GB2154238A

GB2154238A - 2 Imidomethyl-penem derivatives

Info

Publication number: GB2154238A
Application number: GB08507268A
Authority: GB
Inventors: Marco Alpegiani; Ettore Perrone; Giovanni Franceschi
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1984-03-22
Filing date: 1985-03-20
Publication date: 1985-09-04
Also published as: JPS60209587A; DE3510272A1; BE901974A; GB8507268D0; GB8407419D0; GB2154238B

Abstract

2-Imidomethyl-penems of the formula I:- <IMAGE> (R1 = H, C1-C3 alkyl optionally substituted by 1 or more free or protected OH groups, X=O or NH, <IMAGE> = a monocyclic or bicyclic, saturated or unsaturated heterocyclic ring, optionally substituted (but not unsubstituted phthalimido) and R2 = H or a pharmaceutically acceptable organic or inorganic salt or ester forming moeity) and, where appropriate, their pharmaceutically acceptable salts including internal salts are potent, broad-spectrum antibacterial agents. They may be prepared by condensation of the corresponding 2-hydroxymethyl-penem with an appropriate imide, suitably in an inert aprotic solvent in the presence of a trivalent phosphorus compound and an azodicarboxylic acid diester.

Description

SPECIFICATION 2-lmidomethyl-penem derivatives The invention relates to 2-imidomethyl-penem derivatives, to a process for their preparation and to pharmaceutical and veterinary compositions containing them.

The invention provides 2-imidomethyl-penem derivatives having the general formula I

wherein R1 represents a hydrogen atom or a straight chain or branched chain alkyl group having from 1 to 3 carbon atoms and being unsubstituted or substituted by one or more free or protected hydroxy groups; X represents an oxygen atom or an imido group; the group

represents a monocyclic or bicyclic, saturated or unsaturated heterocyclic ring, unsubstituted or substituted by one or more equal or different substituents selected from (a) an oxo group, a cyano group, a nitro group or a halogen atom, (b) a group of the formula -NR3R4, -COOR3, -CONR3Ra -CONR3R4,

= N-OR3,-N=CHR4, -COR4 or -OR3 wherein P3 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms and R4 represents a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms or a phenyl, furyl, thienyl or pyridyl group, and (c) a straight chain or branched chain alkyl or alkenyl group unsubstituted or substituted by one or more of the substituents defined in (a) and (b) above with the proviso that the group

does not represent an unsubstituted phthalimido group, and R2 represents a hydrogen atom, an organic or inorganic cation forming with the penem carboxylate moiety a pharmaceutically or veterinarily acceptable salt, or an organic group forming with the penem carboxylic moiety a chemically or physiologically cleavable ester.

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

When a basic group is present, the invention also includes the pharmaceutically acceptable acid addition salts, i.e. salts with a mineral acid such as hydrochloric acid or with a carboxylic acid such as acetic acid, or inner salts (zwitterions) thereof; when an acid group is present, the invention also includes the pharmaceutically acceptable salts thereof, i.e. salts with inorganic bases such as Na-or K6 salts or with pharmaceutically acceptable organic bases such as lysine and procaine.

Preferred compounds of the general formula I are those wherein R1 represents a 1-hydroxyethyl group; X represents an oxygen atom; the group

represents one of the following heterocyclic rings

said rings being optionally substituted by one or more, and preferably one or two, equal or different substituents selected from (a') an oxo group (b') amino, methylamino, carboxy, carbamoyl, carbamoylxoy, acetamido, ureido, hydroxyimino, acetyl, acetoxy and hydroxy groups and groups of the formula

(c') a methyl or ethyl group optionally substituted by one or two of the substituents defined in (a') and (b') above; and R2 represents a hydrogen, sodium or potassium atom or an acetoxymethyl or (5-methyl-2-oxo-1,3-dioxolen- 4-yl)-methyl group.

Particularly preferred compounds are those having the general formula la

wherein R and G have the values given in Table 1. TABLE 1

Compound R G 1 Na -CH2-CH2 2 K -S-CH2 3 Na -NH-CO- // \\ 4 Na -N-N=CH NO2 2 -CH2 5 Na -NH-CH2 6 Na -NH-CH=CH 7 Na -NH-NH 8 (inner salt) -N-CH2 NH2 CH3 I 9 H -C-NH CH2NH2 10 (inner salt) -CH-CH2 NH2 11 Na -CH-CH2 COONa 12 Na -NH-C=CH COONa 13 Na -NH-C=CH I CH2COONa 14 Na -NH-CO-CH2 15 Na -NH-CO-CO 16 Na -NH-CH=C CH3 17 Na -N-CH=CH o 0 18 Na -NH-CH NHCONH2 19 (inner salt) -CH-CH2 I H3CN=C-N(CH3)2 20 Na -CH2-CH2-CH2 21 Na -CH2-NH-CH2 22 Na -O-CH2 CH3 I 23 Na -NH-C I CH3

Compound R G 24 Na -NH-CH I CH2COOH 25 Na CH2-C = C CH3 CH3 26 Na -NH-CH2-CH2 27 Na -NH-CH-CH2 I CH3 28 Na -NH-N=C I CH3 29 Na -NH ( oko 30 Na -NH-N=CH 31 Na -NH-CH=CF 32 Na -NH-C=CH I CON H2 The compounds of the general formula I are obtained, according to the invention, by condensing a carbinol of the general formula II.

wherein R1 and R2 are as defined above, or a protected derivative thereof, with a compound of the general formula Ill

wherein X and the group

are as defined above, or with a protected derivative thereof and, if necessary, by deblocking the protecting groups.This reaction may be carried out by treating the two reagents, dissolved in an inert aprotic solvent, with a trivalent phosphoros compound and an azodicarboxylic acid diester, or with a preformed complex of the two last reagents, at a temperature of from -80"C to about 40"C. A preferred aprotic solvent is tetrahydrofuran; a preferred phosphoros compound is triphenyl-phosphine; a preferred azodicarboxylic acid diester is diethyl azodicarboxylate; the preferred temperature range for conducting said condensation is between 0 C and 25"C.This method has been found to be invaluable for the preparation of the compounds of the general formula I, since other procedures which can be suggested by analogy with known perse processes (for example activation of the carbinol II through active esters thereof, such as mesylate or tosylates, or processes starting from a 4-acetoxyazetidinone and a substituted ethanethioic acid) give poor yields or no yield of the desired products. Intermediates of the general formula II have been described in our British Patent Specification No.2111496; compounds of the general formula Ill are known compounds or may be obtained from known compounds by known methods. The free acid penem compounds provided by the invention, and their salts, especially their sodium and potassium salts, have been found to be potent, broad-spectrum antibacterial agents in vitro.In particular, introduction of the heterocyclyl moiety into the 2-methylpenem framework has been found unexpectedly to improve the antibacterial activity intrinsically present in the latter. Table 2 shows the activity of a typical compound of the general formula I.

TABLE 2 In vitro activity of "Compound 6" M.l.C. (gimp) Staphylococcus aureus Smith 0.09 Staphylococcus aureus 209 P 0.045 Staphylococcus epidermidi FK 109 0.045 Sarcina lutea ATCC 9341 0.045 Streptococcus pyogenes ATCC 12384 0.18 Klebsiella aerogenes 1522 E 1.56 Klebsiella aerogenes 1082 E* 1.56 Klebsiella pneumoniaeATCC 10031 0.78 Enterobacter cloacae P 99* 6.26 Escherichia coli B 0.39 Escherichia coli B Cef R* 0.78 Escherichia coli 026:B6 0.39 Escherichia coli 026::B6 Cef R* 0.78 Escherichia coli R 6 KTem i* 1.56 Escherichia coli K 12 0.78 Escherichia coli G 227 0.19 Proteus morgani ATCC 25830 1.56 Citrobacterfreundi B 9 3.12 Providencia stuarti 5335/1 0.78 Providencia stuarti 5292/2 1.56 * p-lactamase producer Moreover, it has been found that the compounds are not highly bound to serum proteins and, when the group A contains a basic centre, such as an amino or an amidino group, they are also active against Pseudomas aeruginosa strains. When tested in vivo after parenteral administration, these compounds showed a high degree of therapeutic effectiveness in treating infections caused by both Gram-positive and Gram-negative bacteria, their toxicity being quite negligible. Moreover, especially in the form of zymatically labile esters, such as the acetoxymethyl ester, the compounds I were found effective when administered orally. Included within the invention are therefore pharmaceutical or veterinary compositions containing the compounds I and conventional carriers or diluents. These compositions may be in the form of solutions or suspensions for intravenous or intramuscular administration; tablets, capsules, drops or syrups for oral administration; suppositories for rectal administration; bougies for intravaginal administration; aerosols for inhalation; and lotions, creams and ointmentsfortopical treatment.

The following Examples illustrate the invention.

Example 1 Sodium (5R,6S)-6-(1R-hydroxyethyl)-2-succinimidomethyl-penem-3-carboxylate Step (a) 223 mg of triphenylphosphine and 131 pSl of diethyl azodicarboxylate were stirred at 0 C in 3 ml of dry distilled tetrahydrofuran. After 1 hour, the mixture was added to a solution of 300 mg of allyl 5R,6S)-6-(1R -t-butyl-dimethylsilyloxyethyl)-2-hydroxymethyl-penem-3-carboxylate and 99 mg of succinimide in the same solvent. After a few minutes at room temperature, ethyl acetate and water were added.The dried organic layer was filtered on a sept of silica packed with a cyclohexane:ethyl acetate mixture, to afford allyl (5R, 6S)-6-(1R-t-butydimethylsilyloxyethyl)-2-succinimidomethyl-penem-3-carboxylate as a syrup in nearly quantitative yield #max (film) 1770 and 1710 br cm-1; #(CDC1)3 (inter alia): 2.80 (4H, S, CH2CO), 3.70(1 (1H, dd, J = 1.8 and 4.5 Hz, H-6),4.76 (2H, centre of ABq, J = 16 Hz, CH2N), 5.5 (1H, d,J=1.8 Hz, H-5) ppm.

Step (b) A solution of the above compound in 4 ml of dry tetrahydrofuran was treated in sequence with 290 l of acetic acid and 500 mg of tetrabutylammonium fluoride trihydrate. After 20 hours standing at room temperature, the solvent was removed in vacuo and the residue purified by silica gel chromatography, thereby obtaining allyl (5R, 6S)-6-(1 R-hydroxyethyl)-2-succinimidomethyl-penem-3-carboxylate as a white powder, 210 mg (76.4%); m.p. 124-126 C; vmax (CHCl3 film) 3450, 1790 and 1705 cm-1; #(CDCl3) (inter alia) 2.80 (4H, s, CH2CO),3.70 H, H, dd, J=1 .8 and 6.5 Hz H-6),4.80 (2H, centre of ABq, J= 12 Hz,CH2N),5.55(1,d J=1.8 Hz, H-5) pp.

Step (c) 20 mg of triphenylphosphine and 20 mg of tetrakis(triphenylphosphine) palladium (0) were added to a solution of 200 mg of the material from step (b) in 2 ml of tetrahydrofuran and 2 ml of dichloromethane, soon followed by 100 mg of potassium ethylhexanoate. After 5 minutes stirring, the solvent was partially removed in vacuo and diethyl ether was added to precipitate a white powder, consisting of crude sodium (5R, 6S-6-(1 R-hydroxyethyl)-2-succinimidomethyl-penem-3-carboxylate.This product was purified by reversephase chromotography (Merck C-18 bed), eluting with water, and the appropriate fractions freeze-dried; Rf=0.68 (Merck kieselgel 60 F 254 silanisiert); CHCl3: MeOH: HCOOH 18:2:1); max (H2O) 306 nm; "max (KBr) 1770 and 1700cm-1; #(D2O) 1.30 (3H,d, CH3 -CH),2.85 (4H,s,CH2CO),3.90 (1H,dd, 1.8 and 6Hz, H-6),4.24 (1 H, m, CH3.CH.OH), 4.86 (2H, centre of ABq, J= 16Hz, CH2N),5.60 (1 H, d, J= 1.8 Hz, H-6) ppm.

Example 2 By using procedures similar to those described in Example 1, the following compound was obtained: Potassium (5R, 6S)-6-{1R-hydroxyethyl)-2-t2,4-dioxo-1,3-thiazolidin-3-yl -methyl)-penem-3-carboxylate (I, R1 = hydroxyethyl, R2=K, X=O, A= -S-CH2-) Starting materials: allyl (5R, 6S)-6-(1 R-t-butyl-dimethylsilyloxyethyl)-2-hydroxymethyl-penem-3-carboxylate and 2,4-thiazolidindione.

Step (a) I, R1 = CH (OSiME2But)CH3; R3 = allyl; X and A as above.

Yield: 91%; crystals, m.p. 137-138 C IR: ,'max (KBr) 1780, 1685 br cm- NMR: 3 (CDCl3,60 MHz) 0.07 (6H, s, SiMe2), 0.87 (9H, SiBut), 1.26 (3H, d, J= 6 Hz, CH2,CH), CH),3.65 (1 H, dd, J= 4 and #2 Hz, H-6), 3.97 (2H, s, COCH2S), 4.16(1 H, H, dq, J= 6 and 4 Hz, H-8), 4.50-4.90 (2H, m, CH2-CH=CH2),5.24 and 4.73 (2H, each d, J= 17 Hz, CH2N),5.0-5.30(1H, m

5.30-5.60 (1H, m,

5.60-6.20 (1 H, m, CH2-CH=CH2),5.50 (1 H, d, J # 2 Hz, H-5).

Step (b): I, R2= allyl; R1 X and A as in the title.

Yield: 76.3% white crystals, m.p. 135-137 C IR: Umax (KBr) 3420, 1790, 1735, 1710, 1660 cm-1 NMR: # (CDCl3, 60 MHz) 1.30 (3H, d, J= 6 Hz, CH3CH),3.70 (1 H, dd, J = 5 and # 2 Hz, H-6), 4.00 (2H, s, COCH2S), 4.13 (1 H, dq, J= 6 and 5 Hz, H-8), 4.4-5.0 (2H, m, CH3CH=CH2, 4.77 and 5.24 (2H, each d, CH2N), 5.15-5.4(1H, m,

5.4-5.6(1 H, m,

5.6-6.2 (1 H, m CH2CH=CH2), 5.7 (1 H, d, J# 2 Hz, H-5) Step (c): 1, R1, R2, X, A as in the title.

Reagent: potassium ethyl hexanoate instead of sodium ethyl hexanoate Yield: 88.1%; yellow powder IR: #max (KBR) 3400 br, 1765 br, 1675 br cm-1 NMR: #(D2O,60 MHz) 1.33 (3H, d, J= 6 Hz, CH3CH), 3.96(1 H, dd, J= Sand # and # 2Hz, H-6), 4.30 (2H, s, COCH2S), 4.0-4.4(1 H, m, H-8), 4.79 and 5.33 (2H, each d, J= 17 Hz, CH2N), 5.65 (1 H, d, J # 2 Hz, H-5) UV: #max (H2O) 306 nm ( = 4,850) Example 3 By using procedures similarto those described in Example 1, the following compound was obtained: Sodium (5R, 6S)-6-(1 R-hydroxyethyl)-2-(2,4,5-trioxo-imidazolidin-1 -yl-methyl)penem-3-carboxylate (I, P1 = 1 - hydroxyethyl, R2= Na, X=O,

Starting materials: allyl (5R,6S)-6-(1 R-t-butyl-dimethylsilyloxyethyl)-2-hydroxymethyl-penem-3-carboxylate and parabanic acid Step (a): I, R= CH(OSiMe2But)CH3; P2 = allyl; X and A as above; Yield: 59.2% (plus 28.1% of simmetrically disubstituted trioxoimidazole); white crystals, m.p.173-174 C IR: Vmax (KBr) 1785) sh, 1750 br, 1700 cm-1 NMR: 3 (CD3COCD3, 200 MHz): 0.08 (6H, s, SiMe2),0.88 (9H, s, SiBut),1.25 (3H, d, J = 6 Hz, CH3CH), 3.89 (1 H, dd, J= 3.6 and 1.8 Hz, H-6), 4.31(1H, dq, J= 6 and 3.6 Hz, H-8), 4.68 and 4.76 (2H, each ddt, J= 14.4,5.4 and 1.8 Hz, OCH2CH=CH2), 4.82 and 5.26 (2H, each d, J= 16.8 Hz, CH2N), 5.22(1 H, dq, J= 10.8 and 1.8 Hz,

5.46(1H,dq,J= 19 and 1.8 Hz,

5.71 (1 H, d, J= 1.8 Hz, H-5),5.98 H, ddt, J= 19, 10.8 and 5.4 Hz, CH2.CH=CH2 Step (b): I, R2 = allyl; X and A as in the title.

Yield: 60.6%; amorphous solid IR: Vmax (CHCl3) 1785, 1750, 1710 cm-1 NMR: #(CD3COCD3, 60 MHz) 1.30 (3H, d, J= 6 Hz, CH3CH), 3.85(1 H, dd, J= 7 and # 2), 4.15(1 H, m, H-8), 4.78 (2H, m, CH2.CH=CH2), 5.18 (2H, ABq, CH2N),5.2-5.75 (2H, m, CH2CH=CH2), 5.87 (1 H, d, J# 2, H-6), 5.8-6.3 (1 H, m, CH2CH=CH2) Step (c): I, R1, R2, X and A as in the title.

Yield: 45%, yellowish powder IR: #max (KBr) 1770 sh, 1750, 1700 cm-1 Example 4 By using procedures similar to those described in Example 1, the following compound was obtained: Sodium (5R,6S)-6-(1R-hydroxyethyl)-2- [1-/5-nitro-2-furfurylideneimino)-2,4-dioxo-imidazolidin-3-yl -methylj-penem-3-carboxylate (I, R1= l-hydroxyethyl; R2 =Na; X= O; A

Starting materials: allyl (5R,6S)-6-(1 R-t-butyl-dimethylsilyloxyethyl)-2-hydroxymethyl-penem-3-carboxylate and nitrofurantoine Step (a): I, R1 = CH(OSiMe2ButCH3; R2= allyl; X and A as above.

Yield: 80.7% (no chromatography needed; crystallization induced by adding diethyl ether); yellowish powder, m.p.230 C.

IR: vmaX (KBr) 1785,1725,1700,1575, 1520,1430,1345cm1 NMR: 8 (CDCl3, 200 MHz): 0.04 (6H, s, SiMe2), 0.85 (9H, s, SiBut), 1.19 (3H, d, J=6.2 Hz, CH3CH), 3.70 (1 H, dd, J= 4.7 and 1.6 Hz, H-6), 4.23 (1 H, dq, J=6.2 and 4.7 Hz, H-8), 4.33 (2H, s, NCOCH2N), 4.72 and 4.79 (2H, each ddt, J=12.6 and # 2 Hz, CH2-CH-CH2),4.78 and 5.32 (2H, each d, J=16.8 Hz, CH2-N), 5.28 (1H, dq, J=10 and < 2 Hz,

5.43(1H,dq,J=17 and < 2Hz,

5.58 (1 H, d, J=1.6 Hz, H-5), 5.97 (1H, ddt, J=17, 10 and 6 Hz, CH2-CH=CH2).

Step (b): I, R2 = allyl; R1, X and A as in the title.

Yield: 66.4% (no chromatography needed; trituration with dichloromethane/diethyl ether); yellowish powder, m.p. 158-160 C IR: vmax (KBr) 1775,1725,1695,1575,1520,1420 1520,1420cm1 Step (c): I, R1, R2, X and A as in the title.

Yield: 80%, yellow powder IR: #max (KBr) 1765, 1720, 1670-1690 cm-1 NMR: 3(D2O, 200 MHz) 1.28 (3H, d, J=6.4 Hz, CH3-CH), 3.92 (1 H, dd, 6.15 Hz, H-6), 4.23 (1 H, dq, J =6.4 and 1.5 Hz, H-8), 4.54 (2H, s, N-CO-CH2-N), 4.72 and 5.27 (2H, each d, J=16.5Hz, CH2N), 5.64 H, d, J=1.5Hz, H-5), 7.15 (1H, d, J=3.9 Hz, furyl 3-H),7.61 (1H, d, J=3.9 Hz,4-H),7.85 (1H, s, N-N=CH-) UV: # max (H2O) 266 (# = 16,544) and 366 nm (E = 18, 450) Example 5 By using procedures similar to those described in Example 1, the following compound was obtained: Sodium (SR,6S)-6-(1R-hydroxyethyl-2-(2,4-dioxo-imidazolin-3-yl-methyl)-penem-3-carboxylate(I, R1 = 1hydroxyethyl; P2 = Na; X=O;A=NH-CH2-) Starting materials: allyl (5R, 6S)-6-(1 R-t-butyl-dimethylsilyloxyethyl)-2-hydroxymethyl-penem-3-carboxylate and hydantoin Step (a): I, R1 = CH(OSiMe2But) CH3; R2 = allyl; X and A as above.

Isolated crude together with diethylidrazodicarboxylate and triphenylphosphine oxide Step (b): I, R2 = allyl; R1, X, A as in the title.

Yield: 35.4% overall; white foam IR: #max (CHCl3) 1790 and 1730 cm-1; NMR: #(CDCl3, 60 MHz) 1.30 (3H, d, J =6Hz, CH3-CH), 3.75 (1 H, dd, J =7 and < 2 Hz, H-6), 4.05 (2H, s, COCH2NH), 4.2 (1 H, m, H-8), 4.70 (2H, m, CH2CH=CH2), 4.80 (obscured) (2H, m, CH2CH=CH2) 5.62 (1 H, d, J < 2 Hz, H-5), 5.6-6.2(1H, m, CH2CH=CH2) Step (c):I, R1, R2X, A as in the title Yield: 70%; white powder IR: #max(KBr) 1770, 1710, 1580-1610 cm-1 NMR: 3(D2O. 200 MHz) 1.33 (3H, d, J= 6.3 Hz, CH3-CH),3.95(1H,dd,J= 1.3 and 6.0 Hz, H-6), 4.16 (2H, s, COCH2NH), 4.68 and 5.15 (2H, each d, J= 16.8 Hz, CH2N), 5.68(1 H, d, J= 1.3 Hz, H-5) ppm UV: # max (H2O) (E = 4,518) and 305 nm (E = 5,630) Example 6 By using procedures similar to those described in Example 1, the following compound was obtained; Sodium 65R,6S)-6-(1R-hydroxyethyl)-2- (2,4-dioxo- 1H, 3K -pyrimidin-3-yl -methyl)-penem-3-carboxylate (I, R=1-hydroxyethyl; R2=Na; X=O;A=-NH-CH=CH-) Starting materials: allyl (5R,6S)-6-(1R-t-butyl-dimethylsilyloxyethyl)-2-hydroxymethyl-penem-3-carboxylate and uracil.

(Step (a): I, R1=CH(OSiMe2But)CH3; R2 = allyl; X and A as in the title.

Isolated in admixture with PPh30 and (NHCO2Et)2.

Step (b): I, R2= allyl; R1, X and A as in the title.

Yield: 23% overall; foam IR: vmaX (CHC13) 3395, 1790, 1710 shoulder, 1695 cm-1 NMR: 3 (CDC13, 60 MHz) 1.30 (3H, d, J= 6.5 Hz) 3.76 (1 H, dd, J= 6 and < 2 Hz), 4.2 (1 H, m, H-8), 4.55 and 4.62 (2H, each s, CH2CH=CH2, 5.10 (2H, center of ABq, CH2N), 5.2-5.6 (2H, m, CH2-CHCH2), 5.60 (1 H, s, J < 2 Hz, H-5), 5.70 and 7.40 (2H, each d, J= 8 Hz, CH=CH), 5.6-6.2 (1 H, m, CH2CH=CH2) Step (c): I, R1, R2, X and A as in the title.

Yield: 58%; white powder IR: #max(KBr) 1770, 1700, 1680, 1600, 1580cm-1 NMR: #(D20,200 MHz) 1.27 (3H, d, J= 6.4 Hz, CH3-CH), 3.89 (1 H, dd, J= 1.6 and 5.9 Hz, H-6), 4.22 (1 H, dq, J= 5.9 and 6.4 Hz, H-8), 4.96 and 5.28 (2H, each d, J= 15.9 Hz, CH2N), 5.62(1 H, d, J= 1.6 Hz, H-5), 5.84(1 H, d, J= 7.8 Hz, CO.CK=), 7.68 (1 H, d, J= 7.8 Hz, CH=CH-NH) ppm.

UV: AmaX (H2O) 265 (e = 13,475) and 308 nm ( = 6;125)

Claims

1. A 2-imidomethyl-penem derivative having the general formula I

represents a monocyclic or bicyclic, saturated or unsaturated heterocyclic ring, unsubstituted or substituted by one or more equal or different substituents selected from (a) an oxo group, a cyano group, a nitro group or a halogen atom, (b) a group of the formula -NR3R4r -COOR3, -CONP3P4, -CONR3R4,

= N-ORB, -N=CHR4, -COR4 or -OR3 wherein Rg represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms and R4 represents a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms or a phenyl, furyl, thienyl or pyridyl group, and (c) a straight chain or branched chain alkyl or alkenyl group unsubstituted or substituted by one or more of the substituents defined in (a) and (b) above with the proviso that the group

does not represent an unsubstituted phthalimido group, and R2 represents a hydrogen atom, an organic or inorganic cation forming with the penem carboxylate moiety a pharmaceutically or veterinarily acceptable salt, or an organic group forming with the penem carboxylic moiety a chemically or physiologically cleavable ester or, if the compound contains a basic group, a pharmaceutically acceptable acid addition salt thereof or an inner salt thereof formed by the basic group and the -COOR2 group; or, if the compound contains an acidic group, a pharmaceutically acceptable salt thereof with a base.

2. A compound according to claim 1- wherein P1 represents a 1-hydroxyethyl group.

3. A compound according to Claim 1 or claim 2 in which X represents an oxygen atom.

4. A compound according to claim 3 in which the group

represents one of the following heterocyclic rings

-NH-CH=NH and

and (c') a methyl or ethyl group optionally substituted by one or two of the substituents defined in (a') and (b') above.

5. A compound according to any preceding claim in which R2 represents a hydrogen, sodium or potassium atom or an acetoxymethyl or (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl group.

6. Sodium (5R,6S)-6-(1 P-hydroxyethyl)-2-succinimido-methyl-penem-3-carboxylate.

7. Potassium (5R, 6S)-6-(1 R-hyd roxyethyl)-2-(2,4-dioxo-l,3-th iazol idin-3-yl-methyl )-penem-3-ca rboxylate.

8. Sodium (5R, 6S)-6-( 1 P-hydroxyethyl)-2-(2A,5-trioxo-imidazolin-1 -yl-methyl)-penem-3-carboxylate.

9. Sodium (5R, 5S)-6-(1 R-hydroxyethyl)-2- [1 -(5-nitro-2-furfu rylidenei mi no)-2,4-dioxoimidazolin-3-yl- methyl]-penem-3-carboxylate.

10. Sodium (5R, 6S)-6-( 1 R-hydroxyethyl)-2-(2,4-dioxo-imidazolin-3-yl-methyl)-penem-3-carboxylate.

11. Sodium (5R,6S)-6-(1 R-hydroxyethyl)-2- (2,4-dioxo-1 H,3H-pyrimidin-3-yl-methyl)-penem-3carboxylate.

12. Any one of the compounds 7 to 32 defined herein by the general formula la in a conjunction with Table 1.

13. A process for the preparation of a 2-imidomethyl-penem derivative having the general formula I as defined in claim 1, the process comprising condensing a carbinol of the general formula II

wherein R1 and R2 are as defined in claim 1, or a protected derivative thereof, with a compound of the general formula Ill formula Ill formula 111

wherein X and the group

are as defined in claim 1, or with a protected derivative thereof and, if necessary, deblocking the protecting groups.

14. A process according to claim 13 in which the two reagents are dissolved in an inert aprotic solvent and treated witha trivalent phosphorus compound and an azodicarboxylic acid diester, or with a preformed complex of the phosphorus compound and the diester, at a temperature of from -80 C to 40"C.

15. A process according to claim 14 in which the inert aprotic solvent is tetrahydrofuran.

16. A process according to claim 14 or claim 15 in which the phosphorus compound is triphenylphosphine.

17. A process according to any of claims 14 to 16 in which the azodicarboxylic acid diester is diethyl azodicarboxylate.

18. A process according to any of claims 14 to 17 in which the treatment is carried out at from 00C to 250C.

19. A process for the preparation of a 2-imidomethyl-penem derivative having the general formula las defined in claim 1, the process being substantially as described herein with reference to any of the Examples.

20. A pharmaceutical composition comprising a 2-imidomethyl-penem derivative according to any of claims 1 to 12 or, if the compound contains a basic group, a pharmaceutically acceptable acid addition salt thereof or an inner salt thereof formed by the basic group and the -COOR2 group, or, if the compound contains an acidic group, a pharmaceutically acceptable salt thereof with a base in admixture with a pharmaceutically acceptable diluent or carrier.