GB2207133A

GB2207133A - Penem derivatives

Info

Publication number: GB2207133A
Application number: GB08816559A
Authority: GB
Inventors: Angelo Bedeschi; Bruna Costantino Della; Giuseppina Visentin; Ettore Perrone; Giovanni Franceschi
Original assignee: Farmitalia Carlo Erba SRL; Carlo Erba SpA
Current assignee: Pfizer Italia SRL
Priority date: 1987-07-15
Filing date: 1988-07-12
Publication date: 1989-01-25
Also published as: GB8816559D0; IT8821316A0; GB8716679D0; JPS6434990A; DE3823612A1; IT1227875B

Description

2207 133 -I- TITLE:

Penem Derivatives DESCRIPTION: The invention relates to penem derivatives, to a process for their preparation and to pharmaceutical and veterinary compositions containing them.

The invention provides (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl (SR)-6s(1R-hydroxyethyl)-2-(3-pyridyl).penem-3-carboxylate, 1-(methoxycabonyloxy)-ethyl (SR)-6S-(1R-hydroxyethyl)-2(6-fi.uoromethvl--'j-pyridyl)penem-3-carboxylate, potasa.-'Lum (AR)-6S-('LR-hydroxyethyl)-2-(2fluoromethyl-4-pl,ridyl-)-penem-3-carboxylate, potassium (5R)-6S-(1Rhydroxyethyl)-2-(4-fluoromethyl-3-py.-idy--.)-penem-3-carboxylate, potassium (SR)-6S-(1R-hydroxyethyl)-2-(6-fluoromethyl-3-pyridyl)-penem-3carboxylate, potassiuT (SR)-6S-(1R-hydroxyethy'L)-2-(5-flucromethyl-3pyridy-,)-penem-3-carboxylate, sodium (5R)-6S-(lR-hyd roxyethyl)-2-(2piperidinocarbonyl-4-pyridyl)-penem-3-carboxylate, sodium (5R)-6S-(1Rhydroxyethyl)-2-(3-dimethylsulphamoyl-4-pyridyl)-penem-3-carboxylate, (SR)-65-(IR-hvdroxyethyl)-2-(6-carbamoyl-3- pyridyl)-penem-3---arboxylic acid, (SR)-6S-(1R-hydroxyethyl)-2-(6-ethyl-3-pyridyl)-penem-3-carboxylic acid, (SP,)-6S-(1R-hydroxyethyl)-2-(5-ethyl-3-pyridyl)-penem--carboxylic acid, sodium (1R'J-65-(1R-hydroxyethyl)-2-(6-isopropyl-3-pyridyl) -penem3-carboxylate, sodium (SR)-6s-(1R-hydroxyethyl)-2-(5-isopropyl-3-pyridyl) -penem-3-carboxylate, and sodium (SR)-6S-(1R-hydroxyethyl)-2-(5-methyl-3pyridyl)-penem-3-carboxylate.

The invention also provides a penem derivative having the general formula 1 R 1 0 (CH 2) n-x Y N N R 2 (1) wherein R 1 represents an alkyl group having from 1 to 3 carbon atoms, optionally substituted by one or more free or protected hydroxy groups or halogen atoms, R 2 represents a carboxy group, an esterified carboxy group or a carboxylate anion; n is 0, 1, 2 or 3; Y represents an atom or group selected from (a) a hydrogen atom, (b) an alkyl croup having from 1 to 4 carbon atoms, (c) a halogen atom or a cyano group, (d) a hydroxy, mercapto or amino group, each of which may be in a free or protected form, (e) an alkoxy, alkylthio or alkylamino group, each having from 1 to A carbon atoms, or a dialkylamino group in which each alkyl group has from 1 to 4 carbon atoms, (f) an optionally substitued aryloxy, arylthio-or arylamino 9 rcup, (g) an alkoxycarbonyl group having from 2 to 5 carbon atoms, (h) a nitro group; (i) an acyloxy, acylthio or acylamino group, from 1 to 4 carbon atoms, each having (1) a carbamoyloxy, carbamoylthio or ureido group, (m) an aminocarbonyl group of the general formula R3 R 4 N.COwherein either each of R 3 and R 4 independently represents a hydrogen atom, a straight chain or branched chain alkyl 1 i i 1 1 i i 1 1 1 i i 1 i i 1 1 1 i I group havino from 1 to 4 carbon atoms, an aralkyl group having from 7 to 11 carbon atoms or an aryl group, or R 3 and R 4 together with the nitrogen atom to which they are bonded represent an optionally substituted saturated or unsaturated heteromonocyclic or heterobicyclic group having from 4 to 8 ring atoms which may include oxygen and/or sulphur and/or further nitrogen atoms, and (n) an aminosulphinyl group of the general formula R 3 R 4 N.SO- 3 4 or a sulphamoyl group of the general formula R R. so 2wherein R 3 and R 4 are as defined above, and X represents an atom or group selected frorr, those listed in (b) to (n) above if n is 0 or in (c) to (n):if n is greater than 0, with the proviso that when the pyridyl moiety is a 3or 4-pyridy! moiety, then Y does not represent a hydrogen atom and X and Y do not simultaneously represent chlorine atoms.

Pharmaceutically or veterinarily acceptable salts or ester o-f the penem derivatives I are a-!sG included within. the scope of the invention. Such salts may be salts with inorganic bases such as alkali or alkaline earth metal hydroxides, in particular sodium and potassium hydroxides, or salts with organic bases such as triethylamine, pyridine, benzylamine or collidine. Salts with aminoacids, such as lysine or procaine, are also included as are internal salts, i.e. zwitterions, and addition salts with inorganic acids, in particular salts with hydrochloric and sulphuric acids. The term lle ster prodruas11 refers to esters which can be cleaved under physiological conditions, releasing the parent compound in vivo. In particular, the term refers to esters which promote absorption from the gastro-intestinal tract after oral administration, and then are hydrolyzed in the bloodstrear. by aspecific serum esterases. Such esters irclude a.:v-'.c>:.xmethyl and 1- acyloxyethl7l esters; benzo-x71oxvr.e-L.hvl and. 1-benzoyloxyethyl esters, either unsubstituted or ring substituted by a hydroxy, methoxy, acetox.x, ar.-inc, methylamino or acetamido group., alkoxycarbonvloxymethvl and 1- alkoxycarbonyloxyethyl esters; 3-phthalidy! esters: 2-oxo-1,3-d-Joxo'Lan- 4-yl esters optionally 5-substituted by an alkyl group having from 'L to 4 carbon atoms; 2-oxo-1,3-dioxolen-4-ylmethvl esters, optionally 5- substituted by an alkylgroup having from 1 to 4 carbon atoms or a phenyl group; alkoxycarbonylmethyl esters in which the alkoxy group has from 1 to 4 carbon atoms and is straight chain or branched chain, and benzyloxycarbonylmethyl esters; and 2oxotetrahydrofuran-5-yl esters, optionally 4-substituted by an alkyl group having from 1 to 4 carbon atoms.

The present invention includes all the possible geometrical and optical isomers of the compounds 1 either in the form of isomeric mixtures or in the form of the individual separated isomers.

When Y represents a hydroxy, amino or mercapto group, or i i i 1 1 i i 1 1 i i i i 1 t i when X represents such a group and n=O, the compound 1 may exist in the tautomeric oxo, imino or thioxo dihydropyridyl form, for example N N H 0 N HO N Such tautomers are also included within the scope of the invention.

Preferably the compounds 1 have a 5R,65 conf_iauration. The preferred R group is an a-hydroxye-h.,,1 group having a 1R configuration, i.e. a R configuration at the a-carbon atom of the ethyl group.

The term "an esterified carboxy group,' ineians a group -COO- esterified by a carboxy protecting group. Examples of carboxy protecting groups are alkyl groups having from 1 to 6 carbon atoms, for instance methyl, ethyl o.r t-butyl groups; haloalkyl groups having from 1 to 6 carbon atoms, for example a 2,2,2,-trichloroethyl group: alkenyl groups having from 2 to 4 carbon atoms, for example an allyl group; optionally substituted aryl groups, for example phenyl and p-nitrophenyl groups; optionally substituted aralkyl groups, the alkyl part of which has from 1 to 6 carbon atoms, for example benzyl, p-nitro-benzyl and p-methoxybenzyl groups; aryloxyalkyl - 6 groups, the alkoxy part of which has from 1 to 6 carbon atoms, for example a phenoxymethyl group; and groups such as benzhydryl, o- nitrobenzhydryl, acetonyl, trimethylsilyl, t-butyldiphenylsilyl, and tbutyldimethylsilyl. Carboxy protecting groups also include any residue such as acetoxymethyl, pivaloyloxymethyl or phthalidyl, leading to an ester group which is known to be hydrolyzed in vivo and to have favm=able pharmacokinetic properties. Attention is drawn to the above passage concerning ester prodrugs.

The term "a halogen atom" encompasses fluorine, chlorine, bromine and iodine atoms, but fluorine and chlorine atoms are preferred.

The preferred aryl groups are optionally substituted phenyl groups.

When NR 3 p 4 represents a heterocyclic ring, that ring is preferably a saturated or unsaturated monocyclic ring having 5 or 6 ring atoms of which from 1 to 4 are heteroatoms selected from oxygen, nitrogen and sulphur.

Suitable protecting groups for the hydroxy mercapto and amino groups may be chosen from optionally substituted acyl groups, inorganic residues, triarylmethyl groups, silyl groups, optionally substituted alkoxycarbonyl groups and pyranyl groups. Preferred protecting groups include pnitrobenzyloxy, carbonyl, 2,2,2,-trichloroethoxycarbonyl, allyloxycarbonyl, t-bmtyldimethvls-4lvl, t-butyldiphenylsilyl, trimethvlsil\yl, nitro, pyranyl, 2-methoxy-2-propyl, triphenylmethyl, tri(p-methoxyphenvl)-methyl, chloroacetyl, trifluoroacetyl and pbromophenacyl groups.

i 1 4 1 i i Preferably, each of R 3 and R 4 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, or R 3 and R 4 together with the nitrogen atom to which they are bonded form a 1-pyrazolidinyl, piperidino, 1-piperazinyl, 1-pyrrolidinyl, 1-perhydroazepinyl or perhydro-1,4- thiazin-4-ryl group.

The preferred alkyl groups, and this includes the alkyl part of alkoxy, alkylthio, alkylamino and alkanoyl groups, are methyl, ethyl, and propyl groups, but especially methyl and ethyl groups.

A preferred class of the compounds I is that in which WL represents an r,hvldroxyethyl group; n is 0, ll, 2 cr 3; Y represents an atom or group selected from a') a hydrocen atom, bl) an alkyl group having from 1 to 4 carbon atomE, C) a halogen atom, preferably a fluorine or chlorine atorr.' d') a hydroxy, mercapto or amino group, el) a methoxy, ethoxy, methylthio, ethylthio, methylamino, dimethviamino cr ethylamino group, f.) a phenoxy, phenylthio, phenylamino group in which the phenyl ring is unsubstituted or is substituted by an amino, hydroxy, methoxy, acetoxy, carboxy, carbamoyl or carbamoyloxy group, g,) a methoxycarbonyl or ethoxycarbonyl group, h') a nitro croup, il) an acetoxy, acetylthio or acetamido group, 11) a carbamoyloxy or ureido group m,) a carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, 1-pyrrolidinylcarbonyl or piperidinocarbonyl group; and n') an aminosulphinyl, methylaminosulphinyl, dimethylaminosulphinyl, sulphamoyl,methylsulphamoyl, dimethylsulphamoyl, ethyIsulphamoyl, diethylsulphamoyl, 1-pyrrc,lidinylsulphonyl 1 or piperidinosulphonyl group; X represents an atom or group selected from those listed in (bl) to (nl) above if n is 0 or in (cl) to (nl) above if - n is greater than 0, and R 2 represents sodium or potassium carboxylate; or when the pyridine nitrogen atom is protonated its carboxylate counterpart., or a carboxy group; or an esterified carboxy group of the general formula -COOZ wherein Z is selected from acetoxymethyl, pivaloyloxymethyl, propionoxymethyl, cyclohexylacetoxy- methyl., cyclohexylcarbonyloxymethyl, benzoyloxymethyl or 2-acetoxybenzoyloxymethyl, methoxycarbonyloxymethvl, ethoxycarbonyloxymethyl, i-propoxycarbonyloxymethyl, cyclohexylmethoxycarbonyloxymethyl., 1-(methoxycarbonyloxy) -ethyl, 1-(ethoxycarbonyloxy)-ethyl, 3-phthalidyl, 2-oxo -1,3-dioxolan-4-yl, 5-methyl-2-oxo-1,3-dioxblen-4-yl-methyl 9 ethoxycarbonylmethyl and 2-oxotetrahydrofuran-5-yl groups, with the proviso that when the pyridyl moiety is a 3-pyridyl or 4-pyridyl moiety, then Y does not represent a hydrogen atom and X and Y do not simultaneously represent chlorine atoms.

5-phenyl-2-oxo-1,3-dioxolen-4-yl-methyl The most preferred compounds according to the invention are those listed in claims 1 and 5.

The invention further provides a process for the preparation of a compound of the general formula 1, the said process comprising cyclizing a compound of the general formula II or III (CH 2 -X S Y R ON N PPh 3 COOZ, (11) R 1 S N C00Z 1 (CH 2) jn-x Y N W (III) 2 wherein R ' X, Y and n are are as defined above, Ph represents a phenyl group, Z1 represents a carboxy protecting group or a group Z as defined above, and W represents an oxygen or sulphur atorr'.' and, if desired, removing any protecting groups present: and if desired, converting the resultant 2 compound of the general formula 1 wherein R represents a free carboxy croup, or salt thereof, into a compound of the oeneral formula I wherein R 2 is an in vivo hydrolyzable esterified carboxy group COOZ wherein Z is as defined above.

The cycliization of a compound of the general formula 11 may be carried out by heating it in an inert organic solvent preferably benzene, toluene or dioxan, at reflux or near-to-reflux temperatures.

The cyclization of a compound of the general formula 111 may be carried out by treatment with trimethylphosphite or triethylphosphite in an inert organic so2Yent, such as chloroform, benzene, toluene, xylene or dioxan.

The conversion of a compound of the general formula I 2 wherein R represents a free or salified carboxy group into a compound of the general formula I-wherein R 2 represents an esterified carboxy group COOZ may be carrie4 i i out by reacting the said compound with a compound of formula Z-Q wherein Z is as def ined above and Q represents a chlorine, bromine, or iodine atom or a mesyloxy, trif luoro- methanesulphonyloxy or tosyloxy group.

i The starting materials II and Ill may be obtained from the following known optically active azetidinone precursors i R 1 1r 1, -I (IV) 1 W R Aq N Y Ph 3 (V) C00z 1 R. 1 - 1 Ag (V1) 0 C00z 1 1 wherein R ' ZI and Ph are as defined above and L represents a leaving group, preferably an acetoxy, benzyloxy or phenylsulphonyl group or a chlorine atom, by methods known per se, and summarized in the following scheme:

- ' (CH 2) n X HS y (CH 2 n X N R y N (CE 2) n X HS y N S 0 0%, I(CH 2) n X COC1 1 R y cooz N NB S (V1 (V) 0 NB 0 1 oci C00z 1 (CH 2 n X c., N 0 Ull) 2) 0 3 (CH 2 X cl y 0 1) MC-COOV 2) SOC1 2/Pyr 3) PPh 3 /pyr 1 0 (11) i i i i i The compounds IV, V and V1 and the compounds Z-Q are known compounds or can be obtained from known compounds by methods known per se.

The compounds of the invention and their acceptable salts display antibacterial activity against gram-positive and gram-negative bacteria, such as Staphylococcus aureus, Streptococcus pyrogene, Enterobacteriacee and Hemophylus influenzae, ranging from <0.01 to 50 f Iml and in vivo activity, for instance against Staphylococcus aureus, with ED so from 0.2 to 20 mg/Kg following parenteral or oral administration to humans and animals.

Owinc to their hiah antibacterial activity, the compounds of the invention are thus useful, for example in the treatment of respiratory tract infections such aE bronchJtis, bronchopneumonia, pleuritis, hepatobiliary and abdominal infections and septicemia: in the treatment of urinary tract infections such as pyelonephritis and cystitis: in the- treatment of obstetrical and gynecological infections such as cervicitis and endometritis; and in the treatment of ear, nose and throat infections such as otitis, sinusitis and parotitis.

The compounds of the invention may be administered, either to humans or to other animals, in a variety of dosage forms, for example, orally in the form of tablets, capsules, drops or syrups: rectally in the form of suppositories; parenterally, for example intravenously or intramusculary (as solutions or suspensions), with intraveneous administration being preferred in emergency situations; by inhalation in the form of aerosols or solutions for nebulizers; intravaginally, for example in the form of boucies: or topically in the form of lotions, creams and ointments. The pharmaceutical or veterinary compositions containing the compounds of the invention, which compositions are also within the scope of the invention, way be prepared in a conventional way employing conventional carriers or diluents, such as those for cephalosporins.

Such carriers or diluents are, for example, water, gelatine, lactose, starches, magnesium stearate, talc, vegetable oils, cellulose and the like. Daily doses in the range of about 0.5 to about 100 mg per kg of body weight may be used, in various animal species, the exact dose depending on the.age, weight and condition I i j 1 1 i 1 i i of the subject to be treated and on the frequency and route of administration.

A preferred route of administration of the compounds of the invention is the parenteral one. In this case the compounds may be administered, for example to adult humans, in anamount ranging from about 250 mg to about 100 mg pro dose, preferably about 500 mg pro dose, 1 to 4 times a day, dissolved in a suitable solvent, such as sterile water or lidocaine hydrochloride solution for intramuscular injections, and sterile water, physiological saline solution, dextrose solution or the conventional intravenous fluids or electrolytes, for intravenous injections.

Another preferred route of administration of the compounds of the invention L is the oral one, In this case, they are used as tablets or gelatine capsules that contain the active compound together with diluents for example lactose, dextrose, sucrose, mannitol, sorbitol, celllose and/or glycine, and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol; tablets also contain binders, for example magnesium aluminium silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures or adsorbents, colourings, flavourings or sweeteners.

Furthermore, the compounds of the invention may be used as antibacterial agents in a prophylactic manner, for example in cleaning or as surface disinfecting compositions. For this purpose a concentration of about 0.2 to 1% by weight of such compounds admixed with, - 16 suspended in or dissolved in conventional inert dry or aqueous carriers for application by washing or spraying is suitable.

Example 1 (SR)-6S-(1R-Hydroxvethvl-2-(5-methyl-2-]2yridyl)-penemcarboxylate Method A A solution of 3.2g of 3S-(1R-hydroxyethyl)-4R-(5-methyl-2- -pyridylcarbonylthio)-1[allyloxycarbonyl (triphenylphosphoranylidene)methyll-azetidin-2-one in ml of toluene was refluxed for 3 hours; the solvent was then removed and the residue passed through a silica column, using ethyl acetate and hexane as eluents.

There was obtained 1.63g of allyl (5R)-6S-(lR -hydroxyethyl)-2(5-methyl-2-pyridyl) -penem-3-carboxyl'ate as an oil.

IR: v max (CH Cl 3 1790,1710 cm -1 To the 880 mg of the above product in 100 ml of a 1:1 by volume tetrahydrofuran:dichloromethane mixture, 160 mg of triphenylphosphine was added. 450 mg of sodium 2-ethylhexanoate and 300 mg of tetrakis- triphenylphosphine Pd (0) were then added simultaneously. After 15 minutes stirring, the crude product was precipitated by dilution of the reaction mixture with diethyl ether." The solid was collected by centrifugation and purified by reverse phase chromatography (Lichroprep RP-18 Merck) eluting first with the water and then with water: acetone (9:1 by volume). 'Merck' is a Trade Mark. The appropriate fractions were combined and freeze-dried to obtain 450 mg of the title product as its sodium salt.

IR: v max (KBr) 1750,1600 cm -.L A Method B A solution of 400 mg of allyl (SR)-6S-(1R-hydroxyethyl)-2-(5-methyl-2- pyridyl)-penem-3-carboxylate in 20 M1 dichloromethane: tetrahydrofuran containing 2 ml of acetic acid was treated with 300 mg of triphenyl phosphine an.d 300 mg of tetrakis-triphenylphosphine Pd(O). After 15 minutes stirring, the solution was diluted with diethyl ether and the precipitate was collected by centrifugation. The crude product was purified by reverse phase chromatography (Lichroprep RP-18 Merck) eluting with water acetone mixtures. The collected fractions were evaporated in vacuo until crystallisation occurred." The precipitate was collected by filtration obtaining the penem acid as a white powder (150 mg).

Example 2

Sodiurr, (SR)-6S-(1R-hydroxyethyl)-2-(5-butvl--2-pyridyl)=penem-3carboxylate A solution of 9.76 9 of thiofusaric acid in 50 ml of 1N sodium hydroxide solution was added dropwise at room temperature to a solution of 7.2 9 of 3R-(t-butyldimethylsilyloxyethyl)-4R-acetoxy-azetidin-2-one in 100 ml of a water: acetone mixture. A small excess of sodium hydroxide was added in order to maintain the solution close to a pH of 8.5 and the mixture was stirred at room temperature for one hour. The acetone was removed in vacuo and the aqueous solution was extracted with methylene dichloride. The organic phases were dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was chromatocraphed over silica gel, eluting with ethyl acetate: hexane mixtures yielding 2.8 9 of 3S-[lR-(tbutyldimethyisilyloxyethyl)1-4R-(fusarylthio)-azetidin-2-one.

To a solution of the above product in 30 ml of dry toluene and 30 mI of dimethylformamide, 1.44 9 of allyl glyoxylate was added. After addition of f reshly dried molecular sieve, the mixture was stirred for 15 hours at room temperature and then for 2 hours at 500C. The molecular i 1 -issieve was filtered off and washed with toluene. The combined liquids were concentrated in vacuo. The crude mixture containing 2-(3S-[1R-(tbutyldimethylsilyloxyethyl)1-4R-(fusarylthio)-2-oxo-l-azetidinyl)-2-hydroxyacetic acid allyl ester was dissolved in dry tetrahydrofuran. The solution was cooled to 10C and 0.43 ml of pyridine and 0.44 ml of thionyl chloride were sequentially added. After 30 minutes, the suspension was filtered on a celite bed and the celite carefully washed with two portions of dry tetrahydrofuran. The combined filtrates were evaporated in vaduo to yield 2-(3S-ElR-(t-butyldimethylsilyloxyethyl)1-4R-(fusarylthio)-2-oxo-lazetidinyl)-2-chloroacetic acid allyl ester as a crude oil.

The crude product was dissolved in tetrahydrofuran and 2.8 g of triphenylphosphine was added. 20 g of silica ael was then added and the suspension was concentrated in vacuo to a mobile powder. The powder was allowed to stand overnight and then poured on the top of a chromatographic column, thus eluting 2-(3S-EIR-(tbutyldimethylsilyloxyethyl)l-4-fusarylthio-2-oxo-l-azetidinyl)-2triphenylphosphoranylidene-acetic acid allyl ester (2.5 g).

A catalytic amount of hydroquinone was added to a solution of 1 g of the above product in 50 ml of toluene and the mixture was stirred for 4 hours at 1OCC. The sovlent was removed ' in vacuo and the residue was chromatographed over silica gel, eluting with ethyl acetate: hexane mixtures, to obtain (SR)-6S-[1R-(t-butyldimethylsilyloxyethyl)1-2-(5butyl2-pyridyl)-penem-3-carboxylic acid allyl ester (0.41 g).

Tetrabutylammonium fluoride (1.3 g) was added to a solution of 0.41 g of the above product in tetrahydrofuran. 0.83 ml of acetic acid was then added. The mixture was stirred at room temperature overnight, diluted with ethyl acetate, 1 i i i i i i i i and washed with water, saturated sodium bicarbonate solution and water again. After removing the solvent, the residue was purified by silica gel preparative thin layer chromatography eluting with cyclohexane: ethyl acetate mixtures. 180 mg of allyl (SR)-6S-(1R-hydroxyethyl)-2-(5-butyl-2- pyridyl)-penem-3-carboxylate were obtained. Cleavage of the allyl ester by operating as described in Examplelyielded 50 mg of the title compound.

IR v max (KBr) cm-1: 1760, 1620.

Example 3 operating as described in Example 2, but substituting the appropriate (substituted pyridine) thiocarboxylic acid for thiolusaric acid, the following compounds were prepared:

Potassium (SR)-6S-(1R-hydroxyethyl)-2-(5-fluoromethyl-2pyridyl)-penem-3carboxylate., (SR)-6S-(1R-hydroxyethyl)-2-(5-methoxy-3-methyl-4-pyridyl)-penem-3carboxylic acid; (SR,65)-6-(1R-hydroxyethyl)-2-(5-amino-2-pyridyl)-penem-3-carboxylic acid:

Sodium (SR,6S)-6-(1R-hydroxyethyl)-2-(5-hydroxy-2-pyridyl)-penem-3carboxylate., Sodium (SR,6S)-6-(1R-hydroxyethyl)-2-(6-hydroxy-2-pyridyl)-penem-3- carboxylate; Sodium (SR,6S)-6-(1R-hydroxyethyl)-2-(5-carbamoyl-2lpyridyl)-penem-3carboxylate; Sodium (SR,6S)-6-(1R-hydroxyethyl)-2-(6-carbamoyl-2pyridyl)-penem-3- carboxylete:

(SR,6S)-6-(1P.-.nydroxyethyl)-2-(5-aminomethyl-2-pyridy!) penem-3carboxyl.-L'-- acid; (SR,6S)-6-(1R-hydroxyethyl)-2-(_6-aminomethyl-2-pyridyl)penem-3carboxylic acid; v Sodium (5R,6S)-6-(IR-hydroxyethy)-2-(5-hydroxymethyl-2-pyridyl)-penem-3carboxylate., Sodium (SR,6S)-6-(1R-hydroxyethyl)-2-(6-carbamoyloxymethyl-2-pyridyl)penem-3-carboxylate:

Sodium (SR,6S)-6-(1R-hydroxyethyl)-2-(5-methyl-6-hydroxy 3-pyridyl)-penem3-carboxylate; Sodium (SR,6S)-6-(1R-hydroxyethyl)-2-(4-hydroxy-5-methyl-3 -pyridyl)-penem-3-carboxylate; Sodium (5R,6S)-6-(1R-hydroxyethyl)-2-(4methyl-S-hydroxy- -3:.-pyridyl)-penem-3-carboxylate:

(SR)-6S-(1R-hydroxyethyl)-2-(6-ethyl-2-pyridyl)-penem-3- -carboxylic acid; (SR)-6S-(1R-hydroxyethyl)-2-(5-ethyl-2-pyridyl)-penem-3- -carboxylic acid; Sodium (SR)-6S-(1R-hydroxyethyl)-2-(6-isopropyl-2-pyridyl)-penem-3-carboxylate; Sodium (SR)-6S-(1R-hydroxyethyl)-2-(5-isopropyl-2pyridyl)- -penem-3-carboxylate; Sodium (SR)-6S-(1R-hydroxyethyl)-2-(5-methyl-2- pyridyl)- -penem-3-carboxylate; Sodium (SR)-6S-(1R-hydroxyethyl)-2-(5,6-dihydroxy-3pyridyl)-penem-3-carboxylate; (SR)-65-(1R-hydroxyethyl,)-2-(5-chloro-2pyridyl)-penem- -carboxylic acid; Potassium (SR)-6S-(1R-hydroxyethyl)-2-(5-nitro-2- pyridyl) -penem-3-carboxylate; Potassium-(SR)-6S-(1R-hydroxyethyl)-2-(6- hydroxymethyl-2-pyridyl)-penem-3-carboxylate; (5R)-6S-(IR-hydroxyethyl)-2-(6-amino-2pyridyl)-penem-3-carboxylic acid. (SR)-6S-(1R-hydroxyethyl)-2-(5sulphamoyl-2-pyridyl)-penem(SR)-6S-(1R-hydroxyethyl)-2-(4-methyl-6-ethyl-2-pyridyl) -penem-3carboxylic acid; Sodium (SR)-6S-(1R-hydroxyethyl)-2-(5-isopropyl-2-pyridyl- -penem-3-carboxylate; and Sodium (SR)-6S-(1R-hydroxyethyl)-2-(3-phenoxy-2- pyridyl)-_ -penem-3-carboxylate.

i i i i 1 i i i i i i i i i i i 1 Example 4 (SR)-6s-(1R-hydroxyethyl)-2-(6-carbamoyl-L-pyridyl)-penem3-carboxylic acid To a solution of 1 g of allyl (SR,6S)-6-(1R-hydroxyethyl) dichloromethane tetrahydrofuran containing 2 ml of acetic acid, there were added 300 mg of triphenylphosphine and 300 mg of tetrakis-triphenylphosphine Pd(O). After stirring for 10 minutes, the solution was diluted with diethyl ether and the precipitate was collected by centrifugation. The crude product was purified by reverse phase chromatography (Lichroprep RP-18 Merck.) eluting with water: acetone mixtures. The collected fractions were freeze-dried to obtain 100 mg of the title compound UVXmax (H 2 0)nm.: 266, 350 IR vmax (KBr)cm- 1: 1760, 1675, 1600 NMR 6 (D 2 0)ppm: 8.67(5,1H); 8.04(m,2H); 5.88(d,J=1.7Hz, 1H)-, 4.31' (dq, J=5.9, 64Hz, 1H)., 4.07 (dd, J=1.7,5.9,1H); 1.35 (d, J=6.4Hz,3H).

a Example 5

Sodium (SR)-65-(IR-hydroxyeth 1)-2-(6-ethyl-3-pyridyl)_penem-3-carboxylate 6. 1 g of the silver salt of 3S-(1Rhydroxyethyl)-4Rmercapto-l[allyloxycarbonyl-(triphenylphosphoranylid ene)- methyl]-azetidin-2-one were dissolved in 250 M1 of dichloromethane. To the above solution, 3.6 9 of 6-ethyl-nicotinoyl chloride in dichloromethane were added. After 20 minutes the suspension was filtered on a celite bed. The filtrate was e-i.apcrated in vacuo and the crude product was purified by column chromatography eluting with ethyl acetate: hexane mixtures. The appropriate fractions were combined and evaporated in vacuo. to give 3.5 g of 3s-(1R-hydroxyethyl)-4R-(6-e-thylnicotinoylthio)-1-[allyloxycarbonyl-(triphenylphosphoranylidene)methyllazetidin-2-one operating as described in Example 1, Met-hod A the above compound was transformed in the title compound, obtaining 400 mg as sodium salt.

IR v max(KBr)cm-1: 1760, 1600 UV-.X max(H 2 C))nm: 264, 328 Example 6

Operating as indicated in Example 5, but using. the appropriate chlorocarbonylpyridone, there were obtained: Potassium (5R)-6S-(1Rhydroxyethyl)-2-(2-fluoromethyl-4-pyridyl)-penem-r3-carboxylate; Potassium (SR)-6S-(1R-hydroxyethyl)-2-(4-fluoromethyl-3,-pyridyl)-penem-3carboxylate; Potassium (5R)-6S-(1R-hydroxyethyl)-2-(6-fluoromethyl-3,pyridyl)-penem-3-carboxylate; Potassium (5R)-6S-(1R-hydroxyethyl)-2-(5fluoromethyl-3-pyridyl)-penem-3-carboxylate; (SR)-6S-(1R-hydroxyethyl)-2(5-ethyl-3-pyridyl)-penem-3-carboxylic acid; Sodium (5R)-6-Q-(1Rhvdroxyethyl)-2-(6-isopropyI -3-pyridyl)-penem-3-carboxylate; Sodium (5R)6S-(1R-hydroxyethyl)-2-(5-isopropyl-3-pyridyl) -penem-3-carboxylate; and Sodium (SR)-6S-(1R-hydroxyethyl)-2-(5-methyl-3-pyridyl)-penem-3carboxylate.

Example 7 (S-Methyl-2-oxo-1,3-dioxolen-4-yl)methvI (SR)-6S-UR-hydroxyethyl)-2-(3-pyridyl)-penem-3-carboxylate. To a solution of 2.19 g of 3S-[1R-(t-butyldimethylsilyloxyethyl)1-4R-(nicotinoylthio)azetidin -2-one in anhydrous methylene chloride at CC, 0.6 9 of calcium carbonate, 1.12 ml of oxalyl chloride and 2.23 ml of N,N-diisopropyl_ ethylamine were added sequentially. The mixture was stirred for 10 minutes at CC. The i i i I i i i i i :I 1 1

i i i 1 1 i 1 1 1 suspension was filtered and the filtrate was washed twice with brine, dried over anhydrous sodium sulphate and evaporated in vacuo yielding 2.1 9 of crude 35-(1R-t-butyldimethylsilyloxyethyl)-4R-(nicotinoylthic)-1- [(hydroxycarbonyl)methyll-azetidin-2-one as an oil. The above product was dissolved in 50 ml of dimethylformamide. 0.6 of sodium bicarbonate ' and 1.54 g of 4-bromomethyl-S-methyl -2-oxo-1, 3-dioxolen were added and the mixture was stirred for 1 hour at room temperature. The solution was then partitioned between toluene and water. The organic phase was washed twice with water, dried over anhydrous sodium sulphate and adjusted. to a volume of 20 ril". A sample oJ-1-7 this compound was isolated for analytical purposes.

IR(CHCl 3) v max: 1820, 1760, 1725, 1680 (br).

To the above solution 1. 75 ml of a solution of triethylphosphite in 5 M1 toluene were added. The solution was then refluxed overnight. The crude reaction mixture was purified by column chromotography eluting with ethyl acetate/hexane mixtures.

By collecting the appropriate fractions 1.1 9 of (5-methyl dimethylsilyloxyethyl)1-2-(3-pyridyl)penem-3--carboxylete were obtained.

IR(CHCl 3) v max cm- 1820, 1785, 1705 0 The solution of the above product in 10 ml of tetrahydrofuran was stirred overnight in the presence of 1.28 ml of acetic acid and of 2.01 9 of tetrabutyl ammonium fluoride. The solution was then evaporated in vacuo a n d t h e oily residue partitioned between ethyl acetate and water. The organic phase was evaporated in vacuo and the residue purified by column chromatography eluting with an ethyl acetate: hexane mixture. There was obtained 0.5 g of the title product.

IR(CHCl 3) v max cm-1: 3600, 1820, 1790, 1705 uv (CH 3 OW). max nm: 340 Example 8

1-(Methoxycarbonyloxy)ethyl"(SR)-6S-(1R-hydroxyethyl)-2-(6-fluoromethyl-3-pyridyl)-penem-3-carboxylate To a stirred and cooled (-20C) solution of 500 mg of sodium (SR)-6S-(1R-hydroxyethyl)-2-(6-fluoromethyl-3-pyridyl)-penem-3-carboxylate in 20 ml of dimethylformamide and 10 ml of acetonitrile, 410 mg of 1-(methoxycarbonyloxy) ethyl bromide were added. The solution was allowed to stand overnight at -20C and then poured into a water ethyl acetate mixture. The orcanic lave.r was separated off and washed twice with brine. The washings were discarded and the ethyl acetate phase was dried over anhydrous sodium sulphate and evaporated in vacuo. The oily residue was passed through a short silica gel column eluting with ethyl acetate: hexane mixtures. The appropriate fractions were collected and evaporated in vacuo to give the-title product (290 mg).

IR v max (film): 178b(sh), 1750(sh), 1720(sh)cm-1.

i i i i j 1 i j 1 X - 1

Claims

1. Any one of the following compounds:

(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl (SR)-6S-(lR hydroxyethyl-2-(3-pyridyl)-penem-3 -carboxylate, 1-(methoxycarbonyloxy)-ethyl (SR)-6S-(1R-hydroxyethyl)-2 (6"fluoromethyl-3-pyridyl)-penem-3-carboxylate, potassium (SR)-6S-(1R-hydroxyethyl)-2-(2-fluoromethyl-4-pyridyl)-penem-3-carboxylate, potassium (SR)-65-(1R-hydroxyethyl)-2-(4-fluoromet hyl-3 -pyridyl)-penem-3-carboxylate, potassium (SR)-6s-(1R-hydroxyethyl)-2-(6-fluoromethyl-3-pyridyl)-penem-3-carboxylate,.

potassium (SR)-6S-(1R-hydroxyethyl)-2-(5-fluoromethyl-3-pyridyl)-penem----carboxylate, sodium (SR)-6S-(IR-hydroxyethyl)-2-(2-piperidinocarbonyl- sodium. - (SR) 6S-(1R-hydroxyethyl)-2-(3-dimethylsulphamoyl(SR)-65-(1R-hydroxyethyl)-2-(6-carbamoyl-3-(pyridyl)-penem(SR)-65-(1R-hydroxyethyl)-2-(6-ethyl-3-pyridyl)-penem-3- -carboxylic acid, (SR)-6S-(1R-hydroxyethyl)-2-(5-ethyl-3-pyridyl)-penem-3- -carboxyli.c acid, sodium (SR)-6S-(1R-hydroxyethyl)-2-(6-isopropyl-3-pyridyl -penem-3-carboxylate, sodium (SR)-6S-(1R-hydroxyethyl)-2-(5-isopropyl-3-pyridyl -penem-3-carboxylate, and sodium (SR)-6S-(ILR-hydroxvethyl)-2-(5-methyl-3-pyridyl)-penem-3-carboxylate.

1 2.

A penem derivative having the general formula I R 1 0 (CH 2) D-X Y R 2 (1) wherein R 1 represents an alkyl group having f rom 1 to 3 carbon atoms, optionally substituted by one or more free or prcte=ted hydrcxy groups c. r halogen atoms, R 2 represents a carboxy group, an esterified carboxy group or a carboxylate anion; n is 0, 1, 2 or 3; Y represents an atom or group selected from (a) a hydrogen atom, (b) an alkyl group having from 1 to 4 carbon atoms, (c) a halocen atom or a cyano group, (d) a hydroxy, mercapto or amino group, each of which may be in a free or protected form, (e) an alkoxy, alkylthio or alkylamino group, each having from 1 to 4 carbon atoms, or a dialkylamino group in which each alkyl' group has from 1 toA carbon atoms, (f) an optionally substitued aryloxy, arylthio or arylamino group, (g) an alkoxycarbonyl group having from 2 to 5 carbon atoms, (h) a nitro group; t.) an acyloxy, acylthlo or acylamino group, each having from 1 to 4 carbon atoms, (1) a carbamoyloxy, carbamoylthio or ureido group, (m) an aminocarbonyl group of the general formula R 3 R 4 N.COwherein either each of R 3 and R 4. independently represents a hydrogen atom, a straight chain or branched chain alkyl group having from 1 to 4 carbon atoms, an aralkyl group i 1 i i 1 i i 1 having f rom 7 to 11 carbon atoms or an aryl group, or R 3 and R 4 together with the nitrogen atom to which they are bonded represent an optionally substituted saturated or unsaturated heteromonocyclic or heterobicyclic group having from 4 to 8 ring atoms which may include oxygen and/or sulphur and/or further nitrogen atoms, and (n) an aminosulphinyl group of the general formula R 3 R 4 N.50or a sulphamoyl group of the general formula R 3 R 4. so 2 wherein R 3 and R 4 are as defined above, and X represents an atom or group selected from those listed in (b) to (n) above if n is 0 or in (c) to (n):E n is areater than 0, with the proviso that when the pyridyl moiety is a 3-pyridyl or 4- pyridy! moiety, then Y does not represent a hydrogen atom and X and Y do not simultaneously represent chlorine atoms.

3. A penem de-rivative according to claim 2 in which R 1 represents an ahydr6xyethyl group.

4. A penem derivative according to claim 2 or claim 3 in which n is 0, 1, 2 or 3; Y represents an atom or group selected from a') a hydrogen atom, bl) an alkyl group having from 1 to 4 carbon atoms, c,) a halogen atom, preferably a fluorine or chlorine atom, d') a hydroxy, mercapto or amino group, el) a methoxy, ethoxy, methylthio, ethylthio, methylamino, dimethylaminoor ethylamino group, f 1) a phenoxy, phenylthio, phenylamino group in which the phenyl ring is unsubstituted or is substituted by an amino, hydroxy, methoxy, acetoxy, carboxy, carbamoyl or carbamoyloxy group, 91) a methoxycarbonyl or ethoxycarbonyl g:oup, h,) a nitro group, 7 1 il) an acetoxy, acetylthio or acetamido group, I') a carbamoyloxy or ureido group m&) a carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, 1-pyrrolidinylcarbonyl or piperidinocarbonyl group; and n') an aminosulphinyl, methylaminosulphinyl, dimethylaminosulphinyl, sulphamoyl, methylsulphamoyl, dime thyl sulphamoyl, ethyIsulphamoyl, diethylsulphamoyl, 1-pyrrolidinylsulphonyl or piperidinosulphonyl group; X represents an atom or group selected from those listed in (bl) to (n') above if nis Oorin (cl) to (nI) above if n is greater than 0, "and R 2 represents sodium. or potassium carboxyllate; or when the pyridine nitrogen atom is protonated its carboxylate cour;-Lerpa--t; or a carboxy group; or an esterified carboxy group of the general formula -COOZ wherein Z is selected from acetoxymethyl, pivaloyloxymethyl, propionoxymethyl, cyclohexylacetoxy- methy'L, cyclohexylcarbonyloxymethyl, benzoyloxymethyl or 2 z-acetoxvbenzoyloxymethyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, i-propoxycarbonyloxymethyl, cyclohexylmethoxycarbonyloxymethyl, 1-(methoxycarbonyloxy) -ethyl, 1-(ethoxycarbonyloxy)-ethyl, 3-phthalidyl, 2-oxo -1,3-dioxolan-4-yl, 5-methyl-2-oxo-1,3-dioxolen-4-yl- -methyl, 5-phenyl-2-oxo-1,3-dioxolen-4-yl-met.hyl, ethoxy carbonyl- methyl and 2-oxotetrahydrofuran-S-yl groups, with the proviso that when the pyridyl moiety is a 3 -pyridyl or 4-pyridyl moiety, then Y does not represent a hydrogen atom and X and Y do not simultaneously represent chlorine atoms.

E.

Any one of the fo.Low.-Lno compounds according to claim 2: (SR)-6S-(1Rhydroxyethyl)-2-(5-methyl-2-pyridyl)-penem-3-carboxylic acid, (SR)-6s-(1Rhydroxyethyl)-2-(5-fluoromethyl-2-pyridyl)penem-3-carboxylic acid, 1 1 1 i 1 i i i i i t (SR)-6S-(1R-hydroxyethyl)-2-(5-rnethoxy-3-methyl-4-pyridyl) penem-3- carboxylic acid, (SR)-6S-(IR-hydroxyethyl)-2-(5-amino-2-pyridyl)-penem-3- carboxylic acid,(SR)-6S-(1R-hydroxyethyl)-2-(5-hydroxy-2-pyridyl)-penem- 3carboxylic acid, (SR)-6s-(1R-hydroxyethyl)-2-(6-hydroxy-2-pyridyl)-penem- 3carboxylic acid, (SR)-6S-(1R-hydroxyethyl)-2-(5-carbamoyl-2-pyridyl)penem3-carboxylic acid, (SR)-6S-(1R-hydroxyethyl)-2-(6-carbamoyl-2pyridyl)-penem3-carboxylic acid, (SR)-6S-(!R-hydroxyethyl)-2-(5aminomethyl-2-pyridyl)-penem-3-carboxylicacid, (SR)-6S-(1R-hydroxyethyl)2-(6-aminomethyl-2-pyridyl)-penem-3-carboxylic acid, (SR)-6S-(1Rhydroxyethyl)-2-(5-hydroxymethyl-2-pyridyl) -penem-3-carboxylic acid, (5R)-6S-(1R-hydroxyethyl)-2-(6-carbamoyloxymethyl-2-pyridyl)-penem-3carboxylic acid, (SR)-6s-(1R-hydroxyethyl)-2-(5-methyl-6-hydroxy-3pyridyl)-' penem-3-carboxylic acid, (5R)-6S-(1R-hydroxyethyl)-2-(4hydroxy-5-methyl-2-pyridyl)penem-3-carboxylic acid, (SR)-6S-(1Rhydroxyethyl)-2-(4-methyl-5-hydroxy-3-pyridyl)penem-3-carboxylic acid, (SR)-6S-(1R-hydroxyethyl)-2-(6-ethyl-2-pyridyl)-penem-3-carboxylic acid, (SR)-6S-(1R-hyroxyethyl)-2-(5-ethyl-2-pyridyl)-penem-3-carboxylic acid, (SR)-6S-(!R-hydroxyethyl)-2-(6-isopropyl-2-pyridyl)-penem3-carboxylic acid, (SR)-6S-(1R-hydroxyethyl)-2-(5-isopropyl-2-pyridyl)-penem3carboxylic acid, (5R)-6S-(1R-hydroxyethyl)-2-(5-methyl-2-pyridyl)-penem-3carboxylic acid, i (SR)-6S-(1R-hydroxyethyl)-2-(5,6-dihydroxy-3-pyridyl)-penem-3-carboxylic acid, (SR)-6S-(1R-hydroxyethyl)-2-(5-chloro-2-pyridyl)-penem-3-carboxylic acid, (SR)-6S-(1R-hydroxyethyl)-2-(3-fluoro-2-pyridyl)-penem-3-carboxylic acid, (SR)-6S-(1R-hydroxyethyl)-2-(5-nitro-2-pyridyl)-penem-3-carboxylic acid, (SR)-6S-(1R-hydroxyethyl)-2-(6-hydroxymethyl-2-pyridyl)-penem-3earboxylic acid, (SR)-6S-(1R-hydroxyethyl)-2-(6-amino-2-pyridyl)-penem-3carboxylic acid, (SR)-6S-(1R-hydroxyethyl)-2-(5-sulpl,--&amoyl-2-pyridyl)penem-3-carboxylic acid, (SR)-6s-(1R-hydroxyethyl)-2-(4-methyl-6-ethyl-2pyridyl)-penem-3-carboxylic acid, (5R)-6S-(1R-hydroxyethyl)-2-(5isopropyl-2-pyridyl)-penem-3-carboxylic acid, and (SR)-6S-(1Rhydroxyethyl)-2-(3-phenoxy-2-pyridyl)-penem-3-carboxylic acid.

6. A process f or the preparation of a compound of the general formula 1, the process comprising cyclizing a compound of the general formula II or III (CH 2) n-x S y I pph 3 COOZ, i (11) 1 R 1 - )_ N %, C00z 5 (CH 2)n-x S Y N W (111) 1 wherein R ' X, Y and n are as def ined in claim 2, Ph represents a phenyl group, Z1 represents a carboxy protecting group or a croup 2 as defined in claim 4, and W represents an oxygen or sulphur atom; and, if desired, removing any protecting groups present; and.if desired, converting the resultant compound of the general formula 1 wherein R 2 represents a free carboxy group, or salt thereof, into a compound of the general formula 1 wherein R 2 is an in vivo hydrolyzable esterified carboxy group COOZ wherein Z is as defined in claim 4.

7. A process according to claim 6 in which a compound of the general formula:11 is cyclised by heating it in an inert organic solvent at reflux or near-to-reflux temperatures.

8. A process according to claim 6 in which a compound of the general formula Ill is cyclised by treatment with trimethylphosphite or triethyl phosphite in an inert organic solvent.

9. A pharmaceutical or veterinary composition comprising a penem derivative according to any of claims 1 to 5 or a pharmaceutically or veter inarily acceptable salt or ester prodrug thereof in admixture with a pharmaceutically or veterinarily acceptable diluent or carrier.

Pued 1MB at The Patent Olnoe, State House, 86 71 Sigh Holborn. London WC1R 4Tp. Further copies be obtained from The Patent Office. Oalat Branch, St Mary Cray, Orpington, Xent EM 3RD. Printed by Mult1Plex techniques ltd, St Mary Cray. Kent. Con. 1187.