethyl] -2 - [(1-imidazolyl) ethylthio] t-Pen-S-carboxylate in 7 mL of tetrahydrofuran was added 0.15 mL [2.58 mmol] of acetic acid and 0.774 mL [0.774 mmol] of a 1M solution of tetr ^, aitrole. of fluoride in tetrahydrofuran.

After stirring for 24 hours at room temperature under nitrogen, 50 ml of ethyl acetate are added and the resulting solution is washed successively with 30 ml of saturated aqueous sodium bicarbonate solution, 30 ml of water and 30 ml of saturated aqueous sodium chloride solution.

The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (152 mg) was purified by column chromatography on 50 g of silica gel using a mixture of ethyl acetate and methanol. [85: 15] as eluent. 77 mg (yield 6-3%) of the title compound are obtained as an amorphous solid.

IR (solution in dichloromethane): 5.57, 5, 92 and

6,58 /..m ,.

NMR [deutero-chloroform]:

1.34 (id, 3H).

2.76 to 3.38 (c, 24-1),

3.72 (m, 1H).

4.24 (m, 3H).

5.28 (q, 2H),

5.62 (d, 1 H),

6.93 (m, 2H),

7.5 (d, 3H). and

8.13 (d, 2H) ppm.

B

The process described in Preparation A is used to obtain compounds of Formula XV from the corresponding compounds of Formula XIV. The products produced (meanings of the symbol R) as well as the physical data [the solvents used are given. in brackets) are summarized in Table I below: 241091

1В

Table I

IC (/ zm)

NMR (ppm) Yield (%)

R (4-imidazolyl) methyl

5.57, 5.92 and 6.56 (dichloromethane) (1-methylimidazol-2-yl) methyl

5.6 and 5.92 (nu jol)

1- (1-imidazolyl) prop-2-yl (from less polar diastereomer)

5.58, 5.89 and 6.59 (dichloromethane)

1.28 (d, 3H);

3.68 (m, IH),

4.2 (c, 3H);

5.27 (q, 2H).

5.6 (d, 1 H),

6.98 (s, 1H).

7.6 (m. 3H);

8.2 (d, 2H) (deuterochloroform)

1.17 (d, 3H);

1.64, 64 (s, 3H);

3.87 (m, IH);

4.0 (m, 1 H),

4.42 (q, 2H).

5.24 (d, 1 H),

5.37 (q, 2H).

5.75 (d, IH);

6.83 (d, IH);

7.14 (d, 1H),

7.7 (d. 2H);

8.24 (d, 2H), (250 MHz, perdeuterodimethylsulfoxide)

1.37 (d, 6H).

3.3 to 4.5 (c. 6H),

5.3 (q, 2H).

5.58 (d, 1 H),

6.86 (m, IH),

6.98 (m, IH);

7.44 (m) a

7.52 (d) (3H total)

8.16 (d, 2H) (deuterochloroform)

63.5

1- (1-imidazolyl) prop-2-yl (from the more polariastereomer)

5,59, 5,9 and 6,59 (dichloromethane)

1.36 (d, 6H);

3.28 to 4.45 (c, 6H),

5.28 (q, 2H).

5.62 (d, IH);

6.86 (m, IH);

6.96 (m, 1Ή),

7.42 (m) a

7.52 (d) (3H total)

8.12, (d, 2H) (deuterochlorolorm)

39.8

Preparation C p-Nitrobenzyl (5R, 6S) -6 - [(R) -1-tert-butyldimethylsilyloxyethyl] -2 - [(1-imidazolyl) ethylthio] -2-penem-3-carboxylate

To a solution of 2- (imldazolyl) ethyl thioacetate (715 mg, 4.22 mmol) in anhydrous ethanol (35 mL) cooled to -35 DEG C. was added sodium methoxide (228 mg, 4.22 mmol) under nitrogen. The mixture is cooled to -35 ° C and a solution of 2.5 g (ca. 4.22 mmol) of crude p-nitrobenzyl- (5R, 6S) -1-6 - [(R) -1-tert-butyldimethylsilyloxyethyl] -2 is added. of ethylsulfinyl-2-penem-3-carboxylate in 35 ml of tetrahydrofuran, which had previously been cooled to -50 ° C.

The resulting solution was stirred at a temperature between -35 ° C and -40 ° C for 75 minutes, then 0.24 was added. ml (4.22 mmol) of acetic acid and the solution was concentrated in vacuo. The residue is dissolved in 100 ml of ethyl acetate and the solution is washed successively with 75 ml of saturated aqueous sodium bicarbonate solution, 75 ml of water and 75 ml of saturated sodium chloride solution.

No. 4,1091 starting thioacetate uses 1-methylthiazol-2-ylmethylhioacetate. Yield: 44%.

The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Chromatography of the crude product, 3.08 g per 500 g silica gel, eluting with ethyl acetate / methanol (90:10) gave 980 mg (39%) of the title compound as a viscous gum.

IR (dichloromethane): 5.58, 5.92 and 6.57 μΐη.

NMR (CDCl3):

0.03 (s, 3H).

0.08 (s. 3H),

0.8 (s, 9H);

1.23 (d, 3H),

2.75 to 3.4 (c, 2H),

3.72 (m, IH),

4.28 (m. 3H);

5.3 (q, 2H)

5.66 (d, IH);

7fi (m, 2H);

7.6 (d, 3H)

8.2 (d, 2Ή) ppm.

Preparation of ΰ p-N-Trobenzyl- (‘5 R, 15 S) -6 - [(R) -1-tert-butyldinethylsilyloxyethyl] -2- (4-imidazolyl) methylthio-2-penene-3-carboxylate

The procedure described in Preparation C was followed except that imidazol-4-ylmethyl-haloacetate was used as the starting material instead of the thioacetate shown in Preparation C (15% yield). in the title.

IR. (solution in dichloromethane):

5.58, 5.92 and 6.57 pm.

NMR (CDCl3):

0.02 (s, 3H);

0.06 (s, 3H).

0.8 (s, 9H);

1.22 (d, 3H);

3.68 (m, 1 H),

4.2. (Ο, 3H),

5.24 (q, 2H).

5.6 (d, 1 H).

6.97 (s, 1 H),

7.4 (d) a

7.57 (s) (total 3H);

8.18 (d, 2H) ppm.

Preparation E p-Niitrobenzyl (5R, 6S) -6 - [[R) -1-tert-butyldimethylsilylcyclohexyl] -2- (1-methylenidazol-2-yl) methylthio-2-penem-3-carboxylate

The procedure described in Preparation C is repeated except that sodium ethoxide is used instead of sodium methoxide and

Ic (suspension in nujol). 5.58 and 5.9 µm.

NMR (CDCl3):

0.08 (s, 3H);

0.03 (s, 3H).

0.84 (s, 9H);

1.24 (d. 3H),.

3.56-3.8 (rn together with s at 3.7, total 4H), 13.95 to 4.44 (m together with s at 4.3, total 3H),

5.24 (q, 2H).

564 (d, 1 H),

6.8 (d, 1 H),

6.9 (d, 1 H),

7.5 (d, 2H)

8.1 (d, 2H) ppm.

Preparation F p-N 1 -Benzyl-5R, 6S) -6 - [(R) -1-tert-butyldinethylsilyloxyethyl-2-ethoxybenzyl] -2-nitro-2H-benzenesulfonyl 3-kar boxes of fabrics

To a solution of 2.5 g (4.78 mmol) of p-nitrobenzyl (5R, 6'S) -6 - [(R) -1-tert-butyl-dimethylsilyloxyethyl] -2-ethylthio-2-penem-3-carboxylate in A solution of 970 mg of (4.78 mmol) of m-chloroperbenzoic acid (85% purity) in 25 ml of methylene chloride is added under nitrogen atmosphere to 125 ml of methylene chloride, cooled to -20 ° C. The mixture was stirred at -20 ° C for 3 hours, then washed successively with 70 ml of saturated aqueous sodium bicarbonate solution, 70 ml of water and 70 ml of saturated aqueous sodium chloride solution. The methylene chloride solution was dried over anhydrous. sodium sulfate and concentrated in vacuo to a residue. a yellow, glacial residue consisting of the title compound. Yield 2.2 (86%).

IR (solution in dichloromethane): 5.54, 5.86, 6.53 µm.

NMR (deuttrichlorophorine):

0.06, -0.08, 0.1 and 0.12 (4s, total 6H),

0.8 (s, 9H), 1.12-1.58 (m, 6H),

3.1 (m, 2H).

3.86 (m, 1H),

4.3 (m, 1 H),

5.3 (m. 2H);

0.67 and 5.78 (2d, total .114),

7.54 (d, 2H) and 8.13- (d, 2H) ppm.

Preparation G n-Nitrobenzyl- (51R6S) -6 - [(R) -1-tert-butyldimethylsilyloxyethyl] -2-ethylthio-2-penem-3-carboxylate

To a mixture of 7.3 g (0.02 mol) of (5R, 66) -6- ((R) -1-tert-butyldimethylsilyloxyethyl] -4-ethylthio (thiocarbonyl) thio-2-oxioazetidine and 4.8 g. (0.048 m, ol) calcium carbonate in 70 ml of methylene chloride, cooled to 10 ° C, under nitrogen atmosphere, add 5.85 g (0.024 mol) of p-nitrobenzyl-oxalyl chloride, followed by rapid cooling to bring the temperature While maintaining the temperature below 12 [deg.] C., a solution of 4.17 ml (0.024 mol) of diisopropylethylamine in 20 ml of methylene chloride is added dropwise, the mixture is stirred at 10 [deg.] C. for 60 minutes, washed twice with 50 ml of ice cold water. The resulting crude p-nitrobenzyl [2,3-a- (R) -tert-butyldimethylsilyloixyethyl-2-oxoazetidinyl] oxoacetate is dissolved in 300 ml of ethanol-free chloroform and refluxed under nitrogen for this solution. a solution of 6.85 ml (0.04 mol) of triethylphosphite in 50 ml of ethanol-free chloroform was added dropwise over 2 hours. The solution was heated to reflux for 16 hours and then concentrated in vacuo. The residue was chromatographed on 800 g of silica gel, eluting with toluene / ethyl acetate (95: 5) as the eluent, to give 5.5 g (53% yield) of the title compound as a yellow, pan-like material.

IR (solution in dichloromethane):

5.56, 5.89 and 6.54 μη.

NMR (deuterochlorophore):

0.07 (s, 3H);

0.1 (s, 3H);

0.85 (s, 9H);

1.12 to 1.53 (m, 6H),

2.97 (q, 2H); 3.7 (m, 1H);

4.25 (m, IH),

5.3 (q, 2H).

5.63 (d, IH);

7.38 (d, 2H);

8.18 (d 2H) ppm.

The NMR spectrum of the intermediate 4-ethylthio '(thiocarbonyl) thioazetidone, measured in solution in deuterochloroform, contains the following signals:

0.06 (s, 6H);

0.8 (s, 9H);

1.14 to 1.62 (m, 6H),

3.14 to 3.63 (m, 3H),

4.33 (m IH),

5.16 (s, 2H).

6.7 (d, 1 H),

7.5 (d, 2H);

8.17 (d, 2H) ppm.

Preparation · H

- (R) - tert -Butyldimethyl (Silyloxyethyl-4-ethylthiophthiocarbonyl) thio-2-oxoazetidine

To a solution of 4.18 g (0.104 mol) of sodium hydroxide in 256 ml of water cooled to 0-5 ° C was added, under nitrogen, 8.5 ml (0.1155 mol) of ethanethiol. After 15 minutes, 7.73 ml (0.12 mol) of carbon disulfide are added, the mixture is stirred at 0 to 5 ° C for 35 minutes, then a solution of 15.0 g (0.0522 mol) of 4-acetoxy is added. -3-tert-Butyldimethylsilyloxyethyl-2-azetidinone in 500 ml of methylene chloride and the reaction mixture was stirred vigorously at room temperature for 24 hours. The aqueous phase was separated and extracted twice with 150 ml of methylene chloride each time. The combined methylene chloride fractions were washed with water (2 x 200 ml) and brine (200 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude compound (18 g) was chromatographed on 500 g of silica gel using chloroform / ethyl acetate (99: 1) as eluent. 9.1 g (48% yield) of the title compound were obtained as a yellow, beryllious material.

IC (solution in dichloromethane):

5.62 and 9.2 pm.

NMR (CDCl3):

0.08 (s, 6H);

0.8 (s, 9H);

1.02 to 1.5 (m, 6H), ‘3.0 to 3.48 (m, 3H),

4.12 (m, IH),

5.54 (d, 1H) a

6.57 (b, 1H) ppm.

Preparation

2- (1-Imidazolyl) ethyl thioacetate

A mixture of 4.0 g (0.015 mol) of 2- (1-imidazolyl) ethyl tosylate and 2.6 g (0.0225 mol) of potassium thioacetate in 100 ml of acetone is heated to reflux overnight under nitrogen. . The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in 100 ml of ethyl acetate and 100 ml of water, the ethyl acetate layer was washed with 100 ml of water and 100 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was chromatographed on silica gel, eluting with ethyl acetate / methanol (9: 1). 1.0 g (39% yield) of the title thioacetate is obtained as a yellowish oil.

NMR (CDCl3):

2; 36 (s, 3H),

3.17 (t, 2H); 4.08 (t, 2H);

6.9 (d. 1H);

6.98 (d, 1H) and

7.47 (s, 1 H) ppm.

Preparation J

2- (1-Imidazolyl) ethyl tosylate

A solution of 2- (1-imidazolyl) ethanol (2.24 g [0.02 mol) and 4-dimethylaminopyridine (4.88 g, 0.04 mol) in methylene chloride (100 ml) was cooled to · 0 ° C under nitrogen and added to m.p., 3.8 g (0.02 mol) of ip-olenesulfonyl chloride. The solution was stirred at 0 ° C for 3 hours and then at room temperature overnight. 100 mL of water was added and the pH of the mixture adjusted to 7.0 with 1N aqueous hydrochloric acid. The methylene chloride layer was separated, washed with 70 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. concentrate in vacuo to an oily residue (4.2 g) consisting of the title compound.

NMR (CDCl3):

2.42 (s, 3H);

4.23 (s, 4H);

6.86 (d, IH);

7.0 (d, 1H);

7.16 to 7.8 (m, 5H) ppm.

Preparation

Imidazolyl-methylthioacetate

To a solution of potassium thioacetate (890 mg, 7.8 mmol) in ethanol (30 mL) was added 4- [chloromethyl] imidazole hydrochloride (800 mg, 5.2 mmol). The resulting mixture was stirred at room temperature under nitrogen overnight, then concentrated to dryness in vacuo and 100 ml of ethyl acetate and 100 ml of saturated aqueous sodium bicarbonate solution were added to the residue. The ethyl acetate layer was separated, washed successively with 70 ml of saturated aqueous sodium bicarbonate solution, 70 ml of water and 70 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was chromatographed on 150 g of silica gel using a 9: 1 mixture of ethyl acetate and methanol as eluent. 300 mg (37%) of the title thioacetate are obtained. in the form of a yellowish oil.

NMR (CDCl3):

2.32 (s, 3H);

4.14 (s, 2H).

6.99 (s, 1 H). and

7.64 (s, 1 H) ppm.

Preparation L (1-Methylimidazol-2-yl) methylthioacetate

A solution of 1.0 g (0.0089 mol) of (1-methylimidazol-2-yl) methanol, 4.7 ml of carbon tetrachloride, and 2.93 g (0.011 mol) of triphenylphosphine in 35 ml. The reaction was carried out under nitrogen 2. heated at reflux for 1 hour. The reaction mixture was cooled to 2.5 ° C, 2.8 g (0.0089 mol) of tetrabutane lamonium thioacetate was added thereto, and the resulting solution was stirred at room temperature overnight. The whole mixture was applied to a column of 200 g of silica gel, eluting with a 2: 1 mixture of methylene chloride and acetone. 600 mg of impurity contaminated product is obtained, which is removed by repeated chromatography on a 200 g silica gel column. Elution with methylene chloride / acetone (4: 1) gave 0.3 g (29% yield) of the title thioacetate as a yellowish oil.

NMR (CDCl3):

2.37 (s, 3H);

3.58 (s, 3H);

4.18 (s, 2-H);

6.72 (d, 1 H) and

6.81 (d, 1 H) ppm.

Preparation M p-Nitrobenzyl- (5R, 6S) -6 - [(R) -1-tert-butyldimethyisilyl-oxo-ethyl] -2- [1- (1-imidazolyl) prop-2-yl] -hexyl o-2-enem-3-carboxylate

To a solution of 130 mg (0.71 mmol) of [2- (methylcarbonylthio) propyljimidazole in 7 mL of anhydrous ethanol cooled to -35 degrees Celsius was added 36.5 mg (0.68 mmol) of sodium methoxide under nitrogen. The mixture was stirred at -25 ° C, then cooled to -40 ° C, and a solution of p-nitrobenzyl- (5R, 6S) -6- ((R) -1-tert-butyldimethylsilyloxyethyl) -2- was added. of ethylsulfinyl-2-penem-3-carboxylate in 7 ml of anhydrous tetrahydrofuran, which had previously been cooled to -50 ° C, and the resulting solution was stirred at -40 ° C for 50 minutes. The mixture is concentrated in vacuo, the residue is dissolved in 40 ml of ethyl acetate, and the solution is washed successively with 30 ml of aqueous sodium bicarbonate solution, 30 ml of water and 30 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and chromatographed on 150 g of silica gel. using mixtures of ethyl acetate and methanol (95: 5) ja 72 mg (yield 18.5%) of the less polar diastereomer, 124 mg (yield 31%) of the mixture of diastereomers and 72 mg (yield 18.5%) of the more polar diastereomer were obtained.

Less polar diastereomer:

IC (dichloromethane):

5.57, 5.88 and 6.54.

NMR (CDCl3):

0.04 (s, CD),

0.06 (s, 3H);

0.82 (s, 9H);

1.23 (d. 3H);

1.3 (d)

3.37-4.46 (b, 5H), 5.25 (q, 2H),

5.56 (d, IH),

6.86 (m, IH);

16.98 (m, 1H),

7.42 (m, IH);

7.54 (d, 2H);

8.12 (d, 2H) ppm.

More polar diastereomer: iC (dichloromethane):

5.58, 5.92 and 6.58 μτη.

NMR (CDCl3):

0.05 (s, 3H);

0.08 (s, OD),

0.83 (s, 9H);

1.26 (d, 3H);

1.32 (d, 3H);

3.36 to 4.47 (s, 5H),

5.24 (q, 2H).

5.58 (d, 1 H),

6.86 (m, IH);

6.97 (m, IH);

7.4 (m. 1H);

7.5 (d, 2Ή) a

8.1 (d, 2H) ppm.

Preparation N [2- (Methylcarbonylthio) propyl] imidazole

A solution of [2- (p-methylphenylsulfonyloxy) propyl] -imidazole (500 mg, 1.8 mmol) and tetrabutylammonium thloacetate (1.14 g, 3.6 mmol) in acetone (30 ml) was refluxed overnight under nitrogen. The reaction mixture is concentrated in vacuo to dryness and the residue is dissolved in 40 ml of ethyl acetate. The ethyl acetate solution was washed successively with 40 ml of water, 40 ml of saturated aqueous sodium chloride solution, 40 ml of water and 40 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography on a 80 g column of silica gel, eluting with a 95: 5 mixture of ethyl acetate and methanol. 160 mg (48% yield) of the title compound are obtained.

NMR (CDCl3):

2.32 (s, 3H);

3.56 to 4.27 (s, 3H),

6.95 (m, IH);

7.0 (m, 1H)

7.44 (m, 1 H) ppm.

Preparation O [2- (p-Methylphenylsulfonyloxy) dipropyl] imidazole

To a solution of 1,26 g (0,0.1 mol) of 1- (1-imidazolyl) -2-propanol and 2,44 4 (0,02 mol) of 4-dimethylaminopyridine in 60 ml of methylene chloride which has been cooled to 0 ° C, 1.9 g (0.01 mol) of p-toluenesulfonylchilorld are added in portions under nitrogen. The resulting solution was stirred at 0 ° C for 30 minutes and then at 25 ° C overnight. After addition of 60 ml of water, the resulting mixture was adjusted to pH 7.0 with 1 N aqueous hydrochloric acid, the methylene chloride solution was separated, washed with 50 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The crude product was purified by column chromatography on 200 g of silica gel, eluting with ethyl acetate / methanol (9: 1). 1.5 g (54% yield) of the title compound are obtained.

NMR (CDCl3):

1.27 (d, 3H);

2.42 (s, 3H);

3.97 to 4.2 (s, 3H)

4.77 (m, IH);

6.75 (m. 1H);

7.15 (m. 1H);

6.9 (m. 1H);

7.2 (d, 2H)

7.6 (d, 2H) ppm.

Preparation of P (2-Hydroxypropyl) imidazole

A mixture of Imidazole (27.8 g, 0.41 mol) and propylene carbonate (41.2 ml, 0.48 mol) in toluene (70 ml) was heated under reflux for 5 hours under nitrogen. The reaction mixture was cooled, the lower product layer was separated from the toluene layer and purified by vacuum distillation.

43.5 g (yield 84%) of the desired product are obtained in the form of a colorless liquid, b.p.

1.22 (d, CD),

Claims (8)

CLAIMS 1. A process for the preparation of 2-heterocyclic-alkylthiopenem derivatives of general formula I HO н ₃ с r ~ YI | COOH (.1) in which R is a radical of formula - (allk) - X - Rt where X represents an imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or tetrazolyl group, R 1 represents a hydrogen atom or a C 1 -C 4 alkyl group and alk represents a C 1 -C 4 alkylene group, in the form of isomers or mixtures of isomers, and pharmaceutically acceptable salts thereof, characterized in that the compound of formula IA is hydrogenated , HO in which R is as defined above and R a is a carboxyl-protecting group, and the resulting compound of formula I is optionally converted to a pharmaceutically acceptable salt thereof. 2. The process of claim 1, wherein the corresponding starting materials are used to form a compound of formula (I) wherein R @ 1 is 1- (rimidazolyl) prop-2-yl or (4-imidazolyl). a methyl group. 3. The process of claim 1, wherein the corresponding starting materials, z, are used to form a compound of formula I wherein R is 2- (1-imidazolyl) ethyl. 4. A process according to claim 1, wherein the corresponding starting materials are used to give a compound of formula I wherein R is (1-methylimidazol-2-yl) methyl. 5. The process of item 1, for producing compounds of formula II wherein: R is as defined in 1 above and pharmaceutically acceptable salts thereof; hydrogenates a compound of formula (IIA) wherein: R @ 1 and R @ 2 are as defined in 1 above, and the resulting product is optionally converted into its pharmaceutically acceptable salt. 6. The process of claim 5, wherein the corresponding starting materials are used to form a compound of formula (II) wherein R is 1- (liimidazolyl) prop-2-yl or (4-imidazolyl) methyl. 7. The process of claim 5, wherein the corresponding starting materials are used to form a compound of formula II wherein R is 2- (1-imidazolyl) ethyl. 8. The process of claim 5, wherein the corresponding starting materials are used to form a compound of formula II wherein R is (1-methylimidazol-2-yl) methyl.