HU192593B - Process for producing 2-dioxacycloalkyl-thio-peneme derivatives - Google Patents

Abstract

Certain 2-dioxacycloalkylthio-2-penem-3-carboxylic acid compounds are useful as antibacterial agents for the treatment of mammals and have the formula I or a pharmaceutically acceptable salt thereof, wherein A is carbonyl, methylene or thiocarbonyl, B is alkylene of 2-5 carbon atoms, Alk alkylene of 1-6 carbon atoms, R 1 is hydrogen or a group resulting in an ester which is hydrolyzable in vivo, and n is 0 or 1.

Description

BACKGROUND OF THE INVENTION The present invention relates to a novel family of compounds having a 2-azetidinone (0-lactin) ring having antibacterial activity, which are derivatives of 6α- (1'-hydroxyethyl) -2-substituted-2-penem-3-carboxylic acid.

Although certain 6- (1-hydroxyethyl) -2-penem-3-carboxylic acid derivatives substituted in the 2-position with -SR are those in which R is alkyl, benzyl, phenyl, heteroaryl, heteroarylmethyl or Denotes a 4-piperidyl group - already known (see, e.g. U.S. Patent No. 70,204; European Patent Application, Hayashi et al., Chem. Pharm. Bull., 29, 3158-3162. (1981), Di Ninno et al., Tetrahedron Letters, 23, 3535-3538. (1982)], there is still a need for new compounds having favorable antibacterial therapeutic properties.

SUMMARY OF THE INVENTION The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein

R represents a substituent of formula XIX wherein:

Carbonyl or methylene,

B is C 2 -C 5 alkylene, C 1 -C 4 alkylene and n is 0 or 1, and

R 1 is hydrogen.

The invention also relates to the preparation of compounds of the formula II or their pharmaceutically acceptable salts. In this formula, R and Rj are as defined for formula (I).

Preferred compounds of the formulas I and II are those wherein R 1 is hydrogen, B is ethylene, A is methylene and n = 1; and especially those wherein R is (1,3-dioxa-cyclopent-4-yl) -methyl or (1,3-dioxa-cyclopent-2-yl) -methyl.

Also preferred are compounds of formulas I and II wherein R 1 is hydrogen, B is ethylene and C is carbonyl, π = 1 and alk is methylene, especially when R is (2-oxo-1,3-dioxa-cyclopentyl). 4-yl) methyl.

Further preferred compounds of Formulas I and II are those wherein R 1 is hydrogen, B is propylene, A is methylene, and n = 0; especially if R

Means 1,3-dioxa-cyclohex-5-yl.

Further preferred compounds of the formulas I and II are those wherein R 1 is hydrogen, B is propylene, A is carbonyl and n = 0, especially when R 2 is -oxo-1,3-dioxa-cyclohex-5-. represents an il group.

The invention further relates to a process for the preparation of a pharmaceutical composition comprising admixing a compound of formula (I) or (II) with a pharmaceutically acceptable diluent or carrier.

The compounds of the formulas I and II are valuable antibacterial agents which contain a bicyclic skeleton of the formula III. Frame Λ is referred to herein as "2-penene" and the numbering shown in formula (111) is used. The carbon atom at position 6 of the skeleton is designated as 8. As used herein, the p-nitrobenzyl group is referred to as "BNB".

Hydrogen at the 5-position and at the 6-position may be cis or trans in the compounds of formula (I). The present invention relates to both isomers and mixtures thereof. From a pharmaceutical point of view, the trans isomer is generally preferred and the cis isomer can be easily converted to the trans isomer.

In the present application, the stereochemical designation Prelog-lngold R, S is used and in the sense of pnnck

The carbon at position 5 is generally of the R configuration. Thus, for example, a compound of formula II wherein R1 is 3-dioxa-cyclohex-5-yl and R1 is hydrogen, (5R, 6S) -6 - [(R) - (1'-hydroxyethyl) )] - 2 - [(1,3-dioxa-cyclohex-5-yl) -thio] -3-carboxyl-2-penem.

The novel compounds may have different optically active taste buds. These and their mixtures are also within the scope of the present invention.

The present invention relates to penems substituted in the 2-position with R-S.

Compounds of formula (11) may be prepared according to Schemes A to C.

As shown in Scheme A, compounds of formula II according to Yoshida et al., Chem. Pharm. Bull., 29, 2899-2909. (1981)] starting from the known dibromopenam of formula IV. The dibromopenam of formula IV is reacted with tert-butyl magnesium chloride at a temperature of about -90 to -40 ° C, preferably about -78 ° C, in a reaction-inert solvent such as tetrahydrofuran, diethyl ether, toluene, tetrahydrofuran being preferred. Other organometallic compounds may also be used. The appropriate aldehyde is then added to the reaction mixture ift situ, for example acetaldehyde in the preparation of a 1-hydroxyethyl derivative. The aldehyde is added at a temperature of about -80 to about -60 ° C, preferably about -78 ° C.

The resulting bromo-hydroxypenam derivative of formula (V) is then hydrogenated to cleave the 6-position bromine. Suitable hydrogenation catalysts are noble metals such as palladium. The reaction is carried out in a protic solvent such as 1; The mixture is carried out in a 1: 1 methanol / water, tetrahydrofuran / water mixture, preferably a 1: 1 methanol / water mixture, at a pressure of about 1-4 atmospheres, preferably 4 atmospheres, at a temperature of about 0 to 30 ° C, preferably 25 ° C.

The resulting alcohol (VI) can then be protected with a trialkyl halosilane (XX). In the formula (XX), R _{9 is C} 1 -C 6 alkyl and O is chloro, bromo or iodo. For example, dimethyl tert-butyl chlorosilane in the presence of a proton-acceptor amine such as imidazole in a polar aprotic solvent such as Ν, Ν-dimethylformamide at a temperature of about 5 to 40 ° C, preferably 25 ° C. ) having a trialkylsilyl protected hydroxyl group.

The resultant compound (VII) is treated with mercuric acetate at about 90 ° C in the presence of acetic acid to give the olefin (VIII).

To produce the desired azetidinone of formula (IX), the compound of formula (VIII) is reacted with ozone in a reaction-inert solvent such as dichloromethane. The reaction is carried out at about -80 to -40 ° C, preferably about -78 ° C, and the product is treated with an alkanol such as methanol to give the azetidinone of Formula IX.

The reaction sequence is depicted in Scheme B, and the compound of formula IX is prepared with a tritocarbonate salt of M ⁺ R ₁₀ -SC (S) -S - where R ₁₀ is C 1-4 alkyl, preferably ethyl, and reacting a metal ion such as sodium or potassium to give compound (X). The transformation

192,593 [(IX) - * (X)] is carried out in a reaction inert organic solvent, water or mixtures thereof, preferably a mixture of dichloromethane and water, at a temperature of about 0 to 35 ° C, preferably about 25 ° C.

The compound of formula (X) is subjected to condensation with p-nitrobenzyl chlorooxalate in the presence of a tertiary alkylamine such as ethyl diisopropylamine having alkyl groups of 1 to 4 carbon atoms, such as ethyl diisopropylamine. The compound of formula XI is obtained. The condensation reaction is carried out in a reaction inert solvent, preferably dichloromethane, at a temperature of about 5 to 25 ° C, preferably 10 ° C.

The resulting compound of formula XI is cyclized with a trialkyl phosphine which in the alkyl moiety

It contains 1-4 carbon atoms. For example, triethylphosphite can be used in a reaction inert solvent such as trichloromethane at a temperature of about 40 to 80 ° C, preferably about 60 ° C, to give compounds of formula XIII.

The thio group of the compound of formula XII is oxidized to the corresponding sulfoxide to give the compound of formula XIII. The oxidizing agent is, for example, m-chloroperbenzoic acid in a reaction inert solvent such as dichloromethane at a temperature of about -10 to -30 ° C, preferably -20 ° C.

The sulfoxide compound of formula (XIII) is converted to the corresponding mercaptide derivative of formula RS in the presence of a sodium or potassium salt capable of reacting with the sulfoxide group in the presence of a polar organic solvent such as ethanol or acetonitrile at about -50 to -10 ° C. , preferably at a temperature of about -35 ° C. The reaction gives a compound of formula (XIV).

The mercaptans R-SH and thioacetates RSC (O) CH ₃ used as starting materials are known for a number of meanings or are new, which can be prepared analogously to those described in the literature. For a general description, see JL Wardell, Preparation of ThioIs, in The Chcinistry of the Tliiol Group. Chapter 4 of the book (Edited by S. Pataki, published by John Wiley and Sons, London, 1974), and Volante: Tetrahedron Letters, 22, 3119-3122 (1981), which refers to alcohols as thiols and thiolesters, respectively. is described using triphenylphosphine and a dialkyl azodicarboxylate in the presence of alcohol and the corresponding thiol acid.

It is convenient to remove the trialkylsilyl group from compound (XIV) prior to hydrogenation to remove the carboxyl protecting group (PNB) to give compound (XV). Removal of the trialkylsilyl group is carried out with tetraalkylammonium fluoride in an ethereal solvent such as tetrahydrofuran at a temperature of about 15 to 40 ° C, preferably 25 ° C.

The conversion of the resultant compound (XV) into the compound (II) is accomplished by hydrogenolysis known per se. That is, a solution of the compound of formula XV is stirred or shaken with atmospheric hydrogen or a mixture of hydrogen and an inert diluent gas such as nitrogen or argon in the presence of a catalytic amount of a noble metal catalyst such as palladium on carbonate or Celite (diatomaceous earth). Suitable solvents for hydrogenolysis include lower alkanols such as methanol, ethers such as tetrahydrofuran or dioxane, low molecular weight esters such as ethyl or butyl acetate, water, and mixtures of the solvents listed. dissolves the starting material. These include aqueous ethers such as aqueous tetrahydrofuran at a pH of about 7-8. Hydrogenolysis is generally carried out at room temperature and at pressures between 0.5 and 5 kg / cm *. The catalyst is used in an amount of about 10% by weight based on the starting material, although larger amounts may be used. The reaction time is usually 1 hour, after which the compound of formula II is simply obtained by filtration under vacuum. When palladium on calcium carbonate is used as the catalyst, the product is isolated as calcium salt, while palladium on calcium is used as the sodium salt.

The compounds of formula (I) and (II) may be purified by conventional methods for the (3-lactam) derivatives, for example, the compounds of formula (I) may be purified by gel filtration on Sephadex or by recrystallization.

An alternative synthesis route is illustrated in Scheme C). According to this, an azetidinone of formula (IX) with a tritiated carbonate of formula M ⁺ RSC (S) -S - wherein M is a metal ion such as sodium or potassium, as described above for the preparation of compounds of formula (X).

The resulting trithiocarbonate (XVA) is then treated with (p-nitrobenzyloxycarbonyl) dihydroxymethane in an aprotic solvent such as benzene, toluene or dimethylformamide at about 25 ° C to about 110 ° C, preferably about 80 ° C. At a temperature of about C, the compound of formula XVI is reacted.

The alcohol of formula XVI is converted to the corresponding chloride of formula XVII with thionyl chloride. The reaction is carried out in a reaction inert organic solvent such as dichloromethane and in the presence of a tertiary amine such as 2,6-lutidine used as an acid scavenger at a temperature of about -10 ° C to 75 ° C, preferably 0 ° C.

The resulting chloride of formula (XVII) is reacted with triarylphosphine such as triphenylphosphine in the presence of a reaction inert solvent such as tetrahydrofuran and a tertiary amine such as 2,6-lutidine at a temperature in the region of 25 ° C. The resultant compound (XVIII) is cyclized to the penem (XIV) by boiling in an aromatic solvent such as toluene.

The tritocarbonate salts of the formula AM ⁺ RS- (S = S) -S can be prepared from the corresponding me-capaptans R-SH or from a thioacetate RSC (O) CH _{3 by} alkali metal alkoxide treatment followed by carbon disulfide treatment.

In the penems prepared using the Yoshida method mentioned above, the carbon atom at the 6-position and the attached hydroxyethyl group have the positions represented by the formula (II). The basic stereochemical characteristic of the ring closure product of Reactions B and C is that the hydrogen atom attached to the 5-position carbon atom of the penem ring has the α-configuration and is trans-positioned relative to the 6-position carbon atom hydrogen. Alternatively, this stereochemical position may be described by 5R, 6S, 6- (R) -1-hydroxyethyl.

The compounds of formulas I and II are acidic in nature and form salts with bases. Salts are also considered to be within the scope of the invention. These salts are customary3

192,593, for example, by reacting the acidic and basic components in a stoichiometric ratio in an aqueous, non-aqueous, or partially aqueous medium. The product may be isolated by filtration or precipitated with a solvent which does not dissolve the product, followed by filtration, or by evaporation of the solvent or, in the case of an aqueous solution, by lyophilization. The bases used for the salt formation may be organic or inorganic bases including ammonia, organic amines, alkali metal hydroxides, carbonates, hydrocarbons, hydrides and alkoxides, and hydroxides, carbonates and alkali metal hydroxides of alkali metals. Representative of such bases are, for example, primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine, secondary amines such as diethylamine, morpholine, pyrrolidine and the like. piperidine, tertiary amines such as triethylamine, N-ethylpiperidine, N-methylmorpholine and 1,5-diazabicyclo [4.3.0] non-5-ene, hydroxides such as sodium, potassium, ammonium and barium hydroxide, alkoxides such as sodium and potassium ethoxide, hydrides such as potassium and sodium hydride, carbonates such as potassium and sodium carbonate, bicarbonates such as sodium and potassium hydrocarbonate; and alkali metal salts of long chain fatty acids such as sodium 2-ethylhexanoate.

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

The pharmaceutically acceptable salts of the compounds of formulas I and II are those which do not cause significant deleterious side effects under normal use. These include the sodium, potassium and calcium salts.

The in vitro activity of the compounds of formula (I) and (II) and their salts is illustrated by the minimal inhibitory concentration (MIC) against a microorganism expressed in pg / ml. Our method, which uses brain-heart infusion (Bili) agar for inoculum growth, is recommended by the International Collaborative Study on Antibiotic Sensitivity Testing, Ericsson and Sherris, Acta Pathologica et Microbiologia Scandinav, Supp. 217., Section B: 64-68. (1971)]. The culture in the flask overnight was diluted 100-fold and used as a standard inoculum (20,000-10,000 cells in about 0.002 mL and inoculated onto the agar surface, 20 mL agar / dish). The compound to be tested was diluted in duplicate at a starting concentration of 200 µg / ml using a series of 12 samples. The dishes are kept at 37 ° C for 18 hours, then read, and the individual colonies are ignored. The MIC is defined as the lowest concentration at which complete inhibition of growth by the compound is observed by observation in the naked eye.

The compounds of formulas I and II and pharmaceutically acceptable salts thereof are useful in the treatment of bacterial infections in mammals, including man, such as non-resistant strains of Staphylococcus aureus.

The compounds of the invention may be administered orally or parenterally, i.e., intramuscularly, subcutaneously, intraperitoneally or intravenously, alone or in admixture with a pharmaceutically acceptable carrier. The ratio of drug to vehicle will depend on the properties, solubility and stability of the drug, and the dose employed. The normal carrier: penem ratio may vary from 1: 10 to 4: 1. For oral administration, the compounds may be administered in the form of tablets, capsules, cachets, pills, powders, syrups, elixirs, aqueous solutions or suspensions, or the like. In the case of tablets, the carrier may be lactose, sodium citrate or a phosphoric acid salt. Various disintegrants such as starch, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used in tableting. In the case of capsules, diluents include lactose and high molecular weight polyethylene glycols. If an aqueous suspension for oral administration is desired, the active ingredient is combined with an emulsifier and a dispersant. Sweetening and / or flavoring agents may also be used. For parenteral administration, a sterile solution of the active ingredient is usually prepared which is suitably pH adjusted or buffered. The total concentration of intravenous solutions should be considered and isotonic.

For human use, the prescriber will prescribe the appropriate dose, which may vary with the age, weight, individual response of the patient and the nature and severity of the patient's symptoms. Normally, the compounds of formulas (1) and (II) may be administered orally in a dose of 10-200 mg / kg body weight / day, parenterally 0-400 mg / kg body weight / day, but in some cases doses outside this range may be required.

The invention is further illustrated by the following non-limiting Examples. Infrared spectra (IR) can be taken either with potassium bromide paste or Nujol dispersant or in chloroform (CHCl 3), methylene chloride (CH ₂ Cl ₂ ) or dimethylsulfoxide (DMSO) solution, and the location of typical bonds in micron , or in waves (cm ^-1 ). Nuclear magnetic rezanancia (NMR) spectra were obtained in deuterochloroform (CDCl3) nellézvizcs (D ₂ O), or hexndeiitero-dinictil sulfoxide (DMSO) solution, or a mixture thereof, and peak positions are expressed in ppm n.eg compared to tetramethylsilane. The shapes of the peaks are characterized by the following abbreviations: s: singlet, d: doublet, t: triplet, q: quadruplet, m: multiplet, s: broad, weak: weak, c: complex. The abbreviations ss and sss indicate that a particular proton appears as two or three singlets due to the presence of diastereoisomers. In the examples and methods of preparation, PNB reduction refers to a p-nitrobenzyl group.

Example 1

Sodium (5R, 6S) -6 - [(R) -1- (hydroxyethyl)] -2 - [(1,3-dioxa-cyclohex-5-yl) thio] -2-penem-3- A suspension of 10% palladium on carbon in 10% palladium-on-carbon, 8 ml of distilled water and 8 ml of tetrahydrofuran was adjusted to pH 7.5 with 0.02 M aqueous sodium bicarbonate. To the resulting mixture was added 41 mg of (p-nitrobenzyl) - (5R, 6S) -6 - [(R) - (1'-hydroxyethyl)] - 2 in a mixture of 4 ml of tetrahydrofuran and 4 ml of distilled water. - [(1,3-Dioxa-cyclohex-5-yl) -thio] -2-penem-2-carboxylate and the mixture was hydrogenated with hydrogen at 379.2 kPa for 75 minutes and the catalyst was filtered off from the filtrate in tetrahydrofuran in vacuo. evaporated. The remaining aqueous solution was adjusted to pH 7 and then with ethyl acetate (2 x 20 mL).

Extract with 192,593 fathoms. The aqueous phase was lyophilized to give 30 mg (96%) of the amorphous title compound. IR (Nujol): 5.67 μ.

The operations were repeated to give the title compound in 85% yield with the following spectral data: · 5 ^{J 1} H-NMR (D ₂ 0.250MHJ:

1.29 (3H, d, J = 6.5 Hz); 3.57 (1H, m); 3.90 (2 H, m);

3.92 (1H, dd, J = 6.0, 1.4 Hz); 4.24 (1H, qd, J = 6.5;

6.0 Hz); 4.29 (2 H, m); 4.86 and 4.94 (2H, both d, J _AB = 6.5 Hz); and 5.68 (1H, d, J = 1.4 Hz) ppm. 10

IR (KBr, Pastilles):

3040 (w), 2966 (w), 2846 (w, 1770 (shoulder), 1593,

1378, 1295, 1169, 1136, 1053, 1020 and 924 cm ^-1 .

UV (H ₂ O) (extinction coefficient in parentheses):

254 (4470) and 320 (5240) nm. ¹⁵ [?] _D = + 139.0 ° (c - 1, water).

Example 2

In a manner analogous to that described in Example 1, compounds of formula (H) having various substituents R are prepared in the form of the sodium salt from the corresponding compounds of formula (XV).

The R value, IR spectrum data (medium gel in parentheses) and yield are given in Table 1.

Table 1

R IR (g) I yield% (1,3-dioxa-cyclopent-4-yl) methyl 5.7 (Nujol) 80 (1,3-dioxa-cyclopent-2-yl) methyl 2,93,5,65 and 6.26 (KBr pastilles) 82 (2-oxo-l, 3-dioxa cyclopent-4-yl) - methyl group 2.94, 5.66 and 6.28 (KBr pastilles) 71

The preparation of starting materials is illustrated in the following examples:

Example A (p-Nitrobenzyl) - (5R, 6S) -6 - [(R) <1'-hydroxyethyl)] - 2 - [(1,3- ^45- dioxa-cyclohex-5-yl) ) thio] -2-penem-2-carboxylate to a 0 ⁷ (0.12 mmol) (p-nitrobenzyl) - (5R, 6S) -6 - [(R) - / 1 '- (tert-butyl Dimethylsilyloxy) ethyl 2 - [(1,3-dioxa-cyclohex-5-yl) thio] -2-penem-3-carboxylate was dissolved in 4 ml of anhydrous tetrahydrofuran and 0.07 ml of (1.2 mmol) of acetic acid and 0.36 ml (0.36 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran were added. After stirring for 40 hours at room temperature, ethyl acetate (40 mL) was added under a stream of nitrogen, and the resulting solution was washed with saturated aqueous sodium bicarbonate (25 mL), water (25 mL), and brine (25 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (70 mg) was chromatographed on silica gel (35 g) and eluted with a 2: 1 mixture of chloroform: ethyl acetate.

Yield: 46 mg (82%) of the title compound.

IR (CH ₂ Cl _{2 in} solution): 5.58, 5.91 and 6.58 μl ^. 1 H-NMR (DMSO-d ₆ , 250 MHz):

1.17 (311, d); 3.54 (1H, m); 3.76-3.95 (311, c); 4.02 (3H, m); 4.2 (2 H, m); 4.82 (2H, q); 5.25 (1H, d);

5.38 (2H, q); 5.78 (1H, d); 7.7 (2H, d) and 8.25 (2H, d) ppm.

The procedures were repeated to give the title compound in 94% yield.

214-215 ° C (tetrahydrofuran) 1 H-NMR (DMSO-d 6, 250 MHz):

1.17 (3H, d, J = 6Hz); 3.53 (1H, m); 3.82 (2 H, m);

3.90 (1H, dd, J = 6Hz); 4.01 (1H, m); 4.20 (2 H, m);

4.79 and 4.83 (2H, both d, J _AB = 6 Hz); 5.26 (1H, d, J = Hz); 5.31 and 5.45 (2H, both d,

J _{/ B} = 14 Hz); 5.78 (1H, d, J = 1 Hz); 7.69 (2H, d,

J = 9 Hz) and 8.24 (2H, d, J = 9 Hz) ppm.

IR (KBr pastilles):

3452, 2965, 2851 (gy), 1776 (shoulder), 1693 (shoulder), 1609 (gy), 1520, 1502, 1376 1220, 1194, 1176, 1135,

1119, 1047 and 1023 cm -1.

Example B.

By the procedures described in Example A, compounds of formula (XV) having various substituents R are prepared from the corresponding compounds of formula (XIV). The R values, IR and 1 H-NMR data (in brackets with the solvents used) and yields are shown in Table 2.

Table 2

R IR (m) ^ -NMRÍppm) Yield (%) (1,3-dioxa-cyclopent-4-yl) methyl 5.59, 5.92 and 6.58 (CH ₂ Cl ₂ ) 1.24 (d, 3H); 3.0-3.27 (m, 2H); 3.48-4.4 (c, 6H); 4.83 (s, 1H); 5.0 (s, 111); 5.3 (q, 2H); 5.6 (d, 1H); 7.55 (d, 2H); and 8.12 (d, 2H), (CDCl ₃ ) 69 (L, 3-dioxa-cyclopent-2-yl) methyl 5,58,5,92 and 6.57 (CH ₂ Cl ₂₎ 1.26 (d, 311); 3.18 (d, 2H); 5.64-4.5 (c, 6H); 5.0 (t, 1H); 5.3 (g, 2H); 5.6 (d, 1H); 7.6 (d, 2H); and 8.2 (d, 2H), (CDCl 3) 25 (2-oxo-1,3-dioxa-cyclopent-4-yl) methyl 5,58,5,92 and 6,58 (CH ₂ Cl ₂ ) 1.26 (d, 3H); 2.96 (d, 2H); 3.7 (m, 1H); 4.0-5.0 (c, 4H); 5.3 (q, 2H); 5.62 (d, 1H); 7.58 (d, 2H); and 8.18 (d, 2), ₍₃ CDQ) 52 /

-5192 593

Example C (p-Nitrobenzyl) - (5R, 6S) -6 - / (R) - [1 '- (tert-butyldimethylsilyloxy) ethyl] -2 - [(1,3-dioxa) -cyclohex-5-yl) thio] -2-penem-3-carboxylate mg (0.5 mmol) (1,3-dioxa-cyclohex-5-yl) thioacetate was dissolved in 5 ml of anhydrous ethanol and under a nitrogen atmosphere, After cooling to 35 ° C, sodium methylate (27 mg, 0.5 mmol) was added. The reaction mixture was heated at -35 ° C for 45 min and crude (p-nitrobenzyl) - (5R, 6S) -6 - / (R) - [r - (tert- butyldimethylsilyloxy) ethyl] -2- (ethylsulfinyl) -2-penem-3-carboxylate in 5 ml tetrahydrofuran and cooled to -50 ° C. The resulting solution was stirred at -35 ° C for 60 minutes, then acetic acid (0.029 mL, 0.5 mmol) was added and the solution was concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL) and the solution was washed first with water (25 mL), then with saturated brine (25 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (360 mg) was chromatographed on 100 g silica gel to give 70 mg (24%) of the title compound as a dense, gum-like compound.

IR (CH2Cl2): 5.59.5.9 and 6.57 μ.

¹ H-NMR (CDCl ₃ ):

0.03 (3H, s); 0.07 (3H, s); 0.8 (9H, s); 1.25 (3 H, d);

3.4-3.86 (4H, c); 4.0-M, 5 (3H, c); 4.63 (1H, d); 4.95 (1H, d); 5.27 (2H, q); 5.63 (1H, d); 7.56 (2 H, d); and

8.18 (2H, d) ppm.

Repeat the procedure to obtain the title compound in 65% yield.

133-134 ° C (diethyl ether petroleum ether) ¹ H-NMR (CDCl ₃ , 25O MHz):

0.04 (3H, s); 0.07 (3H, s); 0.83 (9H, s); 1.26 (3H, d,

J = 6.3 Hz); 3.5-3.75 (3 H, m); 3.75 (1H, dd, J = 4.0 and 1.5 Hz); 4.2-4.4 (3H, m); 4.67 and 4.97 (2H, both d, J _An = 6.2 Hz); 5.21 and 5.42 (2H, both d, J _AB = 13.7 Hz); 5.67 (1H, d, J = 1.5 Hz); 7.61 (2H, d, J = 8.7 Hz); and 8.21 (2H, d, J = 8.7 Hz) ppm.

IR (KBr pastilles):

2946, 2927, 2850, 1797 (shoulder), 1697 (shoulder), 1610,

1512, 1374, 1345, 1320, 1230, 1189, 1168, 1122,

1064,1025,982,931,835,801 and 772 cm ^-1 .

I). example

In the same manner as in Example C, compounds of formula (XIV) containing various substituents R are prepared from the corresponding compounds of formula (XIII) and thioacetates. The R values, yields, IR and NMR spectra data (in brackets with the solvent used) are shown in Table 3.

Example E θ (p-Nitrobenzyl) - (5R, 6S) -6 - ((R) -fl- (tert-butyldimethylsilyloxy) ethyl] -2- (ethylsulfinyl) -2 penem-3-carboxylate

A solution of 940 mg (4.78 mmol) of 85% pure m-chloroperbenzoic acid in 25 mL of methylene chloride was dissolved in 125 mL of methylene chloride cooled to -20 ° C (2.5 mL). nitrobenzyl) - (5R, 6S) -6 - [(R) - [1 '- (tert-butyldimethylsilyloxy) ethyl] -2-ethylthio-2-penem-3-carboxylate is added under a nitrogen atmosphere. The mixture was stirred for 3 hours at -20 ° C, then with 70 ml of saturated aqueous sodium bicarbonate solution and then with 70 ml of water; and finally washed with 70 ml of a saturated aqueous solution of sodium chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and evaporated in vacuo to give 2.2 g (86%) of the title compound as a yellow foam.

IR (dichloromethane); 5.54, 5.86 and 6.53 μ.

¹ H-NMR (CDCl 3):

0.06, 0.08, 0.1 and 0.12 (4 s, 6H total); 0.8 (9H, s);

1.12-1.58 (6 H, m); 3.1 (2 H, m); 3.86 (1H, m); 4.3 (1H, m); 5.3 (2 H, m); 5.67 and 5.78 (2d, 1H total); Δ 7.54 (2H, d) and 8.18 (2H, d) ppm.

Example F (p-Nitrobenzyl) - (5R, 6S) -6 - [(R) - [1- (tert-butyldinyldinylsilyloxy) ethyl] -2-ethylthio-2-penem-3 Carboxylate δ 7.3 g (0.02 mol) 3 ° C - ((tert-butyldimethylsilyloxy) ethyl] 4- [ethylthio (thiocarbonyl) thio] -2-oxoazetidine and 4.8 g A suspension of calcium carbonate (0.048 mol) in methylene chloride (70 ml) cooled to 10 ° C was treated with (p-nitrobenzyl) oxalyl chloride (5.85 g, 0.024 mol) in a stream of nitrogen. diisopropylethylamine (4.17 ml, 0.024 mol) in methylene chloride (ml) was added dropwise, keeping the temperature below 12 ° C.

Table 3

R IR (M) ¹ H-NMR (ppm) Yield (%) (1,3-dioxa-cyclopen-t-4-yl) -methyl 5,6,5,92 and 6,57 (CH ₂ Cl ₂ ) 0.03 (3H, s); 0.06 (3H, s); 0.83 (9H, s); 1.23 (3 H, d); 2.97-3.22 (2 H, m); 3.5-4.4 (5H, c); 4.83 (1H, s); 5.02 (1H, s); 5.26 (2H, q); 5.6 (1H, d); 7.54 (2 H, d); and 8.13 (2H, d), (CDCl ₃ ) 37 (L, 3-dioxa-cyclopent-2-yl) methyl 5.58, 5.9 and 6.57 (CH ₂ Cl ₂ ) 0.03 (3H, s); 0.06 (3H, s); 0.82 (9H, s); 1.24 (3 H, d); 3.17 (2 H, d); 3.63-4.5 (511, c): 5.02 (1H, t); 5.3 (211, q); 5.62 (1H, d); 7.58 (2 H, d); and 8.18 (2H, d), (CDCl ₃ ) 41 (2-oxo-1,3-dioxa-cyclopent4-yl) -methyl 5.58, 5.9 and 6.57 (CH ₂ Cl ₂ ) 0.02 (3H, s); 0.06 (3H, s); 0.82 (9H, s); 1.23 (3 H, d); 2.92 (2 H, d); 3.7 (1H, m); 4.0-5.0 (4H, c); 5.25 (2H, q); 5.6 (1H, d); 7.53 (2 H, d); and 8.14 (2H, d), (CDCl ₃ ) 27

The mixture was stirred at -6192 ° C at 593 ° C, washed with ice-cold water (2 x 50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to a viscous oil. The crude (p-nitrobenzyl) - / ⁰⁰ 3 - [(tert-butyldimethylsilyloxy) ethyl] -2-oxo-azetidinyl / oxoacetate in 300 ml ethanol-free chloroform was heated at reflux for 5 under nitrogen and under reflux Triethyl phosphite (6.85 mL, 0.04 mol) in ethanol-free chloroform (50 mL) was added over 2 hours. The resulting solution was refluxed for 16 hours and then concentrated in vacuo. The residue was chromatographed on silica gel (800 g) and eluted with 95: 5 toluene / ethyl acetate to give 5.5 g (53%) of a yellow foam.

IR (dichloromethane): 5.56, 5.89 and 6.54 μ. ¹ H-NMR (CDCl 3):

0.07 (3H, s); 0.1 (3H, s); 0.85 (9H, s); 1.12-1.53 (6 H, m); 2.97 (2H, q); 3.7 (1H, m); 4.25 (1H, m); 5.3 (2H, q); 5.63 (1H, d); 7.38 (2 H, d); and 8.18 (2H, d) ppm. 20

1 H-NMR of 4- [ethylthio (thiocarbonyl) thio] azetidinone:

¹ H-NMR (CDCl ₃ ):

0.06 (6H, s); 0.8 (9H, s); 1.14-1.62 (6 H, m); ₂₅ 3,14-

3.63 (3H, m); 4.33 (1H, m); 5.16 (2H, s); 6.7 (1H, d);

7.5 (2 H, d); and 8.17 (2H, d) ppm.

Example G

3- ^OQ - [(tert-Butyldimethylsilyloxy) ethyl] -4- [ethylthio (thiocarbonyl) thio] -2-oxoazetidine

Sodium hydroxide (4.18 g, 0.104 mol) was dissolved in chilled water (250 ml, 0-5 ° C) and ethanethiol (8.5 ml, 0.115 mol) was added under nitrogen. After 15 minutes

Carbon disulfide (7.73 mL, 0.12 mol) was added and the mixture was stirred at 0 to 5 ° C for 35 min. A solution of 4-acetoxy-3 - [(tert-butyldimethylsilyloxy) ethyl] -2-azetidinone (15 g, 0.0522 mol) in methylene chloride (500 ml) was added and the mixture was stirred vigorously at room temperature for 24 hours. . The aqueous phase was separated and extracted with methylene chloride (2 x 150 mL). The combined methylene chloride extract was washed with water (2 x 200 mL), brine (2 x 200 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product obtained is chromatographed on 45 g (18 g) of silica gel (500 g) and eluted from the adsorbent with 99.1 chloroform-ethyl acetate. 9.1 g (48%) of the title trithiocarbonate are obtained in the form of a yellow foam.

IR (dichloromethane): 5.62 and 9.2 μ. 50 ¹ H-NMR (CDCl 3):

0.08 (6H, s); 0.8 (9H, s); 1.02-1.5 (6H, m); 3.0-3.48 (3 H, m); 4.12 (1H, m); 5.54 (1H, d); and 6.57 (1H, sz)

Example H (1,3-Dioxo-cyclohex-5-yl) - (p-toluenesulfonate)

20.8 g (0.2 mole) of a mixture of cyclic compounds of glycerol and formaldehyde dimethylacetate formed by interaction of 67% 1,3-dioxan-5-ol and 33% (1,3-dioxolane). -4-yl) -methanol - dissolved in 200 ml of pyrldine cooled to 0 ° C and 38.1 g (0.2 mol) of p-toluenesulfonic acid chloride added under nitrogen. After stirring for half an hour at 0 ° C and for 20 hours at 25 ° C, the reaction mixture was poured into 500 ml of 6N aqueous hydrochloric acid and the resulting mixture was extracted four times with 200 ml of ethyl acetate. The combined extracts were washed with 1N aqueous hydrochloric acid (2 x 200 mL) and brine (2 x 200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residual oil was dissolved in 500 ml of diisopropyl ether to give 17.4 g of white crystalline (1,3-dioxa-cyclohex-5-yl) tosylate (m.p. 91-92 ° C). An additional 4.3 g of secondary product crystallized from the mother liquor. overall yield: 42%.

¹ H-NMR (CDCl 3):

2.45 (3H, s); 3.54-4.13 (4H, c); 4.26-4.6 (1H, m);

4.75 (2 H, s); 7.3 (2 H, d); and 7.8 (2H, d) ppm.

Example I (1,3-Dioxa-cyclopent4-yl) -methyl- (p-toluenesulfonate)

104.1 g (1 mol) of a mixture of glycerol and formaldehyde dimethylacetal interactions, consisting of 67% 1,3-dioxa-cyclohex-5-ol and 33% (1,3-dioxa-cyclopentyl) ) -methanol - solution of 1000 ml of pyridine is cooled to 0 ° C and under nitrogen atmosphere

76.2 g (0.4 mol) of p-toluenesulfonic acid chloride are added. The reaction mixture was allowed to stand at 0 ° C for 20 hours, then allowed to warm to room temperature, and finally 1500 ml of 6N aqueous hydrochloric acid was added. The mixture was extracted with ethyl acetate (4 x 500 mL). The combined ethyl acetate extracts were washed twice with 500 mL of 6N aqueous hydrochloric acid, twice with 500 mL of water and 500 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. 78.4 g of an oily residue is obtained, which is a mixture of [(1,3-dioxacyclopent4-yl) methyl] tosylate and (1,3-dioxa-cyclohex-5-yl) tosylate in a ratio of about 2: 1 and is purified by can be used for the next reaction step (Example K).

Example J (1,3-Dioxa-cyclohex-5-yl) -thioacetate

A solution of (1,3-dioxa-cyclohex-5-yl) -p-tosylate (28.0 g, 0.108 mol) and potassium thioacetate (24.6 g, 0.216 mmol) in dimethylformamide (500 mL) was heated at 80 ° C for 20 hours. It is maintained at a temperature of C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with 1000 mL of water. The resulting mixture was extracted with ethyl acetate (6 x 300 mL). The combined ethyl acetate extracts were washed with water (4 x 500 mL) and brine (500 mL), dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was purified by distillation to give 6.25 g (36%) of the title thioacetate. Boiling point: 70 ° C / 0.4 mm Hg.

¹ H-NMR (CDCl 3):

2.34 (3H, s); 3.44.36 (5H, c); and 4.8 (2H, q) ppm.

Repeat the procedure to obtain the title compound (b.p. 85-89 ° C / 0.7 mmHg) in 49% yield.

¹ H-NMR (CDCl ₃ , 250 MHz):

2.34 (311, s); 3.7-3.85 (3 H, m); 4.05-4.2 (211, m); 4.79 (111, d, Jmcm = 6.2 Hz); 4.89 (111, d, Jgem = 6.2 Hz) ppm.

Example K ((1,3-Dioxa-cyclopent4-yl) -methyl] -thioacetate g (0.3 mol), (1,3-dioxa-cyclopent4-yl)-tosylate prepared in Example 1 and 27.4) g (0.24 mol) of potassium thio7

A mixture of 192 593 acetate in 1500 ml of acetone was refluxed under nitrogen overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in 500 ml of ethyl acetate and 500 ml of water. The aqueous phase is extracted with 500 ml of ethyl acetate. The ethyl acetate extracts were combined, washed with water (2 x 500 mL) and brine (500 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue, which is a solid suspended in oil, is filtered off and the filtrate is evaporated under reduced pressure.

Yield: 20.8 g (54%) of [(1,3-dioxa-cyclopent-4-yl) methyl] tosylate. Boiling point: 65-70 ° C (0.2 mm Hg).

The solid collected by filtration was washed with ether to give 18.4 g of (1,3-dioxacyclohcx-5-yl) tosylate. 1 H-NMR (CDCl 3):

2.37 (3H, s); 3.1 (2H, d); 3,4-A; 4 (3H, c); 4.86 (1H, s); and 5.2 (1H, s) ppm.

Example L [(1,3-Dioxa-cyclopent-2-yl) -methyl] -thioacetate

A mixture of 5.0 g (0.03 mole) of 2-bromomethyl-1,3-dioxa-cyclopentane and 5.13 g (0.045 mole) of potassium thioacetate in 60 ml of acetone was refluxed overnight under nitrogen. The mixture was filtered and the filtrate was concentrated in vacuo. The residue is shaken with a mixture of 100 ml of ethyl acetate and 60 ml of water. The aqueous phase was extracted with ethyl acetate (50 mL), and the ethyl acetate layers were combined and washed with water (50 mL) and brine (50 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel to give 4.0 g (83%) of an oily product after elution with methylene chloride.

1 H-NMR (CDD _{1 3} ):

2.36 (3H, s); 3.16 (2 H, d); 3.94 (4H, c) and 5.0 (1H, t) ppm.

Example M [(2-Oxo-1,3-dioxadicyclopent-4-yl) methyl] thioacetate

Triphenylphosphine (5.2 g, 0.02 mol) was dissolved in tetrahydrofuran (50 mL). The solution was cooled to 0 ° C and diisopropyl azodicarboxylate (3.9 mL, 0.2 mol) was added under nitrogen. The solution was stirred at 0 ° C for 30 minutes while a precipitate formed. To the mixture was added dropwise glycerol carbonate (1.18 g, 0.01 mol) and thioacetic acid (1.4 ml, 0.02 mol) in dry tetrahydrofuran (20 ml) at 0 ° C. The reaction mixture was stirred for 1 hour at 0 ° C and for 2 and a half hours at room temperature. The mixture was concentrated in vacuo and the residue was shaken with 70 mL of ethyl acetate and 70 mL of water. The ethyl acetate layer was washed twice with 50 ml of saturated aqueous sodium bicarbonate solution, 50 ml of water and finally with 50 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with 600 mg of impure material with methylene chloride. The crude product was purified by repeated chromatography on silica gel, eluting with 3: 1 hexane: ethyl acetate. Yield: 220 mg (13%).

1 H-NMR (CDCl 3):

2.4 (3H, s); 3.25 (2H, d); and 3.94-5.07 (3H, c) ppm.

Claims (10)

A process for the preparation of a compound of formula I or II or a pharmaceutically acceptable salt thereof R is a substituent of formula XIX wherein A is carbonyl or methylene, B is C 2 -C 5 alkylene, C 1 -C 4 alkylene and n is 0 or 1, and R 1 _{is a} hydrogen atom - characterized in that a compound of formula XXI wherein R is a group represented by formula I and R _{3 is a} carboxyl protecting group, preferably p-nitrobenzoyl, is R; ₃ protecting groups are removed by hydrolysis. A process for the preparation of a compound of the general formula (I) according to claim 1, wherein R 1 is hydrogen and B in the group XIX in which R is R, A and alk are methylene and η = 1. The compound of formula XXI is used as starting material. The process according to claim 1 or 2, wherein R is (1,3-dioxa-cyclopent-4-yl) -methyl or (1,3-dioxa-cyclopent-2-yl) -methyl. For the preparation of compounds of formula I, the appropriate compound of formula XXI is used as starting material. Process for the preparation of a compound of formula (I) in which R _{3 is} hydrogen and in the radical R (XIX) where R is a carbonyl, alkyl methylene and n = 1, characterized in that The compound of formula XXI is used as starting material. Process for the preparation of compounds of formula (I) wherein R is (2-oxo-1,3-dioxa-cyclopent-4-yl) -methyl according to claim 1 or 4, characterized in that The compound of formula XXI is used as starting material. A process for the preparation of a compound of formula (I) according to claim 1 wherein R 1 is hydrogen and R is propylene, A is methylene or carbonyl and n = 0. the appropriate compound of formula XXI is used as starting material. A process according to claim 1 or 6 for the preparation of compounds of formula I wherein R is 1,3-dioxa-cyclohex-5-yl or 2-oxo-1,3-dioxa-cyclohex5-yl. characterized in that the appropriate compound of formula (XXI) is used as starting material. A process for the preparation of isomers of formula (II) or a pharmaceutically acceptable salt thereof, as defined in claim 1, wherein R and R _{1 are} as defined in formula (I): to use the appropriate starting material. The process of claim 8 wherein R is (1,3-dioxa-cyclopent-4-yl) -methyl, (1,3-dioxa-cyclopent-2-yl) -ethyl, (2-oxo-1) Of general formula (II) containing 3-dioxa-cyclopent-4-yl) -methyl, 1-dioxa-cyclohex-5-yl or 2-oxo-1,3-dioxo-cyclohex-5-yl. characterized in that a suitable starting material is used. 192,593 10. A process for the preparation of a pharmaceutical composition comprising the compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof as an active ingredient, wherein R and Rj are as defined in claims 1 and 8, characterized in that The active ingredient of the method of claim 1 is formulated in a pharmaceutical composition in admixture with pharmaceutically acceptable carriers and / or excipients.