NO873500L - PROCEDURE FOR THE PREPARATION OF PYRIDINIO COMPOUNDS. - Google Patents

Description

The invention relates to a method for the preparation of penem compounds of formula

wherein R 1 means hydroxymethyl or 1-hydroxyethyl, Z means a residue

in which R2 means optionally substituted lower alkyl, lower alkyl-

nyl, optionally substituted phenyl, pyridyl or etherified hydroxy, R3 and R4 independently mean hydrogen, optionally substituted lower alkyl, optionally functionally modified carboxyl, etherified hydroxy, esterified hydroxy or optionally substituted amino and m means an integer from 1 to 4. The compound of formula I, can be used for the production of pharmaceutical preparations or as active drugs.

The above and hereinafter stated definitions preferably have the following meaning within the scope of the present invention: Substituted lower alkyl as substituent R2, R3 and R4 is, for example, lower alkyl substituted with hydroxy, etherified or esterified hydroxy, carboxyl, functionally modified carboxyl, amino, azido, optionally substituted phenyl or oxo.

Substituted phenyl is especially phenyl mono- or also di-substituted with lower alkyl, lower alkoxy, halogen, cyano and/or carboxy.

Etherated hydroxy is, for example, lower alkoxy.

Esterified hydroxy is e.g. halogen, lower alkanoyloxy or carbamoyloxy.

Functionally modified carboxyl is e.g. esterified or amidated carboxyl, such as lower alkoxycarbonyl, carbamoyl, N-lower alkyl or N,N-dilower alkyl carbamoyl, or cyano.

Substituted amino is, for example, lower alkylated amino, such as lower alkylamino or dilower alkylamino, lower alkyleneamino or acylated amino, e.g. lower alkanoylamino.

In the present description, it means in connection with the definition of the groups resp. the compounds used the expression "lower", of the corresponding groups resp. compounds, if nothing else is expressly defined, contain 1 to 7, preferably 1 to 4, carbon atoms.

Lower alkyl is e.g. n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and primarily methyl or ethyl.

Lower alkenyl has 2 to 5 carbon atoms and is e.g. allyl, methallyl or crononyl.

Halogen as a substituent is lower alkyl or phenyl residues is fluorine, chlorine, bromine or iodine, while halogen as a pyridine ring substituent R3 or R4 is especially chlorine or bromine.

Lower alkanoyloxy is e.g. formyloxy or acetyloxy.

Low-area coke is e.g. n-propyloxy, n-butyloxy and primarily methoxy or ethoxy.

Lower oxycarbonyl is e.g. methoxycarbonyl or ethoxycarbonyl.

N-lower alkylcarbamoyl is e.g. N-methyl- or N-ethylcarbamoyl, while N,N-lower alkylcarbamoyl e.g. is N,N-dimethylcarbamoyl.

Lower alkylamlno is e.g. methylamlno or ethylamlno, while dilaverealkylamino e.g. is dimethylamino or dlethylamlno.

Lower alkylenamlno is especially C4-C5-alkyleneamino and means, for example, pyrrolidino or piperidino.

Lower alkanoylamino is e.g. formylamino, acetamino or propionylamino.

Pyridyl is e.g. 2-, 3- and especially 4-pyridyl.

In preferred compounds of formula I, R means [1-hydroxyethyl, especially (IR)-1-hydroxyethyl, and m means 1 or 2.

Preferred pyridinium residues

in connection with formula II is 1-lower alkyl-, e.g. 1-methyl- or 1-ethyl-, 1-carboxylower alkyl-, such as 1-carboxy-methyl- or 1-(2-carboxyethyl)-, 1-carbamoyl lower alkyl^, 1-N,N-dilower alkylcarbamoyl lower alkyl- or 1-lower oxy- carbonyl lower alkyl-, such as 1-carbamoylmethyl-, 1-N,N-dimethylcarbamoylmethyl-, 1-methoxycarbonylmethyl- or 1-ethoxycarbonylmethyl-, 1-cyano lower alkyl-, such as 1-cyanomethyl- 1-phenyl lower alkyl-, such as 1- benzyl-, 1-pyridyl-, such as 1-(4-pyridyl)-, 1-acetonyl-, further 1-lower alkyl-2-lower oxycarbonyl-, such as 1-methyl-2-ethylcarbonyl-, 1-lower alkyl-2-

carboxy-, such as l-methyl-2-carboxy-, l-lower alkyl-2-cyano, such as l-methyl-2-cyano-, l-lower alkyl-2-carbamoyl-, such as 1-methyl-2-carbamoyl-, 1-lower alkyl-2-N,N-dilower alkylcarbamoyl-, as l-methyl-2-N,N-dlmethylcarbamoyl-, l-lower alkyl-2-hydroxylower alkyl-, as l-methyl-2-hydroxymethyl-, 1- lower alkyl-2-amlnolower alkyl-, such as l-methyl-2-amlnomethyl-, l-lower alkyl-2-carboxylaverealkyl-, such as l-methyl-2-carboxymethyl-, l-lower alkyl-2-lower carboxycarbonyllower alkyl-, such as l- methyl-2-methoxy(or ethoxy)-carbonylmethyl-, and 1-lower alkyl-2-cyanolower alkyl-, such as 1-methyl-2-cyanomethyl-(or cyanoethyl)-4-pyridinio.

Preferred pyridine residues

in connection with formula I is 1-lower alkyl-, e.g. 1-methyl, 1-lower alkyl-5-carbamoyl-, as 1-methyl-5-carbamoyl-, 1-lower alkyl-5-hydroxylower alkyl-, as 1-methyl-5-hydroxymethyl-, 1-lower alkyl-5-carbamoyloxy lower alkyl- , such as 1-methyl-5-carbamoyloxymethyl-, and 1-lower alkyl-5-aminolower alkyl, such as 1-methyl-5-aminomethyl-2-pyridinium.

Salts of compounds according to the invention are primarily pharmaceutically acceptable, non-toxic salts of compounds of formula I. Such salts are formed, for example, by the acidic groups present in the compound of formula I, e.g. carboxyl groups (as substituents of the residues R2, R3 or R4) and are primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, e.g. sodium, potassium, magnesium or calcium salts, salt ammonium salts with ammonia or suitable organic amines, such as lower alkylamines, e.g. triethylamine, hydroxyl lower alkylamines, e.g. 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tris-(2-hydroxyethyl)amine or 2-amino-1,3-dihydroxy-3-hydroxymethylpropane ("Tris"), basic aliphatic esters of carboxyl -sylic acid, e.g. 4-aminobenzoic acid, 2-diethylaminoethyl ester, lower alkylene amines, e.g. 1-ethylpiperidine, cycloalkyl amines, e.g. dicyclohexylamine or benzylamines, e.g. N,N'-dibenzylethylenediamine, dibenzylamine or N-benzyl-p<->phenethylamine. Compounds of formula I with the basic group, e.g. with an amino group (as a substituent of the residues R3 or R4), can form acid addition salts, e.g. with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, e.g. acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, oxalic acid, citric acid, benzoic acid, mandelic acid, malic acid, ascorbic acid, methanesulfonic acid or 4-toluenesulfonic acid.

For isolation or purification, it can also be used for pharmaceutically unsuitable salts.

For therapeutic use, only the pharmaceutically acceptable, non-toxic salts, which are therefore preferred, are used.

The invention relates in particular to compounds of formula I, in which Ri means hydroxymethyl or (IR)-1-hydroxyethyl, Z means a residue

wherein Rg means lower alkyl, with hydroxy, halogen, lower alkanoyloxy, carbamoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl, - N-loweralkyl- or N,N-di-loweralkylcarbamoyl, cyano,.. amino., azido,. phenyl, "with lower alkyl, lower alkoxy, halogen, cyano and/or carboxy substituted phenyl or oxo substituted lower alkyl, lower alkenyl, phenyl, with lower alkyl, lower alkoxy, halogen, cyano and/or carboxy substituted phenyl, pyridyl or lower alkoxy, R3 and R4 independently mean

hydrogen, lower alkyl, with hydroxy, halogen, lower alkanoyloxy, carbamoyloxy, lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-, or N.N-dilower alkyl-carbamoyl, cyano, amino, azido, phenyl, with lower alkyl, lower alkoxy, halogen, cyano and /or carboxy-substituted phenyl, or oxo-substituted lower alkyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower alkyl- or N,N-di-lower alkylcarbamoyl, cyano, lower alkoxy, halogen, lower alkanoyloxy, carbamoyloxy, amino, lower alkylamino, dilower alkylamino, lower alkyleneamino or lower alkanoylamino, m means an integer of 1 to 4, as well as salts of compounds of formula I.

The invention mainly relates to compounds of formula I, in which ~ Ri means (IR )-1-hydroxyethyl, Z means a residue

wherein R2 is lower alkyl, acetonyl or with carboxy, lower alkoxycarbonyl, carbamoyl, N,N-dilower alkylcarbamoyl or phenyl substituted lower alkyl, R3 is hydrogen, R4 is hydrogen, with hydroxy, carboxy, cyano or amino substituted lower alkyl, carboxy, carbamoyl or cyano, and m means 1 or 2, as well as salts of compounds of formula I.

The invention primarily relates to compounds of formula I, in which Ri means (IR )-1-hydroxyethyl, Z means a residue in which ]?2 means lower alkyl or carbamoyl substituted lower alkyl, R 3 means hydrogen and R 4 means hydrogen or hydroxy substituted lower alkyl, and m means 1 and salts of the compound of formula I.

The invention relates above all to the compounds of formula I mentioned in the examples.

The compounds can be produced according to methods known per se.

The new compounds are produced e.g. in it a too penem compound with formula

in which Ri and m have the meaning given under formula I, is reacted with a pyridinium compound of formula

in which R2, R3 and R4 have the meaning given under formula I, in that functional groups in these residues are possibly present in protected form, X means a cleavable group and Y" means an anion and, if necessary, protected functional groups are transferred in the residues R2, R3 and /or R 4 to the free functional groups, and, if desired, a formed free compound of formula I is transferred to a salt.

The cleavable group X is in particular an easily cleavable with amino replaceable cleavable group, such as lower halogen, e.g. fluorine or chlorine, sulfonyloxy, which in particular optionally halogen-substituted lower alkanesulfonyloxy, e.g. methane or trifluoromethanesulfonyloxy, or optionally with halogen or lower alkyl substituted benzenesulfonyloxy, e.g. benzenesulfonyloxy or 4-bromobenzenesulfonyloxy or lower alkoxysulfonyloxy, such as methoxysulfonyloxy. Preferred cleavable groups X are fluorine and chlorine.

The anion Y" is in particular an anion that favors a good solubility of the compound of formula III, or Illa in the reaction medium. Such anions are, for example, halogen anions, such as chloride, bromide and iodide, further hydrogen sulfate or lower alkyl sulfate, such as methyl sulfate.

Protecting groups in the compounds of formula III resp. Illa are especially those that can be cleaved in a gentle way, i.e. without unwanted side reactions taking place, for example gently reductive or solvolytic.

Preferred protecting groups for carboxyl groups in the residues R 2 , R 3 and/or R 4 are, for example, optionally with lower alkyl, lower alkoxy, halogen or nitro substituted benzyl, such as 4-methoxy- or 4-nitrobenzyl, and also lower alkenyl, such as allyl.

Preferred protecting groups for the amino groups in the residues R3 and/or R4 are, for example, optionally with lower alkoxy or nitro substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, further lower alkenyloxycarbonyl, such as allyloxycarbonyl and azido.

The reaction of the penem compound of formula II with the pyridinium compound of formula III resp. Ill, takes place at room temperature or slightly reduced temperature, e.g. by

-10 to +30h,C, preferred at approx. 0° to 20°C in an inert solvent, such as water, a cyclic ether, eg tetrahydrofuran, dimethylformamide or mixtures thereof, in the presence

of approximately stoichiometric amounts or a small excess of an organic or inorganic base, such as a tertiary amine, e.g. pyridine or ethyl lower alkylamine, e.g. triethylamine or ethyldiisopropylamine, an alkali metal hydroxide, e.g. sodium hydroxide or alkali metal carbonate, e.g. sodium carbonate. Preferably, the reaction mixture's pH value is kept constant at approx. 7 to 9, in which the acid H-X released during the reaction is neutralized by continuous addition of a solution of the base in one of the above-mentioned solvents or solvent mixtures. Usually, the reaction takes place with stoichiometric amounts or with an excess (up to 150% of the theoretically required amount) of the pyridinium compound of formula III or Bad.

Protected functional groups in the penem compounds obtained according to the method are transferred in a manner known per se to the free functional groups. With allyl-protected carboxyl groups and/or with allyloxycarbonyl-protected amino groups in the residues R2, R3 and/or R4 are transferred, for example, with an allyl group acceptor in the presence of tetrakis-triphenyl-phosphine palladium to the free carboxyl and/or amino groups.

Suitable acceptors for lower alkenyl groups, such as especially the allyl group, are e.g. amines, such as particularly sterically hindered amines, e.g. tert-butylamine, morpholine or thiomorpholine, aliphatic or cycloaliphatic p-dicarbonyl compounds, e.g. acetylacetone, acetoacetic acid ethyl ester or dimedone, (C2-C5)-lower alkane carboxylic acid, e.g. acetic acid, propionic acid or hexanoic acid, further salts thereof, e.g. sodium hexanoate, as well as trilower alkyl, such as tri-n-butyl tin hydride. Preferred acceptors are dimedone and tri-n-butyltin hydride.

Optionally substituted benzyloxycarbonyl or benzyloxycarbonylamino as well as azido can be cleaved by hydrogenolysis in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst. All cleavage reactions are preferably carried out in a neutral medium, i.e. at approx. pH 7.

Salts of compounds of formula I with salt-forming groups can be prepared in a manner known per se. Thus, one can form salts of compounds of formula I with a free carboxyl group in the residue Rg, R3 and/or R4, e.g. by treatment with metal compounds such as alkali metal salts of suitable organic carboxylic acids, or with alkali or alkaline earth metal salts, e.g. sodium hydrogencarbonate or with ammonia, or with a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts of compounds of formula I with a free amino, lower alkylamino, dilower alkylamino or lower alkyleneamino group, in the residue R3 and/or R4 are obtained in the usual way, e.g. by treatment with a suitable acid or a suitable anion exchange reagent.

In all subsequent conversions of formed compounds of formula I, such reactions are preferred which take place under weakly alkaline or particularly neutral conditions.

The starting compounds of formula II are known, for example, from DOS No. 3431980, Japanese Application No. 56166194 [Chemical Abstracts 96, 14565u (1982)], European Patent No. 3960 and European Patent Application No. 82113.

The pyridinium compounds of formula III or Illa is also known, for example from Adv. Heterocycl. Chem. 3, 1 (1964) and 22, 71 (1978) and J. Medical Chem. 25, 457 (1982), or can be prepared analogously to the methods mentioned there.

The compounds of formula I have valuable pharmacological properties. In particular, they have antibacterial effects. For example, they are effective in vitro against gram-positive and gram-negative cocci, including methicillin-resistant cocci, e.g. Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus pneumoniae and Streptococcus feacalis, Listeria sp. and Neisseria sp. in minimal concentrations of less than 0.01 to approx. 16 pg/ml, against Gram-negative staphylococci, such as Enterobacteraceae, Haemophilus influenzae and Pseudomonas aeruginosa, in minimal concentrations of approx. 0.01 to approx. 64 pg/ml, and against anaerobes, such as Bacteroides fragilis or Clostridium sp. in minimal concentrations of approx. 0.01 to approx. 2 pg/ml.

The new compounds can find use as orally or especially parenterally applicable antibacterial broad-spectrum antibiotics, e.g. in the form of corresponding pharmaceutical preparations, for the treatment of Infections.

The pharmacologically usable compounds prepared according to the invention can e.g. is used for the production of pharmaceutical preparations, which contain a therapeutically effective amount of the active substance together or in a mixture with inorganic or organic, solid or liquid pharmaceutically acceptable carriers, which are suitable for oral or parenteral use, i.e. e.g. Intramuscular, subcutaneous or intraperitoneal administration.

For oral administration, tablets or gelatin capsules are used, which contain the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and lubricants e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or calcium stearate and/or polyethylene glycol. Tablets also contain binders, e.g. magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatins, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, explosives e.g. starches, agar, alginic acid or salts thereof, such as sodium alginate and/or fizzy mixes or adsorbents, colourings, flavorings or sweeteners.

For parenteral administration, infusion solutions, preferably isotonic aqueous solutions or suspensions, are primarily suitable, as these e.g. can be prepared before use of lyophilized preparations, which contain the active substance alone or together with a carrier material, e.g. mannite. Such preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilisers, wetting agents and/or emulsifiers, solubilizers, salts for regulating the osmotic pressure and/or buffers.

The pharmaceutical preparations which, if desired, can contain further pharmacologically valuable substances, are produced in a manner known per se, e.g. by means of usual mixing, dissolving or lyophilization methods and contain from approx. 0.1% to 100$, especially from approx. 1% to approx. 50%, lyophilisates up to $100 of the active substance.

Depending on the type of infection and the condition of the infected organism, daily doses (oral or parenteral) of approx. 200 mg to approx. 5 g for the treatment of humans and animals of approx. 70 kg weight.

The invention will be explained in more detail with the help of some examples, where the temperatures are indicated in degrees Celsius.

PREPARATION OF OUTPUT COMPOUNDS

A. 4-chloro-2-hydroxymethyl- pyridine

A solution of 72 g (0.42 mol) 4-chloropicolinic acid methyl ester in tetrahydrofuran is mixed in portions at 0-5°C with 10g (0.26 mol) lithium aluminum hydride and stirred for 1.5 hours at 0-5°C. By adding a) 10 ml water in 50 ml tetrahydrofuran, b) 10 ml 2N caustic soda and c) 10 ml water in 50 ml tetrahydrofuran and 100 g sodium sulfate, the reaction mixture is worked up. The suspension is filtered and the filtrate is evaporated. The residue is purified chromatographically on silica gel.

TLC (silica gel, toluene/ethyl acetate 1:1) RH = 0.36;

IR (CH 2 Cl 2 ): 3600, 1580, 1550, 1375 cm-<1>.

B. 4- chloro- 2- hydroxymethyl- 1- methyl- pyrldlnlum. 1

1.29 g (8.9 mmol) of 4-chloro-2-hydroxymethyl-pyridine is dissolved in 5 ml of acetonitrile and mixed with 10 ml of methyl iodide and allowed to stand for 60 hours at room temperature. The formed crystals are filtered off and washed with a little acetonitrile and ether.

DC (Opti UPC12, water/acetonitrile 4:1) RH = 0.38;

IR (KBr): 1632, 1570, 1496, 1430, 1400 cm-<1>.

C. 4- chloro- 2- N. N- dimethylcarbamoylpyrldine

A solution of 35 g (0.2 mol) of 4-chloro-picolinic acid chloride in 300 ml of toluene is mixed with an excess of dimethylamine at approx. 10°C. The mushy mixture is evaporated to dryness and distributed between ethyl acetate and sodium bicarbonate solution. The organic phase is dried over sodium sulphate and the solvent is evaporated in vacuo. The residue is purified chromatographically on silica gel with toluene as eluent.

TLC (silica gel, toluene/ethyl acetate 1:1) Rf = 0.17;

IR (CH 2 Cl 2 ): 1640, 1575, 1550, 1410 cm-<1>.

D. 4-chloro-1-methyl-2-N. N-Dimethylcarbamoylpyridinium. 1 odd

A solution of 1.4 g (7.5 mmol) of 4-chloro-2-N,N-dimethylcarbamoyl-pyridine in 9.5 ml (0.146 mol) of methyl iodide is stirred at 50°C for 24 hours. The crystalline product formed is isolated by filtration.

DC (Opti UPC 12, water/acetonitrile 1:1) Rf = 0.36;

IR (KBr): 1655, 1600, 1410 cm"<1>

E. 4- chloro- 2- chloromethyl- pyridinium chloride

A solution of 25.1 g (174 mmol) of 4-chloro-2-hydroxymethyl-pyridine in 300 ml of chloroform is mixed at approx. 20°C with 24.6 ml (338 mmol) of thionyl chloride. A suspension first forms, after gentle heating sulfur dioxide escapes and a clear solution forms. The reaction mixture is heated for 45 minutes under reflux. It is then cooled to room temperature and diluted with 250 ml of toluene. The precipitated crystals are filtered off and dried.

F. 2-aminomethyl-4-chloropyrlidine. dihydrochloride

A solution of 9 g (45 mmol) of 4-chloro-2-chloromethyl-pyridinium chloride in 250 ml of 25 #-ig aqueous ammonia solution and 30 ml of methanol is heated for 1.5 hours under reflux. The methanol is then evaporated in a vacuum and the product is extracted with ethyl acetate. The solution is mixed with an excess of 1M hydrogen chloride in methanol as the hydrochloride crystallizes out.

TLC (silica gel, methylene chloride/methanol 9:1) Rf = 0.25.

G. 2-Allyloxycarbonylaminomethyl-4-chloro-pyridine

6.8 g (38 mmol) of 2-aminomethyl-4-chloro-pyridine, dihydrochloride are dissolved in 70 ml of water and the pH of the solution is adjusted with 1N NaOH to 9.5. 6.7 ml (63 mmol) of chloroformic acid allyl ester are then added dropwise and stirred for 1.5 hours at room temperature. The solution is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and evaporated.

The residue is purified chromatographically on silica gel with toluene/ethyl acetate 4:1.

TLC (silica gel, toluene/ethyl acetate 1:1) Rf = 0.66;

IR (CH 2 Cl 2 ): 3440, 1720, 1580, 1510 cm-<1>.

H. 2- Allyloxycarbonylaminomethyl- 4- chloro- 1- methyl- pyridinium-.- iodide

A solution of 4.5 g (19.8 mmol) of 2-allyloxycarbonylaminomethyl-4-chloro-pyridine in 41 ml of methyl iodide is allowed to stand for 3 days at room temperature. The reaction mixture is evaporated, the residue is taken up in methanol and brought to crystallization with the addition of ethyl acetate and hexane.

DC (Opti UPC12, water/acetronitrile 1:1) Rf = 0.3.

I. 2- chloro- 5- hydroxymethyl- pyridln

A solution of 8 g (46 mmol) 6-chloronicotinic acid methyl ester in 100 ml tetrahydrofuran is mixed in portions at approx. 5°C with 1.15 g (30.2 mmol) of lithium aluminum hydride and stirred for 3.5 hours at 10°C. After adding a) 1.15 ml of water, b) 1.15 ml of 2N caustic soda and c) 1.15 ml of water and 10 g of sodium sulphate, the reaction mixture is worked up. The suspension is filtered and the filtrate is evaporated. The residue is purified chromatographically on silica gel.

TLC (silica gel, toluene/ethyl acetate 1:1) Rf = 0.2.

J. 2- chloro- 5- hydroxymethyl- 1- methyl- pyrldinium. 1 odd

4 g (27.8 mmol) of 2-chloro-5-hydroxymethyl-pyridine are dissolved in 20 ml of acetonitrile, mixed with 37 ml of methyl iodide and stirred for 95 hours at room temperature. The suspension is stirred with ethyl acetate, the product is filtered off and dried.

DC (Opti UPC12, water/acetonitrile 7:3) Rf = 0.71;

IR (DMS0-d6): 1622, 1509, 1434 cm-<1>.

K. 6-Chloro-nlcotlnsvreamide

Into a suspension of 25 g (0.145 mol) of 6-chloro-nicotinic acid methyl ester in 450 ml of ethylene glycol is introduced with the addition of 0.5 g of ammonium chloride at 20"-40°C ammonia gas. After approx. 1.5 hours the crystals are filtered off and washed with ethanol .

TLC (silica gel, ethyl acetate) Rf = 0.37;

IR (KBr): 1655, 1581, 1407 cm-<1>

L. 5- carbamoyl- 2- chloro- 1- methyl- pyrldinium iodold

1 g (6.4 mmol) of 6-chloronicotinic acid amide is dissolved in a mixture of 6 ml of acetonitrile and 6 mol of methyl iodide and heated in a bomb tube for 48 hours at 80°C. The reaction mixture is brought to room temperature and mixed with ethyl acetate. The crystalline product is filtered off and washed with ethyl acetate.

DC (Opti UPC12, water/acetonitrile 7:3) Rf = 0.5;

IR (KBr): 1684, 1628, 1558, 1497 cm-<1>

M. 2-chloro-5-N-trichloroacetylcarbamoyloxymethyl- pyridine

3.7 g (25.7 mmol) of 2-chloro-5-hydroxymethyl-pyridine are dissolved in 150 ml of methylene chloride and mixed under nitrogen at room temperature with 3.1 ml (25.7 mmol) of trichloroacetyl isocyanate. The white suspension is stirred for 1.5 hours at room temperature and the product is filtered off.

TLC (silica gel, toluene/ethyl acetate 1:1) Rf = 0.56;

IR (DMS0-d6): 1728, 1589, 1569, 1461 cm"<1>

N. 5- carbamoyloxymethyl- 2- chloro- pyridine

9.1 g (27.4 mmol) of 2-chloro-5-N-trichloroacetylcarbamoyloxymethyl-pyridine are dissolved in methanol and stirred with 60 g of silica gel at room temperature for 24 hours. The silica gel is filtered off, the filtrate is evaporated and the residue is dried with hexane.

TLC (silica gel, toluene/ethyl acetate 1:1) Rf = 0.24;

IR (DMS0-d6): 1728, 1589, 1569, 1461 cm-<1>

0. 5- carbamoyloxymethyl- 2- chloro- 1- methyl- pyridinium. A portion of 1.65 g (8.84 mmol) of 5-carbamoyloxymethyl-2-chloro-pyridine is heated in 20 ml of acetonitrile and 10 ml of methyl iodide for 22 hours at 60°C. The reaction mixture is diluted with ethyl acetate and the product is filtered off.

DC (Opti UPC12, water/acetonitrile 9:1) Rf = 0.38;

IR (KBr): 1728, 1700, 1591, 1500 cm-<1>

P. 2- chloro- 5- chloromethyl- pvridln

The title compound is prepared in an analogous manner as stated under point E.

TLC (silica gel, toluene/ethyl acetate 1:1) Rf = 0.75;

IR (CDCl 3 ): 1588, 1565, 1462 cm-<1>.

Q. 5-azidomethyl-2-chloro-pyridine

Dissolve 5 g (30.8 mmol) of 2-chloro-5-chloromethyl-pyridine in 15 ml of dimethylformamide and stir with 2.2 g (33.8 mmol) of sodium azide at room temperature for 1 hour. The reaction solution is distributed between water and ethyl acetate, the organic phase is dried with sodium sulphate and the solvent is evaporated. Thereby the product crystallizes.

TLC (silica gel, toluene/ethyl acetate 4:1) Rf = 0.68;

IR (CDCI3): 2104, 1589, 1568, 1463 cm-<1>

R ♦ 5-azidomethyl-2-chloro-1-methyl- pyridinelum. 1 odid

4 g (23.7 mmol) of 5-azidomethyl-2-chloro-pyridine are heated in 25 ml of methyl iodide for 16 hours at 60°C. The crystalline product is filtered off and washed with ethyl acetate.

DC (Opti UPC12, water/acetonitrile) Rf = 0.28;

IR (KBr): 2101, 1622, 1569, 1495 cm-<1>

Example 1: (5R.6S)-6-f(IR)-1-hydroxymethyl-2-f(1-methyl-4-pyridinio)-aminomethyl-2-penem-3-carboxylate 600 mg (2.45 mmol) (5R,6S)-2-aminomethyl-6-[(1R)-1-hydroxyethyl]-2-penem-3-carboxylic acid is dissolved in 18.6 ml of water and the pH of the solution is adjusted at 0°C with 1N sodium hydroxide solution to 8.5. After adding 759 mg (2.97 mmol) of 4-chloro-1-methyl-pyridinium iodide, the reaction solution is stirred while maintaining the pH value of 8.5 for 4.75 hours at room temperature. The solution is then extracted with ethyl acetate and the aqueous phase is lyophilized. The residue is purified chromatographically on 70 g Opti UPC12 (eluent H20). The title substance is obtained by lyophilization.

DC (Opti UPC12; water/acetonitrile 80:20) Rf = 0.45;

UV (water) Xmax= 282 nm;

IR (DMS0-d6): 1770, 1650, 1625, 1540 cm-<1>

Example 2: (5R.6S)-2-f(1-benzyl-4-pyridinio)-aminomethyl-6-f(IR)-1-hydroxyethyl"1-2-penem-3-carboxylate

A solution of 263 mg (1.08 mmol) (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid 1 8.2 ml of water, adjusted with 1 ml IN caustic soda to pH 8.5. 500 mg (approx. 1.2 mmol) of 1-benzyl-4-fluoro-pyridinium iodide (dissolved in 1.6 ml of water) is added dropwise to this solution at room temperature. When mixed with IN caustic soda, the pH of the solution is kept constant at 8.5. After 75 minutes of stirring, the pH of the solution is set to 7. The reaction mixture is evaporated after 2.5 hours on a rotary evaporator and the residue is purified by chromatography on 30 g Opti UPC12 silica gel with the eluent system water/acetonitrile 80:20. When the aqueous phase is evaporated, the amorphous product is obtained.

DC (Opti UPC12; water/acetonitrile 70:30) Rf = 0.3;

UV (water) Xmax= 283 nm;

IR (DMS0-d6): 1770, 1650, 1620, 1550 cm-<1>

Example 3: (5R.6S)-6-1"(IR)-1-hydroxymethyl-2-f(2-hydroxymethyl-1-methyl-4-pyridinio)-aminomethyl-2-penem-3-carboxylate

3.6 g (14.7 mmol) of (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid is dissolved in 100 ml of water and the pH of the solution is set at 0"C with IN caustic soda to 7.7 After adding 5.05 g (17.7 mmol) of 4-chloro-2-hydroxymethyl-1-methyl-pyridinium iodide, the reaction solution is stirred while maintaining the pH value of 7.5-7.9 For 5 hours at room temperature.The reaction solution is lyophilized and

the residue is purified chromatographically on 200 g Opti UPC12 (eluent H20). The title substance is obtained by lyophilization.

DC (Opti UPC12, water/acetonitrile 9:1) Rf = 0.42;

UV (water) Xmax= 280 nm;

IR (DMS0-d6): 1773, 1649, 1618, 1350 cm"<1>.

Example 4: (5R.6S)-6-f(IR)-1-hydroxymethyl-2-f(1-methyl-2-pyrridine)-aminomethyl-2-penem-3-carboxylate 800 mg (3, 28 mmol) (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid is dissolved in 15 ml of water and the pH of the solution is adjusted at 0°C with 1N caustic soda to 8 ,0. After adding 1.02 g (4.0 mmol) of 2-chloro-1-methyl-pyridinium iodide, the reaction solution is stirred while maintaining the pH value of 8.5 for 3 hours at room temperature. The aqueous phase is then lyophilized. The residue is purified chromatographically on 70 g of UPC12 (eluent H20). The title substance is obtained by lyophilization.

DC (Opti UPC12, water/acetonitrile 9:1) Rf =0.38;

UV (water) Xmax= 312 nm;

IR (DMS0-d6): 1773, 1648, 1620, 1590, 1542 cm-<1>

Example 5: (5R.6S)-6-f(IR)-1-hydroxyethyl-2-\2-(1-methyl-2-pyridinoamino)-ethyl-2-penem-3-carboxylate

300 mg (1.16 mmol) of (5R,6S)-2-(2-aminomethyl)-6-[(1R)-1-hydroxyethyl]-2-penem-3-carboxylic acid are dissolved in 20 ml of water and the pH of the solution is adjusted at 0oC with 0.IN caustic soda at 8.0. After adding 534 mg (2.1 mmol) of 2-chloro-1-methyl-pyridinium iodide, the reaction solution is stirred while maintaining the pH value of 8.5-9.0 for 23 hours at room temperature. The aqueous phase is then lyophilized. The residue is purified chromatographically on 70 g Opti UPC12 (eluent H20). The title substance is obtained by lyophilization.

DC (Opti UPC12, water/acetonitrile 9:1) Rf = 0.22;.

UV (water) Xmax= 307 nm;

IR (DMSO-d 6 ): 1772, 1650, 1625, 1581, 1543 cm-<1>.

Example 6: (5R.6S)-6-1"(IR)-1-hydroxybutyl-2-1"(2-carboxyl-methyl-4-pyridino)-aminomethyl-2-penem-3-carboxylate, sodium salt

1.5 g (6.14 mmol) of (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid is dissolved in 1 20 ml of water and the pH of the solution is set at 0 °C with 0, IN caustic soda at 7.5. After adding 13.2 mg (32.6 mmol) of 4-chloro-1-methyl-2-methoxycarbonylpyridinium iodide, the reaction solution is stirred while maintaining the pH value of 7.5 for 16 hours at room temperature. The aqueous phase is then lyophilized. The residue is purified chromatographically on 70 g Opti UPC12 (eluent H20). The title substance is obtained by lyophilization.

DC (Opti UPC12, water/acetonitrile 9:1) Rf = 0.34;

UV (water) Xjjjax = 282 nm;

IR (DMS0-d6): 1775, 1627, 1347 cm-<1>.

Example 7: (5R.6S)-6-f(IR)-1-hydroxyethyl-2-f(2-allyloxycarbonylaminomethyl-1-methyl-4-pyridinyl)-aminomethyl-2-penem-3-carboxylate

1.5 g (6.1 mmol) of (5R,6S)-2-aminomethyl-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid is dissolved in 30 ml of water and the pH of the solution is set at 0 °C with 0.1N caustic soda to 8.5. After adding 3.2 g (8.6 mmol) of 2-allyloxycarbonylaminomethyl-4-chloro-1-methyl-pyridinium iodide, the reaction solution is stirred while maintaining the pH value of 8.5 for 6.5 hours at room temperature. The aqueous phase is then lyophilized. The residue is purified chromatographically on 70 g of XAD2 (eluent H20). The title substance is obtained by lyophilization.

DC (Opti UPC12, water/acetonitrile 7:3) Rf = 0.3;

UV (water) Xjjjax = 280 nm;

IR (DMS0-d6): 1772, 1719, 1649, 1619 cm-<1>.

Example 8: ( 5R. 6S)- 6- l"( lR ) - 1 - hydroxy ve tvi " 1 - 2- T ( 2 - aml no-methyl - 1 - me tyl- 4- pyr ld in lo ) - aminomethyl - 2- penem-3- carboxylate

1.4 g (3.1 mmol) (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2-allyloxycarbonylaminomethyl-1-methyl-4-pyridinio)-aminomethyl]-2- penem-3-carboxylate is dissolved in 50 ml of dimethylformamide and mixed with 0.54 g (3.45 mmol) of dimethylbarbituric acid. 300 mg of tetrakis-(triphenylphosphine)-palladium are then added under nitrogen. It is stirred for 4 hours at room temperature. The solvent is evaporated in high vacuum and the residue is distributed between saturated sodium bicarbonate solution and ethyl acetate. The aqueous phase is lyophilized and the residue is chromatographed on 80 g Opti UPC12 with water. The title substance is obtained by lyophilization.

DC (Opti UPC12, water/acetonitrile) Rf = 0.25;

UV (water) Xmax= 280 nm;

IR (DMS0-d6): 1773, 1649, 1618 cm-<1>.

Example 9: (5R.6S)-6-f(1R)-1-hydroxymethyl-2-f(5-azidomethyl-1-methyl-2-pyridinio)-aminomethyl1-2-penem-3-carboxylate

Analogous to that discussed in examples 1-8, (5R,6S)-2-aminomethyl-6-[(1R)-1-hydroxyethyl]-2-penem-3-carboxylic acid is reacted with 5-azidomethyl-2-chloro -1-methyl-pyridinium iodide to the title compound.

DC (Opti UPC12, water/acetonitrile 9:1) Rf = 0.43;

UV (water) Xmax=315 nm;

IR (DMS0-d6): 2101, 1773, 1659, 1619, 1576 cm-<1>.

Example 10: ( 5R. 6S )- 6- f( 1R ) - 1 - hydroxy svety li - 2- f ( 5- amlnomethyl- 1- methyl- 2- pyridinium) - aminomethyl - 2- penem- 3- carboxylate

279 mg (0.71 mmol) (5R,6S)-6-[(IR)-1-hydroxyethyl]-2-[(5-azidomethyl-1-methyl-2-pyridinio)-aminomethyl]-2-penem- 3-carboxylate, dissolved in 60 ml is hydrogenated with the addition of

150 mg Pd/C 10$ with hydrogen under normal pressure and at room temperature for 2 hours. The catalyst is then filtered off and the product is isolated by lyophilization.

DC (Opti UPC12, water/acetonitrile 9:1) Rf = 0.39;

UV (water) Xmax= 314 nm;

IR (DMS0-d6): 1773, 1592 cm-<1>.

Example 11: In an analogous way as in examples 1-10, the following compounds are obtained:

DC (Opti UPC12; water/acetonitrile 80:20) RH = 0.40; UV (water) Xmax= 282 nm; IR (DMS0-d6): 1770, 1735, 1650, 1620 cm-<1> DC (Opti UPC12; water/acetonitrile 80:20) Rf = 0.55; UV (water) Xmax= 283 nm; IR (DMS0-d6): 1775, 1710 1650, 1625 cm-<1> DC (Opti UPC12; water/acetonitrile 70:30) Rf = 0.40; UV (water) Xmax= 283 nm; IR (DMS<0->d6): 1770, 1650, 1625 cm-<1>

DC (Opti UPC12; water/acetonitrile 80:20)

R f = 0.55;

UV (water) Xmax= 283 nm;

IR (DMS0-d6): 1770, 1730, 1650, 1625 cm-<1>

DC (Opti UPC12; water/acetonitrile 80:20) Rf = 0.55; UV (water) ^-max = 283 nm; IR (DMS0-d6): 1775, 1650, 1625 cm"<1>

DC (Opti UPC12; water)

R f = 0.31;

UV (water) Xmax= 285 nm;

IR (DMS0-d6): 1773, 1696, 1644 cm_ 1

DC (Opti UPC12; water/acetonitrile 1:1)

R f = 0.50;

UV (water) Xmax= 283 nm;

IR (DMS0-d6): 1773, 1733, 1652, 1618 cm-<1>

DC (Opti UPC12; water/acetonitrile 1:1) Rf = 0.50; UV (water) Xmax<=><2>82 nm; IR (DMS0-d6): 1772, 1664, 1618 cm"<1>

DC (Opti UPC12; water/acetonitrile 1:1)

R f = 0.53;

UV (water) Xmax= 300 nm;

IR (DMS0-d6): 1773, 1651, 1620, 1584 cm-<1>

DC (Opti UPC12; water/acetonitrile 9:1) Rf = 0.45; UV (water) Xmax= 283 nm; IR (DMS0-d6): 1773, 1651 crn-1

DC ^Opti UPC12; water/acetonitrile 9:1)

R f = 0.26;

UV (water) Xmax=283 nm;

IR (DMS0-d6): 1772, 1643, 1619, 1406 cm-<1>

DC (Opti UPC12; water/acetonitrile 9:1)

R f = 0.37;

UV (water) Xjj,ax = 313 nm;

IR (DMS0-d6): 1774, 1687, 1651, 1621 cm-<1>

DC (Opti UPC12; water/acetonitrile 7:3)

R f = 0.68;

UV (water) Xmax =<3>14 nm;

IR (DMS0-d6): 1772, 1658, 1619, 1594 cm-<1>

DC (Opti UPC12; water/acetonitrile 9:1)

R f = 0.36;

UV (water) Xmax= 313 nm;

IR (DMS0-d6): 1773, 1726, 1661, 1594 cm-<1>

DC (Opti UPC12; water/acetonitrile 9:1)

R f = 0.30;

UV (water) Xmax= 286 nm;

IR (DMS0-d6): 2120, 1773, 1642, 1622 crn-1

Example 12: Analogous to what was discussed in the previous examples, the following compounds are prepared:

DC (Opti UPC12; water/acetonitrile 80:20)

R f = 0.50;

UV (water) Xmax= 282 nm;

IR (DM<S>0-d6): 1770, 1650, 1625 cm-<1>

DC (Opti UPC12; water/acetonitrile 70:30) Rf = 0.35; UV (water) Xmax= 283 nm; IR (DMS0-d6): 1770, 1650, 1620 cn<T1> DC (Opti UPC12; water/acetonitrile 80:20) Rf = 0.45; UV (water) Xmax= 282 nm; IR (DMS0-d6): 1770, 1735, 1650, 1620 cm-<1> DC (Opti UPC12; water/acetonitrile 80:20) Rf = 0.60; UV (water) ^max = ^83 nm; IR (DMS0-d6): 1775, 1710, 1650, 1625 cm"<1> DC (Opti UPC12; water/acetonitrile 70:30) Rf = 0.95; UV (water) Xmax= 283 nm; IR (DMS0- d6): 1770, 1650, 1625 cm-<1> DC (Opti UPC12; water/acetonitrile 80:20) Rf = 0.65; UV (water) Xmax= 283 nm; IR (DMS0-d6): 1770, 1730 , 1650, 1625 cm"<1> DC (Opti UPC12; water/acetonitrile 80:20) Rf = 0.60; UV (water) Xmax= 283 nm; IR (DMS0-d6): 1775, 1650, 1625 cm-<1>

DC (Opti UPC12; water/acetonitrile 9:1)

R f = 0.26;

IR (DMS0-d6): 1771, 1651, 1619 cm'<1>

Example 13: Dry ampoules or vials, containing 0.5 g of 6-[(IR)-1-hydroxyethyl]-2-[(2-hydroxymethyl-1-methyl-4-pyridinio)-aminomethyl]-2-penem -carboxylate as active substance, is produced as follows:

A sterile aqueous solution of the active substance and of the mannitol submitted under aseptic conditions in 5 ml ampoules or 5 ml vials, freeze-drying and the ampoules resp. the vials are closed and examined.

Instead of the above-mentioned active substance, the same amount of another active substance according to the previous examples can also be used.

Claims (5)

in which Ri and m have the above-mentioned meaning, are traded with a pyridinium compound of formula in which R2, R3 and R4 have the above meaning, in that functional groups in these residues are possibly present in protected form, X means a leaving group and Y- means a anion, and if necessary, protected functional groups in the residues R2 and R3 and/or R4 are transferred to the free functional groups and, if desired, a formed free compound of formula I is transferred to a salt. 2. Process for the preparation of a compound of formula I according to claim 1, in which R^ means hydroxymethyl or (1R)-1- hydroxyethyl, Z means a residue wherein R 2 means lower alkyl, with hydroxy, halogen, lower alkanoyloxy, carbamoyloxy, lower aloxy, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower alkyl- or N,N-dilower alkylcarbamoyl, cyano, amino, azido, phenyl, with lower alkyl, lower alkoxy, halogen, cyano and /or carboxy substituted phenyl or oxo substituted lower alkyl, lower alkenyl, phenyl with lower alkyl, lower alkoxy, halogen, cyano and/or carboxy substituted phenyl, pyridyl or lower alkoxy, R3 and R4 independently mean hydrogen, lower alkyl with hydroxy, halogen, lower alkanoyloxy, carbamoyloxy, lower alkoxy, carboxy, lower oxycarbonyl, carbamoyl, N-lower alkyl and N,N-di lower alkyl carbamoyl, cyano, amino, azidophenyl with lower alkyl, lower alkoxy, halogen, cyano and/or carboxy substituted phenyl, or oxo substituted lower alkyl, carboxyl, lower alkoxy carbonyl, carbamoyl, N-lower alkyl or N.N-dilower alkyl carbamoyl, cyano, lower alkoxy, halogen, lower alkanoyloxy, carbamoyloxy, amino, lower alkylamino, dilower alkylamino, lower alkyleneamino or lower alkanoylamino, m means an integer from 1 to 4 and salts of compounds of formula I. 3. Process for the preparation of compounds of formula I according to claim 1, wherein (IR)-1-hydroxyethyl means, Z means a rest wherein Rg means lower alkyl, acetonyl or with carboxy, lower alkoxycarbonyl, carbamoyl, N,N-dilower alkylcarbamoyl or phenyl substituted lower alkyl, R3 means hydrogen, R4 means hydrogen with hydroxy, carboxy, cyano or amino substituted lower alkyl, carboxy, carbamoyl or cyano and m means 1 or 2, and salts of compounds of formula I. 4. Process for the preparation of compounds of formula I according to claim 1, in which R 1 means (IR)-1-hydroxyethyl, Z means a residue in which Rg means lower alkyl or carbamoyl-substituted lower alkyl, R3 means hydrogen and R4 means hydrogen or hydroxy-substituted lower alkyl, m means 1 and salts of compounds of formula I. 5. Process for the preparation of a compound of formula I according to claim 1, selected from the group (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[(1-methyl-4-pyridinio)-aminomethyl]-2-penem-3-carboxylate, (5R,6S)-2- [(1-benzyl-4-pyridinio)-aminomethyl]-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylate, (5R , 6S )-2-[(1-aminocarbonylmethyl-4-pyridinio)-aminomethyl]-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylate, (5R , 6S )-6-[(IR )-1-hydroxyethyl]-2-[(1-hydroxymethyl-1-methyl-4-pyridinio )-aminomethyl]-2-penem-3-carboxylate, (5R ,6S )-6-[(IR )-1-hydroxyethyl]-2-[(2-carboxy-1-methyl-4-pyridinio)-aminomethyl]-2-penem-3-carboxylate, ( 5R , 6S )-6 - [ (IR )-1-hydroxyethyl]-2-[(2-aminomethyl-1-methyl-4-pyridinio)-aminomethyl]-2-penem-3-carboxylate, (5R,6S )-6-[(1R) -1-hydroxyethyl]-2-[(1-acetonyl-4-pyridinio)-aminomethyl]-2-penem-3-carboxylate, and pharmaceutically acceptable salts thereof.