PENEM DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: Described are penems derivatives of general formula (I) wherein R1 is chosen in the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, optionally protected C1-C6 hydroxyalkyle; R2 is chosen in the group consisting of carboxyl group free or esterified with a group easily activated "in vivo", carboxylate anion; R3 is chosen in the group consisting of H, C1-C4 alkyl optionally substituted; R4 is chosen in the group consisting of: H, C1-C6 alkyl optionally substituted, C1-C6 hydroxyalkyl optionally substituted, C1-C6 mercaptoalkyl optionally substituted, C1-C6 aminoalkyl optionally substituted, C1-C6 alkyl substituted by a quaternary ammonium group, C1-C6 carboxyalkyl optionally substituted, cycloalkyl, aryl, arylalkyl, heterocyclyl-alkyl optionally substituted, saturated or unsaturated heterocycle wherein the heteroatoms in the heterocyclic ring can be N, O, S, or R3 and R4 linked together form a heterocyclic ring having 3-7 atoms, optionally substituted, saturated or unsaturated which can contain other heteroatoms as O, N, S. R5 and R6 independently from one another are chosen in the group consisting of: H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 mercaptoalkyl, C1-C6 aminoalkyl, alkenyl, cycloalkyl, aryl, arylalkyl, alkylaryl, heterocyclyl-alkyl, C1-C6 alkyl carboxyamide wherein the alkyl group can be linear or branched (all these groups optionally substituted), or R5 and R6 taken together form an heterocyclic ring having 3-7 atoms optionally substituted, n is chosen in the group consisting of: 1, 2, 3; and their pharmaceutically acceptable salts.

Description: PENEM DERIVATIVES , THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM Field of the invention The present invention refers to penem derivatives of general formula ( I) R._ is chosen in the group consisting of H , C^ -Cg alkyl , C-^ -Cg alkoxy , ~ -~ ~ ~ cycloalkyl , optionally protected C^-Cg hydroxyalkyl R2 is chosen in the group consisting of carboxyl group free or esterified with a group easily activated "in vivo" , carboxylate anion Rα is chosen in the group consisting of H, C-^-C j alkyl optionally substituted, R /j is chosen in the group consisting of H, C^-Cg alkyl optionally substituted, ^-Cg hydroxyalkyl optionally substituted, C^-Cg mercaptoalkyl optionally substituted, ~ ι~ ~ , aminoalkyl optionally substituted, ^-Cg alkyl substituted by a quaternary ammonium group, C 1 ~C 6 carboχ yal k yl optionally substituted, Co-Cγ cycloalkyl, Cg-C 10 aryl, Cg-C-^ Q arylC^-Cgalkyl, heterocyclyl-C^-Cgalkyl optionally substituted, the side chain of a natural alpha-aminoacid, saturated or unsaturated ~ -a-~ ~ ~ heterocycle wherein the hetero-atoms in the heterocyclic ring can be N, 0, S or Rn and R / linked together form an heterocyclic ring having 3 _ 7 atoms, optionally substituted, saturated or unsaturated which can contain other hetero-atoms as 0, N, S. Re and Rg independently from one another are chosen in the group consisting of H, ~ ~~^ alkyl, ~ ι ~ ~ _[ hydroxyalkyl, ~ ι ~ - (_ , mercaptoalkyl, C^-Cg aminoalkyl, C2~Cg alkenyl, C -Cγ cycloalkyl, C -C 10 aryl, Cg-C-^arylC^Cgalkyl , C^CgalkylCg-C^aryl, heterocyclyl-C^-Cgalkyl, C^-Cg alkyl carboxyamide wherein the alkyl group can be linear or branched (all these group optionally substituted) or Re and Rg taken together form an heterocyclic ring having 3 " 7 atoms optionally substituted n is chosen in the group consisting of: 1, 2, 3 and their pharmaceutically acceptable salts. State of the art The compounds known as penems represent a wide family of compounds having antibacterial properties. Since bacteria become rapidly resistant to agents used against them it is important to develop new compounds in order to satisfy the pharmacological request of medicaments being effective against infective agents (known or not yet known) , having good stability, less toxicity etc. Description of the invention The present invention makes available new compounds of the penem family having interesting pharmaceutical properties. The compounds according to the present invention are compounds of wherein R-^, R 2 , Ro, R / , Re, Rg and n are as above defined. It is evident from the above formula (I) that the compounds according to the invention may consist of various optical and geometrical isomers, such isomers, as well as their mixtures, are obviously considered to be included in the scope of the present invention. Preferred are those compounds of formula (I) having the configuration (5R, 6S). Preferred are the compounds of formula (I) wherein R = alpha- hydroxy ethyl and more particularly those in which such group has the configuration 1R i.e. the configuration of the alpha-C atom of the ethyl group is R. R2 is carboxylate anion or a carboxylic group free or esterified with a group easily activable "in vivo" chosen in the group consisting of the compunds of general formula (a) and (b) (a) (b) wherein Rγ and Ro are chosen in the group consisting of: H, C-^-Cg alkyl, C2 _ Cg alkenyl, Co-Cg cycloalkyl or cycloalkenyl, Cg-C^g aryl or C-^-CgalkylCg-C^Qaryl and m is 0 or 1. Among the groups easily activable " in vivo" are for example : - acetoxymethyl [ (a) : Rγ = H; Rg = CH ; m = 0] -propanoyloxymethyl [ (a) : R 7 = H ; Rg = CH 2 CH 3 ; m = 0] -pivaloyloxymethyl [(a): Rγ = H; Rg = C(CHo) ; m = 0] -1-acetoxyethyl [(a): Rγ = CH,; Rg = CH ; m = 0] -1-acetoxypropyl [(a): Rγ = CH 2 CHo; Rg = CH,; m = 0] -1-cyclohexylcarbonyloxyethyl [(a): Rγ = CH ; Rg = cyclohexyl; m = 0] -benzoyloxymethyl [(a): Rγ = H; Rg = Ph; m = 0] -1-benzoyloxyethyl [(a): Rγ = CH ; Rg = Ph; m = 0] -methoxycarbonyloxymethyl [(a): Rγ = H; Rg = CH ; m = 1] -1-methoxycarbonyloxyethyl [(a): Rγ = CHo; Rg = CH ; m = 1] -isopropyloxycarbonyloxymethyl [(a): Rγ = H; Rg = 1] -1-isopropyloxycarbonyloxyethyl [(a): Rγ = CH,; R ~ = 1] -ciclohexyloxycarbonyloxymethyl [(a): Rγ = H; Rg = cyclohexyl; m = 1] -cyclohexylmethyloxycarbonyloxymethyl [(a): Rγ = H; Rg = cyclohex-CH2; m = 1] -1-cyclohexyloxycarbonyloxyethyl [(a): Rγ = CH ; Rg = cyclohexyl; m = 1] -(2-oxo-l,3-dioxolen-4-yl) methyl [(b): Rγ = H; Rg = H] -(5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl [(b): Rγ = H; Rg = CH ]- (5-tert-butyl-2-oxo-l,3-dioxolen-4-yl)methyl [(b): Rγ = H; Rg = C(CH 3 ) 3 ] -(5-phenyl-2-oxo-l,3-dioxolen-4-yl)methyl [(b): Rγ = H; Rg = Ph] R is preferably a methyl or ethyl group optionally substituted. R /j is preferably H, C^-Cg alkyl optionally substituted, ~ι~C β hydroxyalkyl, ~ _ \ ~^ f , mercaptoalkyl, ~ ___- (_- . aminoalkyl, ~ _\_~^f, carboxyalkyl , aryl optionally substituted, arylalkyl, for example benzyl, alkyl C^-C substituted by a quaternary ammoni um- group , heterocyclyl-C-^-Cgalkyl or the side chain of a natural alpha- aminoacid. When Ro and R^ are joined together they form a ring having 3 ~ 7 atoms, optionally substituted, wherein other heteroatoms than N can be present for example 1-ρyrrolidine, 1-azetidine, 1-piperidine, 4- morpholine, 1-piperazine, 4-methyl-piperazine. Re and Rg are preferably H, C- j _-Cg alkyl, Cg-C-^ Q aryl, Cg-C^ Q arylC^- Cg alkyl, C-^-CgalkylCg-C-^ Q aryl , C-^-Cgalkylcarboxyamide, or together they form an heterocyclic ring having 3 " 7 atoms optionally substituted, as for example : 1-aziridine, 1-azetidine, 1- pyrrolidine, 1-piperidine, -4-morpholine, 1-piperazine, 4-metyl- piperazine. Among the possible substituent groups are preferred : methyl, ethyl, propyl, butyl, pentyl , cyclopentyl, cyclohexyl, phenyl, benzyl, OH, C-^-Cgalkoxy, carboxyamidic group (optionally substituted), carboxyester, carbamoyloxy. Among the pharmacological acceptable salts of the compounds of formula (I) according to the present invention are those commonly used in the field of penicillin and cephalosporin as for example the salts formed with inorganic bases as alkali metal hydroxide or earth alkaline metal hydroxyde (preferably NaOH, KOH) and salts of organic bases included aminoacids as for example lysine; pharmacological acceptable salts according to the invention include also internal salts (zwitterions) . The products of the present invention can be administered as such other in combination with the excipients commonly used with penicillins and cephalosporins for the preparation of formulations for the oral or parenteral use or in combination with known antibiotics or with inhibitors of beta-lactamases. The compounds according to the present invention have a widespread antibacterial activity and can be administered in the doses and according to the modality already known in pharmacopeia for the analogous penicillins and analogous antibiotics. The compounds according to the present invention can be prepared from the corresponding hydroxymethyl compounds of formula II (TABLE 1) wherein R-^ is as defined (preferably alpha-hydroxyethyl) and Y is an ester-group as for example allyl or p-nitrobenzyl. The compounds of formula II are known and can be prepared (SCHEME 1) from the azetidinone compounds III or from the derivatives of natural penicillins IV using known procedures [for example E. Fontana et al., J.Lab.Comp.Radiopharm. , 24, 4l (1986); A.J.Corraz et al., J.Med.Chem. ,3>, l82δ (1992) here reported for reference]. SCHEME 1 The hydroxymethyl penems II are transformed into the corresponding sulfonyl derivatives V, wherein R^ and Y are as above defined and Z is an alkyl- or aryl-group (preferably methyl or p-tolyl), by reacting compounds II with the appropriate sulfonyl chloride in the presence of an organic base, as for example triethylamine or N,N- diisopropylethylamine, in an inert organic solvent, as for example dichlorome hane or chloroform, at a temperature ranging from -70°C and +20 ° C. The sulfonyl derivatives V are reacted with the compounds of formula VI, where n, Ro, R /j , Re and Rg are as above defined, in an organic solvent as for example dimethylsulfoxide, dimethylformamide, dioxane, tetrahydrofuran or ethyl acetate at a temperature of -20°C - +20 ° C; the reaction can be performed on the derivatives V crude or pure. Alternatively the synthesis can be performed by transforming the sulfonyl derivatives V into the corresponding halides VIII Wherein X is chlorine, bromine or iodine through a reaction with inorganic halides preferably calcium halides. The compounds of general formula VII can be obtained from the halides VIII through a reaction with the compounds of formula VI wherein n, Ro, R j , Re and Rg are as above defined in an organic solvent as for example dimethylsulfoxide, dimethylformamide, dioxane, tetrahydrofuran or ethylacetate at a temperature of -20 C - +20°C; also in this case the reaction can be perfomed starting from the corresponding halides VIII isolated or crude. At the end of the reaction the penems VII are isolated and characterised with conventional methods. When R-, is an hydroxyalkyl group the reaction sequence is performed after protecting the alcoholic function with the conventional protecting groups as for example p-nitrobenzyloxycarbonyl, allyloxycarbonil, t-butyldimethylsilyl or trimethylsilyl. The protecting group is removed at the end of the reactions sequence. Alternatively, the reaction can be performed with the dialcoholic derivative II not protected (R 1 = CHoCHOH-). The compounds of general formula I are finally obtained from the corresponding esters VII through hydrolysis or hydrogenolysis or with other procedures. The compounds of general formula I possess a remarkable antibacterial activity when compared with the conventional beta- lactam antibiotics, both against gram-positive and gram-negative microorganisms and also against anaerobic microorganisms either producing or not-producing beta-lactamases. EXAMPLE 1 Allyl (5R,6S)-2-(N-(2-acetamido)-N-methyl)-aminomethyl)-6- [(lR)-l-ter-butyldimethylsilyloxyethyl]-penem-3-carboxylate 3-2 ml (23.2 mmoles) of triethylamine and 1.8 ml (23.2 mmoles) of methanesulfonyl chloride are added at 0 °C under nitrogen atmosphere to a solution of 6 g (15 mmoles) of allyl (5R,6S)-2-hydroxymethyl-6- [(lR)-l-ter-butyldimethyl-silyloxy-ethyl]-penem-3-carboxylate in 150 ml of anhydrous methylene dichloride. The reaction mixture is stirred at 5°C for 30 minutes. The cold solution is washed with water, NaHCOo 5% and again with water. The solution is dried over Na2S0 /j and is evaporated giving a yellow residue. The crude product is dissolved in dimethylsulfoxide (150ml) and a solution of 2.4 g (19-3 mmoles) of sarcosinamide hydrochloride [prepared according to Marvel et al . J.Am.Chem.Soc. , 68, I685 (1946)] and 2.8 ml (20.1 mmoles) of triethylamine in 40 ml of dimethylsulfoxide is added. 2.8 ml (20.1 mmoles) of triethylamine are added to the solution and the mixture is stirred at room temperature for 4 hours. The mixture is left for 1 night at the same temperature and is poured into water and ice and extracted twice with ethyl acetate. The organic extracts are washed with water and dried over Na2S0[ j and the solvent is evaporated under vacuum. The crude product is purified by column-chromatography (silica gel; ethyl acetate/cyclohexane 70:30 v/v) , giving a pale yellow solid; m.p.: 118-9 ° C EXAMPLE 2 Allyl (5R,6S)-2-(N-(2-acetamido)-N-methyl)-aminomethyl)-6-[(lR)-l- hydroxyethyl]-penem-3-carboxylate Acetic acid 2.9 ml (50.7 mmoles) and tetrabutylammonium fluoride (IM solution in tetrahydrofuran; 25 ml, 25 mmoles) are added at room temperature to a solution of allyl (5R,6S)-2-(N-(2-acetamido)-N- methyl)-aminomethyl)-6-[ (lR)-l-ter t-butyl-dimethylsilyloxyethyl]- penem-3-carboxylate (4 g; 8.5 mmoles) in tetrahydrofuran (200 ml). The mixture is stirred for 24 hours at room temperature, is concentrated at 0 ml, diluted with ethyl acetate, washed with water and NaHCOo 5% , dried and evaporated. The residue is crystallized from ethyl ether, washed on the filter with ethyl ether and dried under vacuum giving a yellow solid; m.p.: 83 - 85°C. EXAMPLE 3 (5R.6S)-2-(N-(2-acetamido)-N-methyl)-aminomethyl)-6-[(lR)-l- hydroxyethyl]-penem-3-carboxylic acid 80 mg (0.30 mmoles) triphenylphosphine , 335 mg (0.29 mmoles) tetrakis(triphenylphosphine)palladium(0) and 0.24 ml (4.2 mmoles) acetic acid are added at 35 ~ 4θ°C under nitrogen atmosphere to a solution of 1 g (2.8 mmoles) of allyl (5R.6S)-2-(N-(2-acetamido)-N- methyl)-aminomethyl)-6-[ (IR)-1-hydroxyethyl]-penem-3~carboxylate in 6θ ml of anhydrous tetrahydrofuran and 60 ml of anhydrous methylene dichloride. The mixture is stirred at the same temperature for about one hour. The solution is concentrated to 50 ml and is added with ethyl ether under stirring; the precipitate is filtered under nitrogen atmosphere, washed with ethyl ether and dried under vacuum. The crude product is purified by reverse phase column chromatography (LiChroprep RP-18 ; water/acetone 9 ^5 v/v) . White solid; m.p.: 92-95°C; M.W. : 315-3 EXAMPLE 4 Allyl (5R,6S)-2-( (N-prolinamido)methyl)-6-T (lR)-l-ter-butyl-di- methylsilyloxyethyl]-penem-3~carboxylate 1.0 ml (7.2 mmoles) of triethylamine and 0.6 ml (7-7 mmoles) of methanesulfonyl chloride are added at 0 ° C under nitrogen atmosphere, to a solution of 2 g (5 mmoles) of allyl (5R,6S)-2- hydroxymethyl-6-[ (lR)-l-ter-butyldimethylsilyloxy-ethyl]-penem-3- carboxylate in 60 ml of anhydrous methylene dichloride. The mixture is stirred for 30 minutes at 5°C and thereafter is washed with water, NaHCOo 5$ and again with water. The solution is dried over Na2S0i, and evaporated giving a yellow residue. The crude product is dissolved in dimethylsulfoxide (60 ml). 0.7 g (6 mmoles) of prolinamide and 0.7 ml (5 mmoles) of triethylamine are added to the solution which is stirred at room temperature for 2 hours and is therefater left at room temperature for a night. The solution is poured into water and ice and is extracted twice with ethyl ' acetate. The organic extracts are collected together, washed with water, dried over Na2S0i j and evaporated under vacuum. The crude product is purified by column chromatography (silica gel; ethyl acetate) giving a pale yellow wax. EXAMPLE Allyl (5R,6S)-2-((N-prolineamido)-methyl)-6-[(lR)-l-hydroxy-ethyll- penem-3-carboxylate 0.9 ml (15-7 mmoles) of acetic acid and 2.5 g (7-9 mmoles) of tetrabutylammonium fluoride trihydrate are added, at room temperature, to a solution of allyl (5R,6S)-2-( (N-prolin-amido)- methyl)-6-[(lR)-l-tert-butyldimethylsilyloxyethyl]-penem-3- carboxylate (1.3 g; 2.62 mmoles) in tetrahydrofuran (70 ml). The mixture is stirred at room temperature for 16 hours, is diluted with ethyl acetate, washed with water and NaHCOo % . dried and evaporated. The compound is purified through column chromatography (silica gel; ethyl acetate). Yellow oil. EXAMPLE 6 ( R. S)-2-( (N-prolinamido)-methyl)-6-[(IR)-1-hydroxyethyl]-penem-3~ carboxylic acid 130 mg (0.50 mmoles) of triphenylphosphine, 56O mg (0.48 mmoles) of tetrakis(triphenylphosphine)palladium(0) and acetic acid (0.27 ml; 4.7 mmoles) are added, at room temperature under nitrogen atmosphere, to a solution of (5R,6S)-2-( (N-prolinamido)-methyl)-6- [(IR)-l-hydroxyethyl]-penem-3-allyl carboxylate (0.93 Si 2-4 mmoles) in 100 ml of anhydrous tetrahydrofuran. The mixture is stirred at the same temperature for 30 minutes, thereafter is diluted with ethyl ether, the precipitate is filtered under nitrogen, washed with ethyl ether and dried under vacuum. The crude product is purified by reverse phase column chromatography (LiChroprep RP-18 ; water/acetone 9 : v/v) White solid, m.p.: 133~5°C; M.W. : 3 1.38 EXAMPLE 7 (5'-Methyl-2'-oxo-l' ,3' -dioxolen-4 'yl) -methyl (5 , 6S) -2- (N- (2- acetamido)-N-methyl)aminomethyl)-6-[ (IR)-l-hydroxyethyl]-ρenem-3~ carboxylate 106 mg (1.0 mmoles) of anhydrous sodium carbonate are added, at room temperature and under nitrogen atmosphere to a solution of 26l mg (0.83 mmoles) of (5R,6S)-2-(N-(2-acetamido)-N-methyl)aminomethyl)-6- [(lR)-l-hydroxyethyl]-penem-3-carbo-xylic acid in dimethylformamide (15 ml). The mixture is stirred for 3 hours at room temperature, is cooled to 0 ° C and is added with 192 mg (1.0 mmoles) of 4-bromomethyl-5-methyl- 1 ,3 _ dioxolen-2-one) which is reacted for 2 hours at room temperature. The solution is diluted with ethyl acetate, washed with water, dried over and evaporated. The residue is precipitated from chloroform/cyclohexane, solubilised with water and lyophilised. p The product is purified by HPLC using a column Hypersil 10 0DS , 10 um, 25 cm x 20 mm, mobile phase: water/acetonitrile 40/60, flow 10 ml/min. Obtained 105 mg (Yield 30% ) . M.W: 427-43- HPLC (analytical): column : Hypersil 5 ODS , 5 urn, 25 cm x 4.6 mm, UV detector: 220 and 320 nm, mobile phase: water/acetonitrile (40/60), flow: 1 ml/min, t R = 5-8 min, lambda---.^ =.325 nm. EXAMPLE 8 Sodium (5R,6S)-2-(N-(2-acetamido)-N-methyl)aminomethyl-6-[ (1R)-1- hydroxyethyl]-penem-3-carboxylate 35 mg (0.13 mmoles) of triphenylphosphine, 14 mg (0.12 mmoles) of tetrakis(triρhenylphosphine)palladium(0) and 326 mg (1-96 mmoles) of sodium 2-ethylhexanoate are added, at room temperature, under nitrogen atmosphere, to a solution of 50 mg (1.26 mmoles) of allyl (5R,6S)-2-(N-(2-acetamido)-N-methyl)aminomethyl)-6-[(lR)-l- hydroxyethyl]-penem-3-carboxylate in 10 ml of anhydrous tetrahydrofuran. The mixture is stirred at room temperature for 30 minutes. The solution is concentrated giving a raw product which is purified through HPLC using a column Hypersil 10 ODS , 10 um, 25 cm x 20 mm; mobile phase: water/acetonitrile: 90/10, flow: 20 ml/min. Obtained : 235 mg (Yield 54/-). M. W.: 338.34. HPLC (analytical), column: Hypersil 5 0DS R , 5 um, 25 cm x 4.6 mm, UV detector: 220 and 320 nm, mobile phase: water/acetonitrile (95/5). flow: 1 ml/min, p = 4.0 min. Following the procedure described in the examples 3. 6, 7 and 8 and using the appropriate reagents the following compounds were also obtained : (5R.6S)-2-(N-methyl-phenylalaninamido)-methyl-6-[ (1R)-1- hydroxyethyl]-penem-3-carboxylic acid M.W. = 405.47 MS(FAB):m/z 4θ6 (M+H + ) HPLC, phase: water/acetonitrile (80/20); t R = 5-1 min (5R,6S)-2-(3'-carboxyamido-ρiperidin-1'-yl)-methyl-6-[(IR)-1- hydroxyethyl]-penem-3-carboxylic acid M.W. = 355.412 [Two diastereoisomers were obtained (A) and (B) ; these were separated by HPLC (preparative), phase: water/acetonitrile (95/5); column Hypersil 100DS R , 10 um, 25 cm x 20 mm, flow 20 ml/min] HPLC (analytical): = 8.2; t R β N = 9-9 min (5R,6S)-2-(N,N-diacetamido)-aminomethyl-6-[(lR)-l-hydroxy-ethyl]- penem-3-carboxylic acid M.W.: 358-37 MS(FAB):m/z 359 (M+H + ) 1 3c NMR (50 MHz, D 2 0) < (ppm) characterising signals: 56.0, 6l.1, 66.8, 69-1, 74.0 (5R,6S)-2-(N-methyl-N-(3'-propionamido)-aminomethyl-6-[(IR)-1- hydroxyethyl]penem-3-carboxylic acid M.W. = 329-37 HPLC: t R n = 5 -^-0 min, lambda-m-,a.-x v = 3 - 1 14 nm (5R,6S) -2-(N-methyl-N-(4'-methyl-1'piperazin)amidocarboxy-methyl- aminomethyl-6-[(lR)-l-hydroxyethyl]-penem-3-carboxylic acid M.W.: 398.48 1 3c NMR (50 MHz, D 2 0) (ppm) characterising signals : 46.3, 47-4, 59.9, 67-9, 69.0, 74.6 (5R,6S)-2-(N-ethyl-N-(2'-acetamido)-aminomethyl-6-[(IR)-1- hydroxyethyl]-penem-3~carboxylic acid M.W.: 329.37 HPLC : t R = 4.8 min; lambda--.^ = 310 nm (5R,6S) -2-(N-methyl-N-((N' ,N'-dimethyl)acetamido)-amino-methyl-6- [(IR)-l-hydroxyethyl]-penem-3-carboxylic acid M.W.: 343-40 HPLC: t R = 9-1 min, lambda ma -. = 315 nm (5R,6S)-2-(2' -carboxyamido-piperidin-1 ' -yl) -methyl-6-[ (1R)-1- hydroxyethyl]-penem-3-carboxylic acid M.W.:355.4ll [Two diastereoisomers were obtained (A) and (B); these were separated by HPLC (preparative), phase: water/acetonitrile (99/1); column Hypersil 100DS R , 10 um, 25 cm x 20 mm, flow 20 ml/min] HPLC (analytical): = 9-1; fc R ( B) = H-0 min ( R,6S)-2-( '-carboxyamido-piperidin-1'-yl)-methyl-6-[(IR)-1- hydroxyethyl]-penem-3-carboxylic acid M.W.: 355.412 m.p.: 136-7 ° C (5' -Methyl-2'oxo-1' ,3' -dioxolen- ' -yl)methyl(5R,6S)-2-(N- prolinamido)methyl-6-[ (IR)-1-hydroxyethyl]-penem-3-carboxylate M.W.: 453.470 MS(EI): m/z 453 (M + ) HPLC: phase water/acetonitrile (20/80), t R = 4.2 min; lambda maχ 325 nm Acetoxymethyl (5R.6S)-2-(N-methyl-N-(2-acetamido) )-amino-methyl-6- [(lR)-l-hydroxyethyl]-penem-3 _ carboxylate M.W.: 387.41 HPLC:phase water/acetonitrile (50/50), t R = 3-0 min MS(TS): m/z 388 (M+H + ) (5R,6S)-2-(2'-carboxyamido-aziridin-1'-yl)-methyl-6-[ (IR)-1- hydroxyethyl]-penem-3 _ carboxylic acid M.W.: 313.33 HPLC: phase water/acetonitrile (98/2), t R = 1.8 min; lambda maχ = 306 nm MS(FAB) : m/z 314 (M+H + ) (5R,6S)-2-(N-(D-prolinamido) )-methyl-6-[ (IR)-l-hydroxy-ethyl]-penem- 3-carboxylic acid M.W.: 341.38 HPLC: phase water/acetonitrile (95/5), t R = 4.4 min MS(FAB): m/z 3 2 (M+H + ) (5R,6S)-2-[N-methyl-(N'-glycinamido)-glycyl]-aminomethyl-6-[ (1R)-1- hydroxyethyl]-penem-3-carboxylic acid M.W. : 372.40 HPLC: phase water/acetonitrile (95/5), t R = 3-4 min; lambda maχ = 308 nm MS(FAB) : m/z 373 (M+H + ) Acetoxymethyl (5R,6S) -2- (N-prolinamido)methyl-6-[ (1R)-1- hydroxyethyl]-penem-3-carboxylate M.W.: 413-449 HPLC: phase water/acetonitrile (50/50); t R = 11.1 min; lambda maχ = 328 nm. MS(TS): m/z 4l4 (M+H + ) (5R,6S)-2-[ (2'S,4'R)-2'-carboxyamido- '-hydroxy-pyrrolidin-1'-yl]- methyl-6-[ (IR)-l-hydroxyethyl]-penem-3-carboxylic acid M.W.: 357-38 HPLC: phase: water (100%), t R = 3.0 min; lambda maχ = 306 nm MS(FAB): m/z 358 (M+H + ) (5R,6S)-2-(N-(2S)-2-propionamido-N-methyl]-aminomethyl-6-[(lR)-l- hydroxyethyl]-penem-3-carboxylic acid M.W.: 329.1 M.p.: 105°C (dec.) Pivaloyloxymethyl ( 5R, 6S) -2- (N-prolinamido) methyl-6-[ ( IR) -1- hydroxyethyl]-penem-3-carboxylate M.W.: 455.17 M.p.: 51-5°C Pivaloyloxymethyl ( 5R , 6S) -2- (N-acetoamido) -N-methyl -6- [ (1R)-1- hydroxyethyl]-penem-3~carboxylate M.W.: 429-16 M.p.: 50-3 ° C The operative conditions of the HPLC (analytical) are the following (when not differently reported) : column Hypersil 50DS R , 5um, 25 cm x 4.6 mm, UV detector 220 and 320 nm, phase water/acetonitrile (95/5). flow 1 ml/min,

Claims: CLAIMS 1. Penem derivatives of general formula (I) Ry- is chosen in the group consisting of H, C^-C alkyl, C^-Cg alkoxy, Co-Cγ cycloalkyl, optionally protected C^-C hydroxyalkyl R2 is chosen in the group consisting of carboxyl group free or esterified with a group easily activated "in vivo", carboxylate anion is chosen in the group consisting of H, C^-C^ alkyl optionally substituted, Rj j is chosen in the group of H, Ci-Cg alkyl optionally substituted, C^-Cg hydroxyalkyl optionally substituted, C^-Cg mercaptoalkyl optionally substituted, C-^-Cg aminoalkyl optionally substituted, C-^- Cg alkyl substituted by a quaternary ammonium group, C* ] _-Cg carboxyalkyl optionally substituted, C -Cy cycloalkyl, C -C^ Q aryl, Cg-C 10 arylC 1 -Cgalkyl , heterocyclyl-C^-Cgalkyl optionally substituted, the side chain of a natural alpha-aminoacid, saturated or unsaturated Co-Cγ heterocycle wherein the hetero-atoms in the heterocyclic ring can be N, 0, S or Ro and R^ linked together form an heterocyclic ring having 3 ~ 7 atoms , optionally substituted , saturated or unsaturated which can contain other hetero-atoms as 0 , N, S . R-- and Rg independently from one another are chosen in the group of H , C 1 -Cg alkyl , C 1 ~Cg hydroxyalkyl , C-^Cg mercaptoalkyl , C 1 ~C aminoalkyl , C 2 -Cg alkenyl , Co -Cy cycloalkyl , Cg-C 10 aryl , Cg- C 10 arylC 1 -Cgalkyl , C 1 -CgalkylCg-C 10 aryl , heterocyclyl-C-^-Cgalkyl , ~l~ ~ β ^^ l carboxyamide wherein the alkyl group can be linear or branched ( all these group optionally substituted) or Re and Rg taken together form an heterocyclic ring having 3 ~ 7 atoms optionally substituted n is chosen in the group consisting of 1, 2, 3 and their pharmaceutically acceptable salts. 2. Penem derivatives according to claim 1 having a configuration 5R.6S 3• Penem derivatives according to claim 2 wherein R-^ is an alpha- hydroxyethyl group wherein the alpha-C atom of the ethyl group has configuration R. 4. Penem derivatives according to claim 3 wherein R2 is chosen in the group consisting of : carboxylate anion, carboxylic group free or esterified with a group chosen in the group consisting of the compounds of general formula (a) and (b) (a) (b) wherein Rγ and Rg are chosen in the group consisting of: H, C^-C alkyl, C2~Cg alkenyl, Co-Cg cycloalkyl or cycloalkenyl, Cg-C^-, aryl or and m is 0 or 1. Ro is chosen in the group consisting of: methyl optionally substituted, ethyl optionally substituted R /j is chosen in the group consisting of : H, C ~Cg alkyl optionally substituted, Cι" c hydroxyalkyl, Cι~Cg mercaptoalkyl, ^ι~^ aminoalkyl, C-^-C carboxyalkyl , optionally substuituted Cg-C^aryl, Cg-C 10 arylC 1 -Cgalkyl , C^-Cg alkyl substituted by a quaternary ammonium group, heterocyclyl-C-^-Cgalkyl or the side chain of a natural alpha-aminoacid or when Ro and R /j are joined together form a ring chosen in the group consisting of: 1-aziridine, 1-pyrrolidine , 1-azetidine, 1- piperidine, 4-morpholine, 1-piperazine, 4-methyl-l-piperazine Re and Rg are chosen in the group consisting of: H, C^-Cg alkyl, Cg- , or when joined toghether form a ring chosen in the group consisting of: 1- aziridine, 1-azetidine, l-pyrrolidine, l-piperidine, 4-morpholine, 1-piperazine, 4-methyl-l-piperazine. 5- Penem derivatives according to claim 4 wherein the said substituents are chosen in the group consisting of: methyl, ethyl, propyl, butyl, pentyl, cyclopentyl, cyclohexyl, phenyl, benzyl, OH, < *-*l~ < - ' g alkoxy, carboxyamidic group (optionally substituted) , carboxyester. 6. Penem derivatives according to claim chosen in the group consisting of : (5R,6S)-2-(N-(2-acetamido)-N-methyl)-aminomethyl)-6-[(lR)-l- hydroxyethyl]-penem-3 _ carboxylic acid ( R,6S)-2-( (N-prolinamido)-methyl)-6-[(IR)-1-hydroxyethyl]-penem-3- carboxylic acid (5R,6S)-2-(N-methyl-phenylalaninamido)-methyl-6-[ (IR)-1- hydroxyethyl]-penem-3~carboxylic acid (5R,6S)-2-(3'-carboxyamido-piperidin-1' -yl)-methyl-6-[ (1R)-1- hydroxyethyl]-penem-3-carboxylic acid (5R,6S)-2-(N,N-diacetamido)-aminomethyl-6-[(IR)-1-hydroxy-ethyl]- penem-3-carboxylic acid (5R.6S)-2-(N-methyl-N-(3'-propionamido)-aminomethyl-6-[(1R)-1- hydroxyethyl]penem-3-carboxylic acid (5R.6S)-2-(N-methyl-N-(4'-methyl-1'piperazin)amidocarboxy-methyl- aminomethyl-6-[(lR)-l-hydroxyethyl]-penem-3-carboxylic acid (5R,6S)-2-(N-ethyl-N-(2'-acetamido)-aminomethyl-6-[ (IR)-1- hydroxyethyl]-penem-3-carboxylic acid ( R,6S)-2-(N-methyl-N-( (N' ,N'-dimethyl)acetamido)-amino-methyl-6- [(lR)-l-hydroxyethyl]-penem-3-carboxylic acid (5R,6S)-2-(2'-carboxyamido-piperidin-1'-yl)-methyl-6-[ (IR)-1- hydroxyethyl]-penem-3-carboxylic acid (5R,6S)-2-(4'-carboxyamido-piperidin-l'-yl)-methyl-6-[(lR)-l- hydroxyethyl]-penem-3~carboxylic acid (5'-Methyl-2'-oxo-l' ,3' -dioxolen- '-yl)methyl(5R.6S)-2-(N- prolinamido)methyl-6-[ (lR)-l-hydroxyethyl]-penem-3-carboxylate Acetoxymethyl (5R,6S)-2-(N-methyl-N-(2-acetamido) )-amino-methyl-6- [(lR)-l-hydroxyethyl]-penem-3-carboxylate (5R,6S)-2-(2'-carboxyamido-aziridin-1'-yl)-methyl-6-[ (IR)-1- hydroxyethyl]-penem-3 _ carboxylic acid (5 , S)-2-(N-(D-prolinamido) )-methyl-6-[ (IR)-1-hydroxy-ethyl]-penem- 3-carboxylic acid (5R,6S)-2-[N-methyl-(N'-glycinamido)-glycyl]-aminomethyl-6-[ (IR)-1- hydroxyethyl]-penem-3~carboxylic acid Sodium (5R.6S)-2-(N-methyl-N-(2-acetamido)-aminomethyl-6-[ (IR)-1- hydroxyethyl ] -penem-3~carboxylate Acetoxymethyl ( 5R , 6S ) -2- ( N-prolinamido ) methyl - 6- [ ( IR ) - 1 - hydroxyethyl ] -penem-3-carboxylate ( 5 * -methyl -2 * -oxo-l * , 3 ' -dioxolen-4 ' -yl ) methyl ( R , 6S ) -2 - ( N- ( 2 - acetamido) -N-methyl ]-aminomethyl-6-[ ( lR) -l-hydroxyethyl]-penem-3~ carboxylate (5R,6S)-2-[(2'S,4'R)-2'-carboxyamido-4'-hydroxy-pyrrolidin-l'-yl]- methyl-6-[(lR)-l-hydroxyethyl]-penem-3-carboxylic acid (5R,6S)-2-(N-(2S)-2-propionamido-N-methyl]-aminomethyl-6-[(lR)-l- hydroxyethyl]-penem~3-carboxylic acid Pivaloyloxymethyl (5R,6S)-2-(N-prolinamido)methyl-6-[ (IR) -1- hydroxyethy1]-penem-3-carboxy1ate Pivaloyloxymethyl (5R,6S)-2- (N-acetamido)-N-methyl-6-[(IR)-1- hydroxyethyl]-penem-3-pivaloyloxymethyl carboxylate 7- Process for the preparation of the compounds of general formula I according to claim 1 wherein the hydroxymethyl penems of formula II wherein R^ is as above defined and Y is an ester group, are reacted with the appropriate sulfonyl chloride in the presence of an organic base in an inert organic solvent at a temperature of - 70 - +20 ° C; the sulfonyl derivative (V) wherein R^ and Y are as above defined and Z is an alkyl or aryl is reacted with a compound of general formula (VI) wherein n, Ro, R^ , Re and Rg are as above defined in an organic solvent at -20° - +20 ° and the obtained penem derivatives of formula (VII) wherein n, Y, R.^ , Ro, R^ , Re and Rg are as above defined are transformed into the compounds of formula (I) by hydrolysis, hydrogenolysis or the like. 8. Process according to claim 7 wherein the sulfonyl derivatives of formula (V) wherein R^, Y and Z are as above defined are transformed into the corresponding halides of formula (VIII) wherein X is chosen in the group consisting of: chlorine, bromine, iodine by reaction with an inorganic halide and then are reacted as above said. 9 - Use of the penem derivatives according to claim 1 for the preparation of pharmaceutical compositions having antibacterial properties . 10. Pharmaceutical compositions for oral or parenteral use containing as active principle a derivative according to claim 1 in combination with the appropriate excipients and optionally with other antibiotics or inhibitors of beta-lactamases .

Inventors: ALTAMURA MARIA, ARCAMONE FEDERICO MARIA, CASCIO GIUSEPPE, PERROTTA ENZO, PESTELLINI VITTORIO, SBRACI PIERO, ALTAMURA, MARIA, ARCAMONE, FEDERICO, MARIA, CASCIO, GIUSEPPE, PERROTTA, ENZO, PESTELLINI, VITTORIO, SBRACI, PIERO
Applicants: ALTAMURA MARIA, ARCAMONE FEDERICO MARIA, CASCIO GIUSEPPE, LUSO FARMACO INST, MENARINI FARMA IND, PERROTTA ENZO, PESTELLINI VITTORIO, SBRACI PIERO, A. MENARINI INDUSTRIE FARMACEUTICHE RIUNITE S.R.L., ISTITUTO LUSOFARMACO D'ITALIA S.P.A.
Application year: 1993
Main classification: C07D499
IPC codes: A61K31, A61P31, C07D499