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WO1991017995A1 - Nouveaux dithiocarbamates de peneme, leur utilisation et procedes de production - Google Patents

Nouveaux dithiocarbamates de peneme, leur utilisation et procedes de production Download PDF

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Publication number
WO1991017995A1
WO1991017995A1 PCT/IT1991/000041 IT9100041W WO9117995A1 WO 1991017995 A1 WO1991017995 A1 WO 1991017995A1 IT 9100041 W IT9100041 W IT 9100041W WO 9117995 A1 WO9117995 A1 WO 9117995A1
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WO
WIPO (PCT)
Prior art keywords
penem
carboxylate
hydroxyethyl
thiocarbonylthiomethyl
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IT1991/000041
Other languages
English (en)
Inventor
Maria Altamura
Federico Arcamone
Danilo Giannotti
Vittorio Pestellini
Piero Sbraci
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
A Menarini Industrie Farmaceutiche Riunite SRL
Original Assignee
A Menarini Industrie Farmaceutiche Riunite SRL
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by A Menarini Industrie Farmaceutiche Riunite SRL filed Critical A Menarini Industrie Farmaceutiche Riunite SRL
Publication of WO1991017995A1 publication Critical patent/WO1991017995A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2

Definitions

  • the invention relates to penem compounds of general formula
  • Penem derivatives are well known in the art as antibacterial agents.
  • UK-A-2 097 786 discloses for example the process for the production of
  • penem derivatives have poor chemical stability. This instability is one of the most frequent limitations to the pharmaceutical use of penem derivatives (vide R.B.Morin, M.Gorman “Chemistry and Biology of ⁇ -Lactam Antibiotics” Academic Press, 1982, vol.2, page 323).
  • - Ri is a hydrogen atom, lower alkyl, lower alkoxy, cycloalkyl or hydroxyalkyl , the alcoholic function of the hydroxyalkyl being free or protected.
  • the substituent in the 6 position has the -configuration as well as the ⁇ -configuration.
  • R2 is a free or esterified carboxy group or a carboxylate anion.
  • R2 is an esterified carboxy group it is a group COO- linked through the oxygen atom to a organic radical, such as a C1-C6 alkyl group, for example methyl or ethyl; a halo-substituted C-i-C ⁇ alkyl group, for example 2,2,2-trichloroethyl; a C2-C6 alkenyl group, for example allyl; an optionally substituted aryl group, for example phenyl and p-nitrophenyl; an optionally substituted aryl-C-
  • R 2 as an esterified carboxy group includes also a carboxy group esterified with any residue which is known to undergo metabolic activation in vivo and having favorable pharmacokinetic properties, including acetoxymethyl, pivaloyloxymethyl or any group of the general formula
  • R5, Re, R7 are alkyl having from 1 to 6 carbon atoms or aryl.
  • R 3 and R 4 are each independently either hydrogen or: a) a C1-C6 alkyl group, optionally substituted without limiting the present invention with halogen, CF 3 , CN, CONRsRg, OR10, SRn, wherein Rs, R9, R .o, F.11 represent hydrogen atom, Ci-C ⁇ alkyl, aryl, arylalkyl b) an optionally substituted C- 1 -C 6 hydroxyalkyl or mercaptoalkyl c) an optionally substituted aminoalkyl group or an alkyl group substituted with a quaternary ammonium group + / R 12
  • R12, R13, R14 are each independently a hydrogen atom or an optionally substituted alkyl, arylalkyl or aryl radical d) an optionally substituted cycloalkyl, arylalkyl or heterocyclyl-alkyl group e) a heterocyclyl group, wherein the heterocycle has a 5-6 membered, saturated or unsaturated ring and can contain supplementary heteroatoms, such as oxygen, sulfur and nitrogen f) an aryl group.either unsubstituted or substituted with OH, OCH3, NH2, COOH, CONH2 or similar groups or g) R3 and R4 can together form an optionally substituted, 3-7 membered, saturated or unsaturated heterocyclic ring, which can contain supplementary heteroatoms, such as oxygen, sulfur or nitrogen, the nitrogen atom of the heterocyclic ring being optionally substituted with a Ci-C ⁇ alkyl , formyl, arylalkyl, aryl or heterocycly
  • the present invention includes all the possible geometrical and optical isomers of the compounds of formula (I) either in the form of isomeric mixture or in the form of the individual separated isomers.
  • the compounds of formula (I) have a (5R.6S) configuration.
  • the preferred R1 group is a lower hydroxyalkyl such as an ( ⁇ -hydroxy)ethyl radical.
  • the ( ⁇ -hydroxy)ethyl radical has preferably the (1 R) configuration, i.e. a
  • the protecting group is preferably p-nitrobenzyloxycarbonyl, allyloxycarbonyl, t- butyldimethylsilyl or trimethylsilyl.
  • R2 is an esterified carboxy group, it is preferably allyl, although other known protecting groups such as p-nitrobenzyl can also be included, or it is an ester residue which is known to be hydrolized in vivo , such as acetoxy methyl, ⁇ -acetoxyethyl or pivaloyloxymethyl and equivalent groups.
  • R3 and R4 are preferably hydrogen, optionally substituted C-i-C ⁇ alkyl, hydroxyalkyl, optionally substituted aryl, arylalkyl, such as benzyl, or heterocyclyl-alkyl, or are linked together in a saturated heterocyclic ring or in a heteroaromatic five or six atom ring system, also containing one or more additional heteroatoms, including N, O, S, such as for example 1 -pyrrolidyl, 4-morpholyl or 1-piperazinyl, wherein the nitrogen atom in the position 4 of the piperazine ring can be optionally substituted with a C-i-C ⁇ alkyl, aryl, arylalkyl or heterocyclyl group.
  • the pharmaceutically acceptable salts of the compounds of formula (I) wherein R2 is COOH are included within the scope of the invention.
  • the said salts may be salts with inorganic bases such as for example alkali or alkaline- earth metal hydroxides, preferably sodium and potassium hydroxides, and salts with organic bases, including aminoacids such as for example lysine and like salts usually formed with penicillins and cephalosporins.
  • the invention includes also internal salts, i.e. zwitterions.
  • compositions containing the compounds of formula (I), wherein R2 is preferably a carboxy group or a salt thereof or a metabolically activable ester group, in admixture with the usual carriers for oral and parenteral administration are also included in the present invention.
  • the compounds of the present invention possess a wide spectrum of antibacterial activity and also have ⁇ -lactamase inhibiting activity.
  • Compounds of formula (I) can be prepared from the corresponding hydroxymethyl compounds (II) (Scheme 1 ), wherein R1 is as defined above (usually ⁇ -hydroxyethyl) and Y is an ester residue, such as for example allyl or p-nitrobenzyl.
  • Compounds of formula (II) are well known intermediates which can be prepared (Scheme 1 ) from the azetidinone compounds (III) or from the natural penicillin derivatives (IV) following published procedures (see for example W.J.Leanza et al., Tetrahedron, 15, 2505 (1983); E.Fontana et al., J.Lab.Comp.Radiopharm., 24, 41 (1986)).
  • the penem alcohols (II) are activated as their sulfonyl derivatives (V), wherein R1 and Y are as defined above, and Z is an alkyl or aryl residue (usually methyl or p-tolyl), by reacting compounds (II) with the suitable sulfonyl chloride and an organic base, such as for example triethylamine or N.N-diisopropylamine, in an inert organic solvent, such as for example methylene dichloride or chloroform, at a temperature ranging from -70 to +20°C.
  • V sulfonyl derivatives
  • R1 and Y are as defined above
  • Z is an alkyl or aryl residue (usually methyl or p-tolyl)
  • an organic base such as for example triethylamine or N.N-diisopropylamine
  • an inert organic solvent such as for example methylene dichloride or chloroform
  • the sulfonyl derivatives (V) are allowed to react with an inorganic (usually sodium or ammonium) salt of an optionally substituted carbamodithioic acid in an organic solvent such as for example methyl sulfoxide, dimethyl formamide, dioxane or tetrahydrofuran, usually at a temperature of -20°/+20°C; the reaction can be carried out on the crude or isolated sulfonyl derivatives (V).
  • the dithiocarbamoyl penems (VI) are recovered by conventional work-up.
  • the reaction sequence is carried out with the alcoholic function protected with the conventional protecting groups, such as p-nitrobenzyloxycarbonyl, allyloxycarbonyl, t- butyldimethylsilyl or trimethylsilyl.
  • the 2-dithiocarbamoyl penems (I) can be prepared in a particularly favorable proportion between the penem and penam isomers; the final products thus obtained are provided with a high level of antibacterial activity, compared with standard ⁇ -lactam antibiotics, particularly against gram positive strains, such as Sarcina lutea, Bacillus subtilis, Staphylococcus aureus.
  • the crude product was dissolved in methyl sulfoxide (50 mL). 1.3 g (6.5 mmol) of sodium N-benzyldithiocarbamate were added and the mixture stirred at room temperature for 40 min. The solution was poured into cold water and extracted with ethyl acetate. The organic extract was washed with water, dried over Na2S ⁇ 4 and evaporated under vacuum. The crude product was purified by column chromatography on silica gel (diethyl ether/n-hexane 20:80 v/v). Yield: 1.12 g (40%). Yellow oil.
  • the crude product was dissolved in methyl sulfoxide (50 mL). 1 .2 g (6 mmol) of sodium N-(4-methyl-piperazin-1 -yl)-dithiocarbamate were added and the mixture stirred at room temperature for 1 h. The solution was poured into cold water and the separated product solified by treating with a saturated aqueous NaCI solution. The white crystalline product was collected, washed with water and dried under vacuum.
  • N-phenyldithiocarbamate were added and the mixture stirred at room temperature for
  • the crude product was dissolved in methyl sulfoxide (80 mL). 2.8 g (12 mmol) of sodium N-methyl-N-(2-(2-pyridyl)ethyl)dithiocarbamate were added and the mixture ' stirred at room temperature for 90 min. The solution was poured into cold water and extracted with ethyl ether. The organic extract was washed with water, dried over Na2S04 and evaporated under vacuum. The crude product was purified by column chromatography on silica gel (hexane/ethyl ether 20:80 v/v) Yield: 5.2 g (73%). Yellow oil.
  • the crude product was dissolved in methyl sulfoxide (50 mL). 1.2 g (6 mmol) sodium N-methyl-N-(2-N',N'-dimethylaminoethyl)dithiocarbamate were added and th mixture stirred at room temperature for 2 h. The solution was poured into cold wate and extracted with ethyl acetate. The organic extract was washed with water, drie over Na2S ⁇ 4 and evaporated under vacuum. The crude product was purified b column chromatography on silica gel (ethyl acetate). Yield: 0.6 g (21 %). Yellow oil.
  • Trifluoroacetic acid (4 mL) was added to a stirred solution of allyl (5R,6S)-2-[(4-(tert- butoxycarbonyl)piperazin-1 -yl)-thiocarbonylthiomethyl]-6-[(1 R)-1 -hydroxyethyl]- penem3-carboxylate (1.1 g; 2.08 mmol) in dichloromethane (20 mL). After stirring at room temperature for 10 min, the mixture was treated with NaHC0 3 (10 g), diluted with water and extracted with chloroform. The organic extract was washed with water, dried over MgS ⁇ 4 and evaporated under vacuum. The crude residue was purified b column chromatography on silica gel (chloroform/methanol 90:10 v/v).
  • Lichroprep RP18 (water/acetonitrile 97:3 v/v).
  • Lichroprep RP18 (water/acetonitrile 95:5 v/v).
  • the title product was obtained starting from allyl (5R,6S)-2-[(piperazin-1 -yl)- thiocarbonylthiomethyl]-6-[(1 R)-1-hydroxyethyl]-penem-3-carboxylate following the procedure described above for the (5R,6S)-2-((4-methyl-piperazin-1 -yl)- thiocarbonylthiomethyl)-6-[(1 R)-1 -hydroxyethyl]-penem-3-carboxylic acid (see
  • reaction product was recovered by extraction with water; the acqueous solution was lyophylized and the mixture separated by reverse phase column chromatography on Lichroprep RP18 (water/acetonitrile 90:10 v/v) Yield: 48% as a mixture of the penem and 2-methylenepenam isomers (3:1 from 1 H-NMR spectrum).
  • reaction product was recovered by extraction with water; the acqueous solution was lyophylized and the mixture separated by reverse phase column chromatography on Lichroprep RP18 (water/acetonitrile 90:10 v/v)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pens And Brushes (AREA)
  • Inks, Pencil-Leads, Or Crayons (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Un composé de la formule générale (I), dans laquelle R1 représente un atome d'hydrogène, C1-C6 alkyle, C1-C6 alkoxy, cycloalkyle ou hydroxyalkyle, la fonction alcoolique de l'hydroxyalkyle étant libre ou protégée; R2 représente un groupe carboxy libre ou estérifié ou un anion de carboxylate; R3 et R4 représentent chacun indépendemment soit hydrogène ou C1-C6 alkyle, C1-C6 hydroxyalkyle ou mercaptoalkyle, aminoalkyle ou alkyle substitués par un groupe d'ammonium quaternaire; cycloalkyle, arylalkyle ou hétérocyclyle-alkyle; un noyau hétérocyclique à 5-6 membres, saturé ou non saturé, qui peut contenir des hétéroatomes supplémentaires comme l'oxygène, le soufre et l'azote; un groupe aryle ou R3 et R4 forment ensemble un noyau hétérocyclique à 3-7 membres, saturé ou non saturé, qui peut contenir des hétéroatomes supplémentaires comme l'oxygène, le soufre ou l'azote.
PCT/IT1991/000041 1990-05-16 1991-05-14 Nouveaux dithiocarbamates de peneme, leur utilisation et procedes de production Ceased WO1991017995A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT9393A/90 1990-05-16
IT9393A IT1239275B (it) 1990-05-16 1990-05-16 Penem ditiocarbammati, loro uso e procedimento di fabbricazione relativi

Publications (1)

Publication Number Publication Date
WO1991017995A1 true WO1991017995A1 (fr) 1991-11-28

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AU (1) AU7853591A (fr)
IT (1) IT1239275B (fr)
PT (1) PT97676A (fr)
WO (1) WO1991017995A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0503597A3 (en) * 1991-03-13 1992-12-09 Otsuka Kagaku Kabushiki Kaisha Penam derivatives and processes for producing the same
WO1994006803A1 (fr) * 1992-09-17 1994-03-31 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Derives de peneme, leur preparation et compositions pharmaceutiques contenant ces derives
US6971676B2 (en) 2002-06-27 2005-12-06 Nacam France S.A. Device for absorbing energy from an automobile vehicle steering column
CN106220588A (zh) * 2016-07-22 2016-12-14 郑州大学 金属β‑内酰胺酶抑制剂环状胺基二硫代甲酸盐衍生物及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4302578A (en) * 1970-12-09 1981-11-24 Merck & Co., Inc. Cephalosporin antibiotics
GB2097786A (en) * 1981-05-06 1982-11-10 Erba Farmitalia Antibacterial Agents
US4711886A (en) * 1984-07-02 1987-12-08 Merck & Co., Inc. β-lactam derivatives as anti-inflammatory and antidegenerative agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4302578A (en) * 1970-12-09 1981-11-24 Merck & Co., Inc. Cephalosporin antibiotics
GB2097786A (en) * 1981-05-06 1982-11-10 Erba Farmitalia Antibacterial Agents
US4711886A (en) * 1984-07-02 1987-12-08 Merck & Co., Inc. β-lactam derivatives as anti-inflammatory and antidegenerative agents

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0503597A3 (en) * 1991-03-13 1992-12-09 Otsuka Kagaku Kabushiki Kaisha Penam derivatives and processes for producing the same
WO1994006803A1 (fr) * 1992-09-17 1994-03-31 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Derives de peneme, leur preparation et compositions pharmaceutiques contenant ces derives
AU674874B2 (en) * 1992-09-17 1997-01-16 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Penem derivatives, their preparation and pharmaceutical compositions containing them
US6971676B2 (en) 2002-06-27 2005-12-06 Nacam France S.A. Device for absorbing energy from an automobile vehicle steering column
CN106220588A (zh) * 2016-07-22 2016-12-14 郑州大学 金属β‑内酰胺酶抑制剂环状胺基二硫代甲酸盐衍生物及其制备方法

Also Published As

Publication number Publication date
IT1239275B (it) 1993-10-01
AU7853591A (en) 1991-12-10
IT9009393A0 (it) 1990-05-16
PT97676A (pt) 1992-02-28
IT9009393A1 (it) 1991-11-16

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