WO1997002268A1 - 7,7-disubstituted cephem-4-ketones - Google Patents

7,7-disubstituted cephem-4-ketones Download PDF

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Publication number
WO1997002268A1
WO1997002268A1 PCT/EP1996/002883 EP9602883W WO9702268A1 WO 1997002268 A1 WO1997002268 A1 WO 1997002268A1 EP 9602883 W EP9602883 W EP 9602883W WO 9702268 A1 WO9702268 A1 WO 9702268A1
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Prior art keywords
methyl
group
tert
cephem
dioxide
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PCT/EP1996/002883
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French (fr)
Inventor
Pierluigi Bissolino
Marco Alpegiani
Riccardo Corigli
Ettore Perrone
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Pharmacia & Upjohn S.P.A.
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Application filed by Pharmacia & Upjohn S.P.A. filed Critical Pharmacia & Upjohn S.P.A.
Priority to JP9504808A priority Critical patent/JPH10505363A/en
Priority to EP96924842A priority patent/EP0781286A1/en
Publication of WO1997002268A1 publication Critical patent/WO1997002268A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to new 7, 7-disubstituted cephem-4-ketones, to a process for their preparation and to pharmaceutical and veterinary compositions containing them.
  • the compounds according to the invention are useful as protease inhibitors, especially human leukocyte elastase (HLE) inhibitors, and for the prevention, control and treatment of diseases involving the uncontrolled release of proteolytic enzymes, in particular emphysema, metastasis, cystic fibrosis, adult respiratory distress syndrome, rheumatoid arthritis, osteoarthritis, periodontal diseases, septic and traumatic shock, infectious arthritis, rheumatic fever, spondylitis, gout, lupus and psoriasis.
  • HLE human leukocyte elastase
  • the invention provides a compound of the formula (la) or (lb) or a pharmaceutically acceptable salt thereof:
  • A is as defined above or acylamino -NH-Z wherein Z is a mono, di- or tripeptide composed of D or L ⁇ -aminoacids chosen from Ala, Gly, Val, Leu, Ile, Phe and with the terminal amino group either free or acylated by a group -C(O)A or -C(O))A wherein A is as defined above;
  • R 1 is either hydrogen or an optionally substituted straight or branched C 1 -C 12 alkyl or a C 2 -C 12 alkenyl group, or a C 7 -C 14 aralkyl group, or a (heterocyclyl)alkyl group;
  • R 2 represents:
  • R 1 and R 2 taken together with the carbon atom to which they are attached constitute a carbocyclic or heterocyclic group; where approprite R 1 and/or R 2 are optionally substituted;
  • R 3 represents:
  • A' being the same or different, is as defined above for A; or A and A' taken together with the nitrogen atom to which they are attached represent a heterocyclic ring;
  • R 3 is optionally substituted
  • X represents O, NR or S, wherein R is
  • the C 1 -C 12 alkyl group is a straight or branched alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl .
  • the C 2 -C 12 alkenyl group is a straight or branched alkenyl group such as vinyl, allyl, crotyl,
  • the C 2 -C 12 alkynyl group is a straight or branched alkynyl group such as ethynyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl.
  • the C 6 -C 14 aryl group is a monocyclic, bicyclic or tricyclic aromatic hydrocarbon group of 6 to 14 carbon atoms, such as phenyl, naphthyl, phenanthryl or anthryl.
  • the C 3 -C 8 cycloalkyl group is a saturated carbocyclic group of 3 to 6 carbon atoms, such as cyclopropyl,
  • the C 5 -C 8 cycloalkenyl group is an unsaturated
  • carbocyclic group such as cyclopentenyl, cyclohexenyl .
  • the C 7 -C 22 aralkyl group is an alkyl group of 1 to 4 carbon atoms linked to one , two or three monocyclic aromatic hydrocarbon groups of 6 carbon atoms or to a bicyclic aromatic hydrocarbon group of 10 carbon atoms.
  • aralkyl groups examples include benzyl, phenylethyl,
  • the C 8 -C 14 aralkenyl group is an alkenyl group of 2 to 4 carbon atoms linked to a monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 carbon atoms.
  • Examples of aralkenyl groups are styryl, 2-phenyl-1-propenyl,
  • the C 8 -C 14 aralkynyl group is an alkynyl group of 2 to 4 carbon atoms linked to a monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 carbon atoms.
  • aralkynyl groups are 2-phenylethynyl, 2-naphthylethynyl .
  • the (cycloalkyl)alkyl group is an alkyl group of 1 to 4 carbon atoms linked to a cycloalkyl group.
  • the (cycloalkyl)alkenyl group is an alkenyl group of 2 to 4 carbon atoms linked to a C 3 -C 8 cycloalkyl group as defined above.
  • the heterocyclyl group is a 3- to 6-membered .
  • saturated or unsaturated heterocyclyl ring containing at least one heteroatom selected from O, S and N, which is optionally fused to a second 5- or 6-membered , saturated or unsaturated heterocyclyl group or to a cycloalkyl group or to an aryl group.
  • heterocyclyl groups are pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
  • azetidinyl pyridinyl, pyrazinyl, pyrimidinyl, pyranyl, pyridazinyl, benzothienyl, benzothiazolyl, benzoxazolyl, isobenzofuranyl, benzofuranyl, chromenyl, indolyl,
  • indolizinyl isoindolyl, cinnolinyl, indazolyl, purinyl.
  • the (heterocyclyl)alkyl group is an alkyl group of 1 to 4 carbon atoms linked to a heterocyclyl group.
  • the (heterocyclyl)alkenyl group is an alkenyl group of 2 to 4 carbon atoms linked to a heterocyclic group.
  • halogen preferably encompasses fluorine, chlorine, bromine or iodine.
  • alkyl alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, aralkenyl, aralkynyl,
  • halo i.e., fluoro, bromo, chloro or iodo
  • R' ' which are the same or different, are C 1 -C 12 straight or branched alkyl groups or phenyl or benzyl; - formyl (i.e., -CHO);
  • R' is as defined above and t is 0, 1, 2 or 3; - sulfo (i.e., -SO 3 H) ;
  • - acyl i.e., -C(O)R'
  • R' is as defined above or trifluoroacetyl (i.e., -C(O)CF 3 );
  • R' is as defined above;
  • - acylamino i.e., -NHC(O)R' ' ' or -NHC(O) OR' ' '
  • R' ' ' is C 1 -C 12 straight or branched alkyl, phenyl, benzyl, CH 2 CH 2 COOH or CH 2 CH 2 CH 2 COOH;
  • carbamoylmethyl carbamoyloxymethyl, hydroxymethyl, C 1 -C 4 alkoxycarbonylmethyl, guanidinomethyl.
  • the carboxy, amino, hydroxy and mercapto groups may be any suitable carboxy, amino, hydroxy and mercapto groups.
  • the carboxyl-protecting group may, for example, be a lower alkyl group such as methyl, ethyl, propyl, isopropyl or tert-butyl; a halogenated lower alkyl group such as a 2,2,2-trichloroethyl or a 2,2,2-trifluoroethyl; a lower alkanoyloxyalkyl group such as acetoxymethyl,
  • propionyloxymethyl pivaloyloxymethyl, 1-acetoxyetyl, 1-propionyloxyethyl; a lower alkoxycarbonyloxyalkyl group such as 1-(methoxycarbonyloxy)ethyl,
  • Particularly preferred are a tert-butyl group, a
  • p-nitrobenzyl group a p-methoxybenzyl group, a benzhydryl group, a tert-butyldimethylsilyl, tert-butyldiphenylsilyl group or a propenyl group.
  • amino, hydroxy or mercapto protecting groups possibly present may be those usually employed in the chemistry of penicillins and cephalosporins for this kind of functions. They may be, for instance, optionally
  • acyl groups e.g. acetyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl, benzoyl or p-bromophenacyl; triarylmethylgroups, e.g.
  • Preferred protecting groups of the hydroxy function are p-nitrobenzyloxycarbonyl; allyloxycarbonyl;
  • p-bromophenacyl triphenylmethyl, pyranyl, methoxymethyl, benzhydryl, 2-methoxyethoxymethyl, formyl, acetyl,
  • the present invention provides the salts of those compounds of formula (la) or (lb) that have salt-forming groups, especially the salts of the compounds having a carboxylic group, a basic group (e.g. an amino or guanidino group), or a quaternary ammonium group.
  • the salts are especially physiologically tolerable salts, for example alkali metal and alkaline earth metal salts (e.g. sodium, potassium, lithium, calcium and magnesium salts), ammonium salts and salts with an appropriate organic amine or amino acid (e.g.
  • arginine, procaine salts and the addition salts formed with suitable organic or inorganic acids, for example hydrochloric acid, sulfuric acid, carboxylic and sulfonic organic acids (e.g. acetic, trifluoroacetic, p-toluenesulfonic acid).
  • suitable organic or inorganic acids for example hydrochloric acid, sulfuric acid, carboxylic and sulfonic organic acids (e.g. acetic, trifluoroacetic, p-toluenesulfonic acid).
  • the present invention encompasses all the possible stereoisomers as well as their racemic or optically active mixtures.
  • compounds (la) or (lb) may include, for example,
  • methoxycarbonylmethyl 1-methoxycarbonyloxy-1-ethyl, indanyl, phtalidyl, methoxymethyl, pivaloyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl or 5-methyl-2-oxo-1,3-dioxolan-4-yl esters, and other physiologically
  • antibiotics more preferably, methoxycarbonyloxymethyl, 1-methoxycarbonyloxy-1-ethyl, methoxymethyl or
  • Typical solvates of the cephalosporin compounds of formula (I) may include solvates with water miscible solvents, e.g. methanol, ethanol, acetone or acetonitrile or acetonitrile; and more preferably, ethanol.
  • heterocycyl and is optionally substituted by one or more of halo, sulfo, carboxy, C 1 -C 5 alkylcarbonyloxy, C 1 -C 5 alkoxy, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 carbamoyl, sulfamoyl, C 1 - C 5 carbamoyloxy, C 1 -C 5 alkylcarboxamido, C 1 -C 5 haloalkylcarboxamido, nitro, cyano, diazo, hydroxy, benzhydryloxy, amino, C 6 -C 10 arylcarbonyl, C 6 -C 10 aryloxy, C 7 -C 13 aralkyloxy, C 7 -C 13 alkaryloxy, C 1 -C 5 alkanoyl, C 1 -C 5 alkanoyloxy, C 1 -C 5 alkylsulfonyl, C 6 -C 10 aryl
  • substituents for the groups defined under (1')-(11') being selected from halo, sulfo, carboxy, C 1 -C 5 alkylcarbonyloxy, C 1 -C 5 alkoxy, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 carbamoyl, sulfamoyl, C 1 -C 5 carbamoyloxy, C 1 -C 5
  • alkylcarboxamido C 1 -C 5 haloalkylcarboxamido, nitro, cyano, diazo, hydroxy, benzhydryloxy, amino, C 6 -C 10 arylcarbonyl, C 6 -C 10 aryloxy, C 7 -C 13 aralkyloxy, C 7 -C 13 alkaroloxy, C 1 -C 5 alkanoyl, C 1 -C 5 alkanoyloxy, C 1 -C 5 alkylsulfonyl, C 6 -C 10 arylcarbonyloxy, C 6 -C 10 arylcarboxy, C 7 -C 13 alkarylcarboxy, C 7 -C 13 aralkylcarbonyloxy, C 7 -C 13 alkarylcarboxy, C 7 -C 13 aralkanoyloxy, C 1 -C 5
  • alkylcarbonyloxy C 1 -C 5 alkylthio C 2 -C 10 secondary amino, C 3 -C 15 tertiary amino, di-C 1 -C 5 alkylamino, di-C 1 -C 5 -alkylamino C 1 -C 5 alkyl, oxo, halo C 1 -C 5 alkanoyl, straight or branched C 1 -C 5 alkyl and straight or branched C 2 -C 5 alkenyl;
  • R 1 is either hydrogen or halogen, or an optionally
  • substituents being selected from nitro, cyano, carbamoyl, hydroxy, carboxy, amino, methoxycarbonyl, benzhydryloxycarbonyl, tert-butoxycarbonyl, acetyl, acetoxy, formamido, methoxy, sulfonyl, methylthio, phenoxy, halogen;
  • R 2 is either
  • the optional substituents being selected from halo, sulfo, carboxy, C 1 -C 5 alkylcarbonyloxy, C 1 -C 5 alkoxy, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 carbamoyl, sulfamoyl, C 1 -C 5
  • alkarylcarbonyloxy C 7 -C 13 aralkanoyloxy, C 1 -C 5
  • halocarbanoyl C 1 -C 5 alkylcarboxy, C 1 -C 5 alkanoylamido, C 7 -C 13 alkarylcarbonyl, C 7 -C 13 aralkylcarbonyl, C 1 -C 5 alkylthio, C 6 -C 10 arylthio, C 1 -C 5 alkylsulfonyl, C 6 -C 10 arylsulfonyl, sulfo C 1 -C 5 alkyl, carboxy C 1 -C 5 alkylthio, C 2 -C 10 secondary amino, C 3 -C 15 tertiary amino, di-C 1 -C 5 -alkylamino, di-C 1 -C 5 -alkylamino-C 1 -C 5 alkyl, oxo, C 1 -C 5 haloalkanoyl, straight or branched C 1 -C 5 alkyl and straight or branched C 2
  • heterocyclyl ring either unsubstituted or substituted by one group or two equal or different groups chosen from the following: hydroxy, carboxy, amino, sulfo,
  • X represents O, S or NR, wherein R is as defined above.
  • a further preferred class of compounds of formula (la) and (lb) is when A is a group selected from methyl, tert-butyl, 2-phenyl-2-propyl, benzyl and diphenylmethyl, which groups are optionally substituted by one or more
  • methanesulfonyl methoxy, ethoxy, tert-butoxy, benzyloxy, acetoxy, pivaloyoxy, benzoxy, carboxymethyl,
  • Q and W which are as defined above, are independently each optionally substituted, where appropriate, by one or more substituents selected from fluoro, chloro, bromo, carboxy, tetrazolyl, carbamoyl, methanesulfonyl, benzyloxy, benzoxy, acetoxy, pivaloyloxy, methylthio, phenylthio, benzenesulfonyl, sulfomethyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxymethylthio, -C 6 H 4 -COOH, C 6 H 5 COO-, -CH 2 -C 6 H 4 -COOH, CH 3 -C 6 H 4 -COO-, C 6 H B -CH 2 -COO- , -C 6 H 4 CH 2 COOH, acetyl, trifluoroacetyl, benzoyl, pivaloyl, dimethylamino,
  • R 2 which is as defined above, is optionally substituted where appropriate by one or more substituents selected from fluoro, chloro, bromo, carboxy, tetrazolyl, carbamoyl, methanesulfonyl, benzyloxy, benzoxy, acetoxy, pivaloyloxy, methylthio, phenylthio, benzenesulfonyl, sulfomethyl, carboxymethyl, carboxyethyl, carboxypropyl,
  • cephem-4-carboxylic acid/cephem-4-ketone can be carried out for example as described in EP-A-0337704 (18.10.89) and may precede or follow the
  • C-7 substituents can be introduced by modifying cephem derivatives already bearing the ketone group at C-4 and prepared according to literature methods.
  • compounds of formula (I) wherein Q and W constitute a methylene or substituted methylene group can be prepared by reaction of 7-oxocephems with the suitable Grignard or Wittig-Horner reagent (see e.g.: Heterocycles 24 (1986) 289).
  • a particularly preferred process for the preparation of compounds of formula (la) and (lb) comprises:
  • reaction of a diazocephem of formula (II) [step (i a )] with a compound of formula (III) is usually performed in an aprotic solvent such as dichloromethane, chloroform, benzene, toluene, xylenes, cyclohexane, n-hexane, diethyl ether, ethyl acetate, dioxane, acetonitrile,
  • an aprotic solvent such as dichloromethane, chloroform, benzene, toluene, xylenes, cyclohexane, n-hexane, diethyl ether, ethyl acetate, dioxane, acetonitrile,
  • Reaction temperatures range between -50° and 140 °C, preferably between -20 °C and +110 °C.
  • a catalyst can sometimes have a beneficial effect enhancing the reativity of diazo-derivatives .
  • Said catalyst can be either an acid, preferably a Lewis acid such as boron trifluoride, aluminum trichloride, tin tetrachloride and the like, or a metal reagent such as rhodium acetate.
  • the reaction between diazo-derivatives of formula (II) and reagents of formula (III) can be
  • the leaving group L is typically a halogen, preferably bromine, chlorine or iodine, or an imido group, preferably succinimido or phthalimido.
  • the reagent W-L (V) is usually used in stoichiometric amount or a slight excess thereof, while the reagent Q-H (IV) can sometimes be used in large molar excess.
  • Suitable solvents for the reaction (i b ) are the same as those of the reaction (i a ) and reaction temperatures usually range between -30 °C and +110 °C.
  • compounds of formula (Ia) and (Ib) can be prepared from compounds of formula (Ia) by way of known chemical reactions or in analogy with known processes, i.e. the groups A, Q, W, R 1 , R 2 and R 3 can be converted by conventional methods into different groups included within those previously defined, if desired, at the end or at any stage of the process above.
  • a compound of the formula (Ia), wherein R 3 is a substituted methyl group may be converted into a compound of the formula (Ib) as described in
  • R 1 , R 2 , R 3 and R 5 are as defined above;
  • carboxylic moiety is typically activated as the halide, anhydride, mixed anhydride, thioester or ester thereof, and then reacted with a synthetic equivalent of A-, wherein A is as defined above.
  • Suitable synthetic equivalents of A- include the following organometallic derivatives of A:
  • A-MgX (Grignard reagents)
  • A-Li organolitium reagents e.g.phenyllithium
  • a 2 CuLi lithium dialkylcopper reagents
  • A-Cu cuprous reagents; e.g. cuprous acetylides
  • AZnX organozinc reagents
  • AMnX organomanganese reagents
  • a n SnX (4-n) (organotin reagents, wherein X is C 1 -C 12 alkyl, chloro, phenyl, and n may be 0,1,2,3).
  • reaction solvents are non-protic solvents such as tetrahydrofuran, diethyl ether, dichloromethane, benzene, toluene, hexamethylphosphoramide, dimethoxyethane, dioxane, dichloroethane, xylene, chloroform, n-hexane or mixtures thereof.
  • Suitable reaction temperatures can vary from -100 °C to +120 °C, preferably between -80 °C and +60°C.
  • inorganic or organometal derivatives e.g. copper salts such as cuprous iodide, iron derivatives such as tris [acetylacetonato] iron(III), palladium
  • Preferred oxidizing agents are inorganic or organic
  • peracids are, for example, peracetic acid, m-chloroperoxybenzoic acid (MCPBA), monoperphthalic acid, alkaline monoperoxysulfate, tetrabutylammonium
  • peroxydisulfate suitable solvents are chloroform,
  • dichloromethane tetrahydrofuran (THF)
  • acetonitrile ethanol
  • acetic acid ethyl acetate or mixtures thereof.
  • the oxidation is usually carried out at a temperature of from -20 °C to +80 °C.
  • Typical nitrosating agents are nitrosyl chloride, dinitrogen tetroxide, dinitrogen trioxide.
  • solvents are protic or aprotic organic solvents such as chloroform, dichlorometane, tetrahydrofuran, ethyl acetate, acetic acid, acetic anhydide, acetonitrile or mixtures thereof.
  • protic organic solvents such as chloroform, dichlorometane, tetrahydrofuran, ethyl acetate, acetic acid, acetic anhydide, acetonitrile or mixtures thereof.
  • R 5 group Removal of the R 5 group (i.e. unmasking the amino function) from compounds of formula (VII) is carried out under conditions dependent on the nature of the amino protecting group R 5 .
  • Typical R 5 groups are groups which withstand the tranformations referred to under (ii) annd (iii) and still can be removed under selective and mild conditions.
  • Typical R 5 groups are acid sensitive groups such as tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, trityl, 1-adamantyloxycarbonyl and so on (which can be removed under mild conditions in the presence of organic or inorganic acids e.g. formic acid, trifluoroacetic acid, p-toluensulfonic acid, methansulfonic acid, aluminum
  • the diazotation reaction can usually be carried out either in an aprotic organic solvent (e.g. ethyl acetate,
  • acetonitrile in the presence of organic nitrites (e.g. alkyl nitrites such as butyl nitrite, tert-butylnitrite, amyl nitrite, propyl nitrite and so on) with or without an acid catalyst (e.g. formic acid, trifluoroacetic acid, p-toluensulfonic acid, acetic acid, methanesulfonic acid) or in a biphasic system in the presence of nitrous acid
  • organic nitrites e.g. alkyl nitrites such as butyl nitrite, tert-butylnitrite, amyl nitrite, propyl nitrite and so on
  • an acid catalyst e.g. formic acid, trifluoroacetic acid, p-toluensulfonic acid, acetic acid, methanesulfonic acid
  • an inorganic nitrite e.g. alkaline metal, alkaline-earth metal or ammonium nitite
  • an organic or inorganic acid e.g. p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, perchloric acid, hydrochloric acid and the like.
  • HLE human leukocyte elastase
  • inhibitors appear to have a number of advantages over natural high molecular weight protease inhibitors from either plant or animal sources: 1) they can be obtained in quantities; 2) they can be rationally designed or
  • optimised they are not antigenic; and 4) they may be used orally or in aerosols.
  • Many low molecular weight elastase inhibitors discovered so far contain reactive functional groups (chloromethyl ketones, isocyanates, etc); they may react with functional groups of proteins, and therefore they may be quite toxic.
  • j ⁇ -lactam compounds are of potential interest because, though reactive towards serine protease, they are, as it is known, non-toxic at very high concentrations.
  • the compounds of the present invention are:
  • HLE human leukocyte elastase
  • V z zero time rate
  • the compounds prepared respectively in examples 5 and 8 have a K on of 3000 and 3400 M -1 sec -1 , K i SS 0.1 and 6 ⁇ M.
  • the compound of example 8 showed a chemical stability, expressed as half-life in aqueous buffer at 37°C, of 410 hours at pH 7.4 and of 3000 hours at pH 1.2.
  • the compounds of the present invention can be used in the treatment of inflammatory and degenerative diseases caused by proteolytic enzymes in mammals including humans.
  • the compounds can be used to make medicaments useful to prevent or arrest the progression of diseases caused by proteolytic degradation of lungs and connective tissues, reduce inflammation and fever, and relieve pain.
  • diseases are emphysema, acute
  • the present invention also provides pharmaceutical and veterinary compositions containing a suitable carrier and/or diluent and, as an active principle, a
  • compositions containing a compound of formula I or salt thereof may be prepared in a conventional way by employing conventional non-toxic pharmaceutical carriers or diluents in a variety of dosage forms and ways of administration.
  • the compounds of formula I can be administered:
  • compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such
  • compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulation for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example, sodium
  • dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation
  • alkylene oxide with fatty acids for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol
  • anhydrides for example polyoxyethylene sorbitan
  • the said aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, or one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspension may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation.
  • Dispersible powders and granules suitable for peparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present .
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water
  • the oily phase may be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol
  • anhydrides for example sorbitan mono-oleate
  • condensation products of the said partial esters with ethylene oxide for example polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents .
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • TheT pharmaceutical compositions may be in the form of a sterile injectable aqueous or olagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing of wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic
  • parenterally-acceptable diluent or solvent for example as a solution in 1,3-butane diol.
  • acceptable vehicles and solvents that may be employed are water,
  • Ringer's solution and isotonic sodium chloride solution are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides .
  • fatty acids such as oleic acid find use in the preparation of injectables;
  • Still a further object of the present invention is to provide a method fo controlling inflammatory and
  • degenerative diseases by administering a therapeutically effective amount of one or more of the active compounds encompassed by the formula I in humans or mammalians in need of such treatment .
  • Daily dose are in the range of about 0.1 to about 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the
  • daily dosage levels for humans are in the range of 20 mg to 2 g.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration to humans may contain from 5 mg to 2 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 5 mg to about 500 mg of active ingredient .
  • Compounds of formula (VI) are known compounds or can be prepared from known compounds by known methods.
  • Trietylamine (56 ml) was added dropwise to a mixture of 7 ⁇ -amino-3-deacetoxy cephalosporanic acid (42.8 g) in dioxane (800 ml) and water (400 ml).
  • tert -Butylpercarbonate (66 g) was then added and the resulting mixture was vigorously stirred at room temperature for 6 hours, thence poured into water/diethyl ether (ratio 3:1; 800 ml).
  • the aqueous phase was acidified with 8%
  • cephalosporanic acid (40.8 g) in dry tetrahydrofuran (400 ml) was cooled to 0°C. Under nitrogen, oxalyl chloride (16.8 ml) was added, soon followed by 0.7 ml of N,N-dimethylformamide.
  • Step B 7 ⁇ -tert-Butoxycarbonyl amino-4-tert-butyl carbonyl-3-methyl-3-cephem
  • Step B 7 ⁇ -tert-butoxycarbonylamino-3-methyl-4-phenylcarbonyl-3-cephem 1,1-dioxide
  • reaction mixture was stirred for 0.5 h at room temperature thence poured into a 1M solution of aqueous NaHCO 3 .
  • reaction mixture was let stand at reflux for 2 h, then poured into water-ethyl acetate. The organic layer was collected, dried over Na 2 SO 4 and concentrated in vacuo.
  • reaction mixture was let stand at reflux for 4 h, then poured into water/ethyl acetate. The organic layer was collected, dried over Na 2 SO 4 and concentrated in vacuo.
  • reaction mixture was diluted with ethyl acetate, sequentially washed with saturated NaHCO 3 and brine and dried over Na 2 SO 4 . Removal of the solvent in vacuo left the crude product which was obtained pure as a white solid by silica gel chromatography (120 mg).
  • the second eluted product was the 3'-bromo cephem derivative (250 mg):
  • composition for intramuscular injection is a composition for intramuscular injection
  • Step 1 Dissolve the active ingredient in the buffer
  • Step 2 Aseptically filter the solution from step 1.
  • Step 3 The sterile solution is aseptically filled into sterile ampoules
  • Step 4 The ampoules are sealed under aseptic conditions

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Abstract

The present invention provides compounds of formulae (Ia) and (Ib) and pharmaceutically or veterinarily salts thereof; wherein A, R1, R2 and R3 are hydrogen, halogen or an organic group; Q and W are appropriate substituents and X is either oxygen or sulphur or NR, wherein R is either hydrogen or an organic group. A process for their preparation is also described. The compounds of formulae (Ia) and (Ib) and the pharmaceutically and veterinarily acceptable salts thereof are elastase inhibitors.

Description

7,7-DISUBSTITUTED CEPHEM-4-KETONES
The present invention relates to new 7, 7-disubstituted cephem-4-ketones, to a process for their preparation and to pharmaceutical and veterinary compositions containing them. The compounds according to the invention are useful as protease inhibitors, especially human leukocyte elastase (HLE) inhibitors, and for the prevention, control and treatment of diseases involving the uncontrolled release of proteolytic enzymes, in particular emphysema, metastasis, cystic fibrosis, adult respiratory distress syndrome, rheumatoid arthritis, osteoarthritis, periodontal diseases, septic and traumatic shock, infectious arthritis, rheumatic fever, spondylitis, gout, lupus and psoriasis.
The invention provides a compound of the formula (la) or (lb) or a pharmaceutically acceptable salt thereof:
Figure imgf000003_0001
Figure imgf000003_0002
wherein A is an organic radical which is optionally substituted and is selected from C1-C12 straight or branched alkyl , C2-C12 alkenyl , C2-C12 alkynyl , C6-C14 aryl , C3-C8 cycloalkyl , C3-C8 cycloalkenyl C7-C22 alkaryl , C7-C22 aralkyl , C8-C14 alkenylaryl , C8-C14 aralkenyl , C8-C14 alkynylaryl , C8- C14 aralkynyl , ( cycloalkyl ) alkyl , ( cycloalkyl ) alkenyl , heterocyclyl , (heterocyclyl ) alkyl , (heterocyclyl ) alkenyl ; Q and W, each independently, represent
(1) chloro, fluoro, bromo or iodo;
(2) A as defined above
(3) hydroxy or an ether OA wherein A is as defined above (4) a thioether, sulfoxide or sulfone -S(O)mA wherein m is either zero, one or two and A is as defined above; (5) a selenoether, selenoxide or selenone -Se(O)mA wherein m is either zero, one or two and A is as defined above;
(6) acyl -C(O)A wherein A is as defined above;
(7) formyloxy -OC(O)H or acyloxy -OC(O)A wherein A is as defined above;
(8) sulfonyloxy -OS(O)2A wherein A is as defined above;
(9) formamido -NHC(O)H or an acylamino group -NHC(O)A
wherein A is as defined above or acylamino -NH-Z wherein Z is a mono, di- or tripeptide composed of D or L α-aminoacids chosen from Ala, Gly, Val, Leu, Ile, Phe and with the terminal amino group either free or acylated by a group -C(O)A or -C(O))A wherein A is as defined above;
(10) azido, nitro or cyano;
or Q and W taken together constitute an oxo group (=O) or a group of formula =CHA, =CHC(O)A, =CHC(O)OA or
=CHS(O)2A wherein A is as defined above;
or Q and W taken together with the carbon atom to which they are attached constitute an oxylane or
cyclopropyl group; with the proviso that in the compounds of formula (la) Q and W do not both represent chloro or fluoro atoms;
and where appropriate Q and W are optionally substituted;
R1 is either hydrogen or an optionally substituted straight or branched C1-C12 alkyl or a C2-C12 alkenyl group, or a C7-C14 aralkyl group, or a (heterocyclyl)alkyl group; R2 represents:
(1) hydrogen;
(2) A as defined above; (3) halo;
(4) a sulfenyl, sulfinyl or sulfonyl group -S(O)mA wherein A and m are as defined above;
(5) an acyloxy group -OC(O)A wherein A is as defined
above;
or R1 and R2 taken together constitute a methylene group or a group of formula =CHA, =CHC(O)A or =CHC(O)OA wherein A is as defined above;
or R1 and R2 taken together with the carbon atom to which they are attached constitute a carbocyclic or heterocyclic group; where approprite R1 and/or R2 are optionally substituted;
R3 represents:
(1) A as defined above;
(2) chloro or fluoro or hydrogen;
(3) a sulfenyl, sulfinyl or sulfonyl group -S(O)mA wherein A and m are as defined above;
(4) hydroxy or an oxy group -O-A wherein A is as defined above;
(5) formyl -C(O)H, carboxy -CO2H, or an acyl group -C(O)A or C(O)OA wherein A is as defined above;
(6) on oxymethyl group -CH2-OA wherein A is as defined
above;
(7) a thiomethyl group or a derivative thereof of formula
-CH2S(O)mA wherein m and A are as defined above;
(8) formyloxymethyl -CH2OC(O)H or an acyloxymethyl group -
CH2OC(O)A or -CH2O-Z wherein A and Z are as defined above;
(9) an acylthiomethyl group -CH2SC(O)A wherein A is as defined above;
(10) an aminomethyl group -CH2-N(A)A' wherein A is as
defined above and A', being the same or different, is as defined above for A; or A and A' taken together with the nitrogen atom to which they are attached represent a heterocyclic ring;
(11) ammoniomethyl -CH2N+(A)(A')A'' wherein A and A' are as defined above and A'', being the same or different, is as defined for A; or A is alkyl and A' and A'' together with the nitrogen atom to which they are attached represent a heterocyclic ring, or A and A' and A'' together with the nitrogen atom to which they are attached represent a heterocyclic ring;
(12) formamidomethyl -CH2NHC(O)H or an acylaminomethyl
group -CH2NH-C(O)A or -CH2NH-Z wherein A and Z are as defined above;
where appropriate R3 is optionally substituted;
and X represents O, NR or S, wherein R is
hydrogen or straight or branched C1-C12 alkyl, C3- C8 cycloalkyl, C6-C14 aryl or C7-C22 aralkyl group;
or an isomer thereof which is a stereoisomer,
diastereoisomer, epimer, geometrical isomer or tautomer, or a mixture of any of these isomers.
The C1-C12 alkyl group is a straight or branched alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl .
The C2-C12 alkenyl group is a straight or branched alkenyl group such as vinyl, allyl, crotyl,
2-methyl-1-propenyl, 1-methyl-1-propenyl, butenyl,
pentenyl.
The C2-C12 alkynyl group is a straight or branched alkynyl group such as ethynyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl.
The C6-C14 aryl group is a monocyclic, bicyclic or tricyclic aromatic hydrocarbon group of 6 to 14 carbon atoms, such as phenyl, naphthyl, phenanthryl or anthryl.
The C3-C8 cycloalkyl group is a saturated carbocyclic group of 3 to 6 carbon atoms, such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl .
The C5-C8 cycloalkenyl group is an unsaturated
carbocyclic group such as cyclopentenyl, cyclohexenyl .
The C7-C22 aralkyl group is an alkyl group of 1 to 4 carbon atoms linked to one , two or three monocyclic aromatic hydrocarbon groups of 6 carbon atoms or to a bicyclic aromatic hydrocarbon group of 10 carbon atoms.
Examples of aralkyl groups are benzyl, phenylethyl,
naphthylmethyl, benzhydryl or trityl.
The C8-C14 aralkenyl group is an alkenyl group of 2 to 4 carbon atoms linked to a monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 carbon atoms. Examples of aralkenyl groups are styryl, 2-phenyl-1-propenyl,
3-phenyl-2-butenyl, 2-naphthylethenyl.
The C8-C14 aralkynyl group is an alkynyl group of 2 to 4 carbon atoms linked to a monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 carbon atoms. Examples of aralkynyl groups are 2-phenylethynyl, 2-naphthylethynyl .
The (cycloalkyl)alkyl group is an alkyl group of 1 to 4 carbon atoms linked to a cycloalkyl group.
The (cycloalkyl)alkenyl group is an alkenyl group of 2 to 4 carbon atoms linked to a C3-C8 cycloalkyl group as defined above.
The heterocyclyl group is a 3- to 6-membered ,
saturated or unsaturated heterocyclyl ring, containing at least one heteroatom selected from O, S and N, which is optionally fused to a second 5- or 6-membered , saturated or unsaturated heterocyclyl group or to a cycloalkyl group or to an aryl group. Examples of heterocyclyl groups are pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
thiadiazolyl, thienyl, furyl, aziridinyl, oxiranyl,
azetidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyranyl, pyridazinyl, benzothienyl, benzothiazolyl, benzoxazolyl, isobenzofuranyl, benzofuranyl, chromenyl, indolyl,
indolizinyl, isoindolyl, cinnolinyl, indazolyl, purinyl.
The (heterocyclyl)alkyl group is an alkyl group of 1 to 4 carbon atoms linked to a heterocyclyl group.
The (heterocyclyl)alkenyl group is an alkenyl group of 2 to 4 carbon atoms linked to a heterocyclic group.
The term halogen (or halo) preferably encompasses fluorine, chlorine, bromine or iodine.
The above said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, aralkenyl, aralkynyl,
(cycloalkyl)alkyl, (cycloalkyl)alkenyl, heterocyclyl,
(heterocyclyl)alkyl, (heterocyclyl)alkenyl, oxirane and cyclopropyl groups can be either unsubstituted or
substituted by one or more substituents selected from the following ones:
- halo (i.e., fluoro, bromo, chloro or iodo);
- hydroxy;
- nitro;
- azido;
- mercapto (-SH);
- amino (i.e., -NH2, or -NHR' or -NR'R' ') wherein R' and
R' ', which are the same or different, are C1-C12 straight or branched alkyl groups or phenyl or benzyl; - formyl (i.e., -CHO);
- cyano;
- carboxy (alkyl) (i.e., (CH2)tCOOH or (CH2)tCOOR')
wherein R' is as defined above and t is 0, 1, 2 or 3; - sulfo (i.e., -SO3H) ;
- acyl (i.e., -C(O)R') wherein R' is as defined above or trifluoroacetyl (i.e., -C(O)CF3);
- carbamoyl (i.e., -CONH2); N-methylcarbamoyl (i.e.,
-CONHCH3) or N-carboxymethylcarbamoyl (i.ee,
-CONHCH2COOH);
- carbamoyloxy (i.e., -OCONH2);
- acyloxy (i.e., -OC(O)R') wherein R' is as defined
above or formyloxy (-OC(O)H);
- alkoxycarbonyl or benzyloxycarbonyl (i.e., -C(O)OR') wherein R' is as defined above;
- alkoxycarbonyloxy or benzyloxycarbonyloxy (i.e.,
-OC(O)OR') wherein R' is as defined above;
- alkoxy, phenoxy or benzyloxy (i.e., -OR') wherein R' is as defined above;
- alkylthio, phenylthio or benzylthio (i.e., -SR')
wherein R' is as defined above;
- alkylsulfinyl, phenylsulfinyl or benzylsulfinyl (i.e.,
-S(O)R') wherein R' is as defined above; - alkylsulfonyl, phenylsulfonyl or benzylsulfonyl (i.e., -S(O)2R') wherein R' is as defined above;
- acylamino (i.e., -NHC(O)R' ' ' or -NHC(O) OR' ' ') wherein R' ' ' is C1-C12 straight or branched alkyl, phenyl, benzyl, CH2CH2COOH or CH2CH2CH2COOH;
- sulfonamido (i.e., -NHSO2R' ) wherein R' is as defined above;
- guanidino ( i .e., -NHC (=NH)NH2) ;
- C1-C4 alkyl, C2-C4 alkenyl or alkynyl;
- C3-C6 cycloalkyl;
- phenyl
- substituted methyl selected from chloromethyl,
fluoromethyl, difluoromethyl, trifluoromethyl,
aminomethyl, N,N-dimethylaminomethyl, azidomethyl, cyanomethyl, carboxymethyl, sulfomethyl,
carbamoylmethyl, carbamoyloxymethyl, hydroxymethyl, C1-C4 alkoxycarbonylmethyl, guanidinomethyl.
The carboxy, amino, hydroxy and mercapto groups may
optionally be protected.
The carboxyl-protecting group may, for example, be a lower alkyl group such as methyl, ethyl, propyl, isopropyl or tert-butyl; a halogenated lower alkyl group such as a 2,2,2-trichloroethyl or a 2,2,2-trifluoroethyl; a lower alkanoyloxyalkyl group such as acetoxymethyl,
propionyloxymethyl, pivaloyloxymethyl, 1-acetoxyetyl, 1-propionyloxyethyl; a lower alkoxycarbonyloxyalkyl group such as 1-(methoxycarbonyloxy)ethyl,
1-(ethoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)ethyl; a lower alkenyl group such as 2-propenyl,
2-chloro-2-propenyl, 3-methoxycarbonyl-2-propenyl,
2-methyl-2-propenyl, 2-butenyl, cinnamyl; an aralkyl group such as benzyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl,
bis(p-methoxyphenyl)methyl; a (5-substituted
2-oxo-1,3-dioxol-4-yl)methyl group such as
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl; a silyl group such as trimethylsilyl, tert-butyldimethylsilyl,
tert-butyldiphenylsilyl, triphenylsilyl; or an indanyl group; a phthalidyl group; a pyranyl group; a methoxymethyl or methylthiomethyl group; a 2-methoxyethoxymethyl group. Particularly preferred are a tert-butyl group, a
p-nitrobenzyl group, a p-methoxybenzyl group, a benzhydryl group, a tert-butyldimethylsilyl, tert-butyldiphenylsilyl group or a propenyl group.
The amino, hydroxy or mercapto protecting groups possibly present may be those usually employed in the chemistry of penicillins and cephalosporins for this kind of functions. They may be, for instance, optionally
substituted, especially halo-substituted, acyl groups, e.g. acetyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl, benzoyl or p-bromophenacyl; triarylmethylgroups, e.g.
triphenylmethyl; silyl groups, in particular
trimethylsilyl, dimethyl-tert-butylsilyl,
diphenyl-tert-butylsilyl,; or also groups such as
tert-butoxycarbonyl, p-nitrobenzyloxycarbonyl,
2,2,2-trichloroethoxycarbonyl, benzyl and pyranyl.
Preferred protecting groups of the hydroxy function are p-nitrobenzyloxycarbonyl; allyloxycarbonyl;
dimethyl-tert-butylsilyl; diphenyl-tert-butylsilyl;
trimethylsilyl; 2,2,2-trichloroethoxycarbonyl; benzyl;
dimethoxybenzyl; p-methoxybenzyloxycarbonyl;
p-bromophenacyl; triphenylmethyl, pyranyl, methoxymethyl, benzhydryl, 2-methoxyethoxymethyl, formyl, acetyl,
trichloroacetyl.
The present invention provides the salts of those compounds of formula (la) or (lb) that have salt-forming groups, especially the salts of the compounds having a carboxylic group, a basic group (e.g. an amino or guanidino group), or a quaternary ammonium group. The salts are especially physiologically tolerable salts, for example alkali metal and alkaline earth metal salts (e.g. sodium, potassium, lithium, calcium and magnesium salts), ammonium salts and salts with an appropriate organic amine or amino acid (e.g. arginine, procaine salts), and the addition salts formed with suitable organic or inorganic acids, for example hydrochloric acid, sulfuric acid, carboxylic and sulfonic organic acids (e.g. acetic, trifluoroacetic, p-toluenesulfonic acid). Some compounds of formula (I) which contain a carboxylate and an ammonium group may exist as zwitterions; such salts are also part of the present invention.
The present invention encompasses all the possible stereoisomers as well as their racemic or optically active mixtures.
Furthermore, physiologically hydrolyzable ester, hydrates and solvates of compounds of formula (la) or (lb) are included within the scope of the present invention.
The physiologically hydrolyzable esters of the
compounds (la) or (lb) may include, for example,
methoxycarbonylmethyl, 1-methoxycarbonyloxy-1-ethyl, indanyl, phtalidyl, methoxymethyl, pivaloyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl or 5-methyl-2-oxo-1,3-dioxolan-4-yl esters, and other physiologically
hydrolyzable esters which have been widely used in the technical fields of penicillin and cephalosporin
antibiotics: more preferably, methoxycarbonyloxymethyl, 1-methoxycarbonyloxy-1-ethyl, methoxymethyl or
pivaloyloxymethyl; and most preferably,
methoxycarbonyloxymethyl or methoxymethyl .
Typical solvates of the cephalosporin compounds of formula (I) may include solvates with water miscible solvents, e.g. methanol, ethanol, acetone or acetonitrile or acetonitrile; and more preferably, ethanol.
The compounds of formula (la) or (lb) are particularly preferred when A is selected from C1-C12 straight or
branched alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-C10 aryl, C7-C13 aralkyl, C7-C13 alkaryl, C3-C8 cycloalkyl and
heterocycyl, and is optionally substituted by one or more of halo, sulfo, carboxy, C1-C5 alkylcarbonyloxy, C1-C5 alkoxy, C1-C5 alkoxycarbonyl, C1 -C5 carbamoyl, sulfamoyl, C1- C5 carbamoyloxy, C1-C5 alkylcarboxamido, C1-C5 haloalkylcarboxamido, nitro, cyano, diazo, hydroxy, benzhydryloxy, amino, C6-C10 arylcarbonyl, C6-C10 aryloxy, C7-C13 aralkyloxy, C7-C13 alkaryloxy, C1-C5 alkanoyl, C1-C5 alkanoyloxy, C1-C5 alkylsulfonyl, C6-C10 arylcarbonyloxy, C6-C10 arylcarboxy, C7-C13 aralkanoyloxy, C7-C13 alkarylcarboxy, C7-C13 aralkylcarboxy, C7-C13 alkarylcarbonyloxy, C7-C13 aralkylcarbonyloxy, C1-C5 halocarbamoyl C1-C5 alkyl carboxy, C1-C5 alkanoyl amido;
Q and W, each independently, are
(1') chloro, fluoro or bromo;
(2') straight or branched C1-C5 alkyl or C1-C5 alkenyl;
(3') C1-C5 alkyloxy, C1-C5 alkenyloxy, C6-C10 aryloxy, C7-C10 aralkyloxy, heterocyclyloxy;
(4') C1-C5 alkylthio, C2-C5 alkenylthio, C6-C10 arylthio, C7-C10 aralkylthio, heterocyclylthio;
(5') C1-C5 alkylsulfinyl, C2-C3 alkenylsulfinyl, C6-C10 arylsulfinyl, C7-C10 aralkylsulfinyl, heterocyclylsulfinyl;
(6') C1-C5 alkylsulfonyl, C2-C5 alkenylsulfonyl, C6-C10 arylsulfonyl, C7-C10 aralkylsulfonyl, heterocyclylsulfonyl;
(7') phenylselenyl, phenylseleninyl, phenylselenonyl;
(8') C1-C5 alkylcarbonyl, C2-C5 alkenylcarbonyl, C6-C10 arylcarbonyl, C7-C10 aralkylcarbonyl, heterocyclylcarbonyl;
(9') C1-C5 alkylcarbonyloxy, C2-C3 alkenylcarbonyloxy, C6-C10 arylcarbonyloxy, C7-C10 aralkylcarbonyloxy,
heterocyclylcarbonyloxy;
(10') C1-C5 alkylsulfonyloxy, C2-C5 alkenylsulfonyloxy, C6-C10 arylsulfonyloxy, C7-C10 aralkylsulfonyloxy,
heterocyclylsulfonyloxy;
(11') C1-C5 alkylcarboxamido, C2-C5 alkenylcarboxamido, C6-C10 arylcarboxamido, C7-C10 aralkylcarboxamido,
heterocyclylcarboxamido;
(12') nitro, azido, cyano, formyloxy, formamido;
or Q and W taken together constitute an oxo group, or a methylene group, or an optionally substituted cyclopropyl or oxirane group, or a group of formula =CHY or =CHC(O)Y or
=CHC(O)OY or =CHS(O)2Y, wherein Y is C1-C5 alkyl, C1-C5 alkenyl, C6-C10 aryl, C7-C10 aralkyl or heterocyclyl;
and, where appropriate, are optionally substituted by one or more substituents for the groups defined under (1')-(11') being selected from halo, sulfo, carboxy, C1-C5 alkylcarbonyloxy, C1-C5 alkoxy, C1-C5 alkoxycarbonyl, C1-C5 carbamoyl, sulfamoyl, C1-C5 carbamoyloxy, C1-C5
alkylcarboxamido, C1-C5 haloalkylcarboxamido, nitro, cyano, diazo, hydroxy, benzhydryloxy, amino, C6-C10 arylcarbonyl, C6-C10 aryloxy, C7-C13 aralkyloxy, C7-C13 alkaroloxy, C1-C5 alkanoyl, C1-C5 alkanoyloxy, C1-C5 alkylsulfonyl, C6-C10 arylcarbonyloxy, C6-C10 arylcarboxy, C7-C13 alkarylcarboxy, C7-C13 aralkylcarbonyloxy, C7-C13 alkarylcarboxy, C7-C13 alkarylcarbonyloxy, C7-C13 aralkanoyloxy, C1-C5
halocarbamoyl, C1-C5 alkylcarboxy, C1-C5 alkanoylamido, C7-C13 alkarylcarbonyl, C7-C13 aralkylcarbonyl, C1-C5 alkylthio, C6-C10 arylthio, C1-C5 alkylsulfonyl, C6-C10 arylsulfonyl, sulfo C1-C5 alkyl, carboxy C1-C5 alkylthio, C1-C5
alkylcarbonyloxy C1-C5 alkylthio, C2-C10 secondary amino, C3-C15 tertiary amino, di-C1-C5 alkylamino, di-C1-C5-alkylamino C1-C5 alkyl, oxo, halo C1-C5 alkanoyl, straight or branched C1-C5 alkyl and straight or branched C2-C5 alkenyl;
R1 is either hydrogen or halogen, or an optionally
substituted straight or branched C2-C5 alkyl or C1-C5 alkenyl, or an optionally substituted C7-C10 aralkyl or (heterocyclyl)alkyl;
optional substituents being selected from nitro, cyano, carbamoyl, hydroxy, carboxy, amino, methoxycarbonyl, benzhydryloxycarbonyl, tert-butoxycarbonyl, acetyl, acetoxy, formamido, methoxy, sulfonyl, methylthio, phenoxy, halogen;
R2 is either
(1') hydrogen;
(2') halogen
(3') an optionally substituted straight or branched C1-C5 alkyl, C1-C5 alkenyl or C7-C10 aralkyl;
(4') optionally substituted C6-C10 arylthio, or heterocyclylthio;
(5') a group OC(O)R4 wherein R4 is hydrogen, or an
optionally substituted C1-C5 straight or branched alkyl or alkenyl or an optionally substituted C3-C6 cycloalkyl, C6-C14 aryl C7-C14 aralkyl, heterocyclyl;
the optional substituents being selected from halo, sulfo, carboxy, C1-C5 alkylcarbonyloxy, C1-C5 alkoxy, C1-C5 alkoxycarbonyl, C1-C5 carbamoyl, sulfamoyl, C1-C5
carbamoyloxy, C1-C5 alkylcarboxamide, C1-C5
haloalkylcarboxamido, nitro, cyano, diazo, hydroxy,
benzhydryloxy, amino, C6-C10 arylcarbonyl, C6-C10 aryloxy, C7-C13 aralkyloxy, C7-C13 alkaryloxy, C1-C5 alkanoyl, C1-C5 alkanoyloxy, C1-C5 alkylsulfonyl, C6-C10 arylcarbonyloxy, C6-C10 arylcarboxy, C7-C13 alkarylcarboxy, C7-C13
aralkylcarbonyloxy, C7-C13 aralkylcarboxy, C7-C13
alkarylcarbonyloxy, C7-C13 aralkanoyloxy, C1-C5
halocarbanoyl, C1-C5 alkylcarboxy, C1-C5 alkanoylamido, C7-C13 alkarylcarbonyl, C7-C13 aralkylcarbonyl, C1-C5 alkylthio, C6-C10 arylthio, C1-C5 alkylsulfonyl, C6-C10 arylsulfonyl, sulfo C1-C5 alkyl, carboxy C1-C5 alkylthio, C2-C10 secondary amino, C3-C15 tertiary amino, di-C1-C5-alkylamino, di-C1-C5-alkylamino-C1-C5 alkyl, oxo, C1-C5 haloalkanoyl, straight or branched C1-C5 alkyl and straight or branched C2-C5 alkenyl; R3 is either hydrogen or
(1') methyl, chloromethyl, bromomethyl, benzyl, ethyl, propyl, phenyl
(2') chloro
(3') methoxy or benzyloxy
(4') methylthio
(5') formyl, acetyl, benzoyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzy1oxycarbonyl;
(6') methoxymethyl, ethoxymethyl, isopropoxymethyl; or benzyloxymethyl, phenoxymethyl, 3-pyridyloxymethyl wherein the phenyl and pyridyl rings are either unsubstituted or substituted by one group or two equal or different groups chosen from hydroxy, carboxy, amino, halogen and C1-C4 alkoxycarbonyl;
(7') a heterocyclylthiomethyl group wherein the
heterocyclyl ring either unsubstituted or substituted by one group or two equal or different groups chosen from the following: hydroxy, carboxy, amino, sulfo,
dimethylaminomethyl, carboxymethyl, carboxymethylthio, cyano, cyanomethyl, nitro, methoxy, methylthio, acetoxy, halogen or C1-C4 alkyl or alkenyl;
(8') acetoxymethyl, benzoyloxymethyl, phenylacetoxymethyl or C3-C6 alkanoyloxymethyl wherein the above groups are either unsubstituted or substituted by one or more groups selected from carboxy, hydroxy, C1-C5 alkoxy;
(9') trialkylammoniomethyl wherein the alkyl group is chosen from methyl, ethyl or propyl; N-methylpyrrolidiniomethyl, N-methylpiperidimiomethyl, N-methylmorpholiniomethyl;
(10') pyridiniomethyl which is either unsubstituted or substituted on the heterocyclic ring by fluoro, clhoro, methoxy, hydroxy, carboxy or carbamoyl;
(11') carbamoyloxymethyl;
(12') carboxy;
and X represents O, S or NR, wherein R is as defined above.
A further preferred class of compounds of formula (la) and (lb) is when A is a group selected from methyl, tert-butyl, 2-phenyl-2-propyl, benzyl and diphenylmethyl, which groups are optionally substituted by one or more
substituents selected from carboxy, carbamoyl,
methanesulfonyl, methoxy, ethoxy, tert-butoxy, benzyloxy, acetoxy, pivaloyoxy, benzoxy, carboxymethyl,
-C6H4-COOH, C6H5COO-, -CH2-C6H4-COOH, CH3-C6H4-COO- , C6H5-CH2- COO- , -C6H4-CH2COOH, benzoyl, pivaloyl, formamido,
acetamido, trifluoroacetamido and pivalamido;
Q and W, which are as defined above, are independently each optionally substituted, where appropriate, by one or more substituents selected from fluoro, chloro, bromo, carboxy, tetrazolyl, carbamoyl, methanesulfonyl, benzyloxy, benzoxy, acetoxy, pivaloyloxy, methylthio, phenylthio, benzenesulfonyl, sulfomethyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxymethylthio, -C6H4-COOH, C6H5COO-, -CH2-C6H4-COOH, CH3-C6H4-COO-, C6HB-CH2-COO- , -C6H4CH2COOH, acetyl, trifluoroacetyl, benzoyl, pivaloyl, dimethylamino,
diethylamino, dimethylaminoethyl, formamido, acetamido, trifluoroacetamido, pivalamido, vinyl and allyl; and
R2, which is as defined above, is optionally substituted where appropriate by one or more substituents selected from fluoro, chloro, bromo, carboxy, tetrazolyl, carbamoyl, methanesulfonyl, benzyloxy, benzoxy, acetoxy, pivaloyloxy, methylthio, phenylthio, benzenesulfonyl, sulfomethyl, carboxymethyl, carboxyethyl, carboxypropyl,
carboxymethylthio, -C6H4-COOH, C6H5COO-, -CH2-C6H4-COOH, CH3-C6H4-COO-, -OCOCH2C6H5, HOCOCH2C6H4-, acetyl, trifluoroacetyl, benzoyl, pivaloyl, dimethylamino, diethylamino,
dimethylaminoethyl, formamido, acetamido,
trifluoroacetamido, pivalamido, vinyl and allyl.
Compounds of formula (la) and (lb) and their
pharmaceutically and veterinarily acceptable salts are particularly preferred when they are of formula (lc) and (Id) respectively:
Figure imgf000016_0001
Figure imgf000016_0002
Specific examples of the preferred compounds of the present invention are those listed in Tables l - 6.
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Strategies for the preparation of compounds of formula (I) can vary depending on the nature of the substituents of the cephem nucleus. For example cephem-4-carboxylic acids which bear the suitable substituents at C-7 can be
synthesized according to or by analogy with known
procedures and then converted to the desired cephem-4-ketones. The conversion cephem-4-carboxylic acid/cephem-4-ketone can be carried out for example as described in EP-A-0337704 (18.10.89) and may precede or follow the
oxidation of the thiazolidine sulfur to sulfone.
Alternatively the proper C-7 substituents can be introduced by modifying cephem derivatives already bearing the ketone group at C-4 and prepared according to literature methods. For example compounds of formula (I) wherein Q and W constitute a methylene or substituted methylene group can be prepared by reaction of 7-oxocephems with the suitable Grignard or Wittig-Horner reagent (see e.g.: Heterocycles 24 (1986) 289).
A particularly preferred process for the preparation of compounds of formula (la) and (lb) comprises:
(i) reacting a compound of formula (II)
O O
Figure imgf000024_0001
wherein A, R1, R2 and R3 are as defined above with either (ia) a reagent of formula (III)
Q-W (III) wherein Q and W, being the same or different, are as defined above; or (ib) reagents of formulae (IV) and (V)
Q-H (IV)
W-L (V) wherein Q and W are as defined above and L is a leaving group
(ii) if needed, subjecting a compound of formula (la), wherein A, Q, W, R1, R2 and R3 are as defined above, to known processes and/or conventional reactions which entail the transformation of any of the groups A, Q, W, Rl , R2 and R3 of a compound of formula (la) to afford a different compound of formula (la) wherein A, Q, W, Rlf R2 and R3 are as defined above or a compound of the formula (Ib);
(iii) if desired, converting the resulting compound of formula (la) or (Ib) into a pharmaceutical or veterinarily acceptable salt thereof.
The reaction of a diazocephem of formula (II) [step (ia)] with a compound of formula (III) is usually performed in an aprotic solvent such as dichloromethane, chloroform, benzene, toluene, xylenes, cyclohexane, n-hexane, diethyl ether, ethyl acetate, dioxane, acetonitrile,
tetrahydrofurane, dimethoxyethane and so on.
Reaction temperatures range between -50° and 140 °C, preferably between -20 °C and +110 °C. The presence of a catalyst can sometimes have a beneficial effect enhancing the reativity of diazo-derivatives . Said catalyst can be either an acid, preferably a Lewis acid such as boron trifluoride, aluminum trichloride, tin tetrachloride and the like, or a metal reagent such as rhodium acetate. In some instances the reaction between diazo-derivatives of formula (II) and reagents of formula (III) can be
advantageously performed under photochemical conditions (i.e. irradiation with UV light).
In step (ib) the leaving group L is typically a halogen, preferably bromine, chlorine or iodine, or an imido group, preferably succinimido or phthalimido. The reagent W-L (V) is usually used in stoichiometric amount or a slight excess thereof, while the reagent Q-H (IV) can sometimes be used in large molar excess. Suitable solvents for the reaction (ib) are the same as those of the reaction (ia) and reaction temperatures usually range between -30 °C and +110 °C.
As above mentioned, it is understood that compounds of formula (Ia) and (Ib) can be prepared from compounds of formula (Ia) by way of known chemical reactions or in analogy with known processes, i.e. the groups A, Q, W, R1, R2 and R3 can be converted by conventional methods into different groups included within those previously defined, if desired, at the end or at any stage of the process above. For example, a compound of the formula (Ia), wherein R3 is a substituted methyl group, may be converted into a compound of the formula (Ib) as described in
PCT/EP94/01643. For example compounds of formula (Ia) or (Ib) wherein Q and/or W are bromine can be transformed into compounds of formula (Ia) or (Ib) wherein Q and/or W are alkenyl groups by reaction with the suitable
alkenylstannane reagent under radical conditions according to a procedure already applied to penicillins (Tetrahedron, 45 (1989), 941). In some instances a bromine atom at C-7 (e.g. compounds of formula (Ia) or (Ib) wherein Q is bromine and W is alkoxy) can be displaced by suitable nucleophiles (e.g.: thiolates, carboxylates...) providing different compounds of formula (I). Modifications of the R1, R2 and R3 groups of compounds of formula (Ia) can be performed for example as described in EP-A-0337704
(18.10.89), WO-A-91/09036 (27.06.91), European Patent Application No. 9304440 (04.03.93), British Patent
Application No. 93103904 (25.06.92).
Compounds of formula (II) can be prepared by a process which comprises:
(i) converting the carboxy group -CO2H at the 4-position of a compound of formula (VI)
Figure imgf000027_0002
wherein R1, R2 and R3 are as defined above, and R5 is an amino protecting group, into a carbonyl group -C(O)-A wherein A is as defined above, and oxidizing the sulfur atom at the 1-position to give a compound of formula (VII
Figure imgf000027_0001
wherein A, R1, R2, R3 and R5 are as defined above; and
(ii) if needed, subjecting a compound of formula (VII) wherein A, R1, R2, R3 and R5 are as defined above, to known reactions which entail the conversion of any of the groups A, R1, R2, R3 and R5 of a compound of formula (VII) to afford a different compound of formula (VII) wherein A, R1, R2, R3 and R5 are as defined above; and
(iii) converting the resulting compounds of formula (VII) into diazo-cephems of formula (II) wherein A, R1, R2, and R3 are as defined above.
In the conversion step referred to under (i), the
carboxylic moiety is typically activated as the halide, anhydride, mixed anhydride, thioester or ester thereof, and then reacted with a synthetic equivalent of A-, wherein A is as defined above. Suitable synthetic equivalents of A- include the following organometallic derivatives of A:
A-MgX (Grignard reagents);
A-Li (organolitium reagents e.g.phenyllithium); A2CuLi (lithium dialkylcopper reagents);
A(PhS)CuLi (lithium phenylsulphenyl (alkyl) copper
reagents);
A2CuMgX (magnesium diorganocopper reagents)
ACu(CN)ZnX (copper-zinc reagents)
A-Cu (cuprous reagents; e.g. cuprous acetylides);
A2Cd (organocadmium reagents);
AZnX (organozinc reagents);
AMnX (organomanganese reagents);
A3Tl (organothallium reagents);
and
AnSnX(4-n) (organotin reagents, wherein X is C1-C12 alkyl, chloro, phenyl, and n may be 0,1,2,3).
Sometimes these reagents are conveniently prepared in situ starting from suitable precursors and according to customary methods. The conditions of the above-stated reactions are described or referred to in major textbooks (see among others, J. March, "Advanced Organic Chemistry", McGraw-Hill) and can vary widely according to the
individual substrate and group A.
Typical reaction solvents are non-protic solvents such as tetrahydrofuran, diethyl ether, dichloromethane, benzene, toluene, hexamethylphosphoramide, dimethoxyethane, dioxane, dichloroethane, xylene, chloroform, n-hexane or mixtures thereof. Suitable reaction temperatures can vary from -100 °C to +120 °C, preferably between -80 °C and +60°C. The addition of inorganic or organometal derivatives (e.g. copper salts such as cuprous iodide, iron derivatives such as tris [acetylacetonato] iron(III), palladium
derivatives such as bis [triphenylphosphine]benzylpalladium chloride, aluminum derivatives such as aluminum trichloride, titanium derivatives such as titanium
tetrachloride and so on), in amount ranging from catalytic to equimolecular, has sometimes led to milder reaction conditions, decreased formation of by-products, improved yields and easier work-ups.
In the oxidation step referred to under (i) the compounds are oxidized to the corresponding sulphones .
Preferred oxidizing agents are inorganic or organic
peracids or salts thereof in an inert organic solvent or in a mixture of water and an organic solvent. Suitable
peracids are, for example, peracetic acid, m-chloroperoxybenzoic acid (MCPBA), monoperphthalic acid, alkaline monoperoxysulfate, tetrabutylammonium
peroxydisulfate; suitable solvents are chloroform,
dichloromethane, tetrahydrofuran (THF), acetonitrile, ethanol, acetic acid, ethyl acetate or mixtures thereof. The oxidation is usually carried out at a temperature of from -20 °C to +80 °C.
As above referred to under (ii), it is understood that the groups A, R1, R2, R3 and R5 of compounds of formula (VII) can be converted by conventional methods into
different groups A, R1, R2, R3 and R5 included within those previously defined. These conversions are well known on cephems of formula (VII) or analogues thereof.
The conversion of compounds of formula (VII) to compound of formula (II) referred to under (iii) is
generally realized either by nitrosation followed by rearrangement of the intermediate N-nitroso derivatives or by prior removal of the R5 group and diazotization of the intermediate 7-amino derivatives.
Typical nitrosating agents are nitrosyl chloride, dinitrogen tetroxide, dinitrogen trioxide. Suitable
solvents are protic or aprotic organic solvents such as chloroform, dichlorometane, tetrahydrofuran, ethyl acetate, acetic acid, acetic anhydide, acetonitrile or mixtures thereof. The rearrangement of N-nitroso derivatives
generally takes place in aprotic solvents under thermal conditions or under acid- or base-catalyzed conditions.
Removal of the R5 group (i.e. unmasking the amino function) from compounds of formula (VII) is carried out under conditions dependent on the nature of the amino protecting group R5. Typical R5 groups are groups which withstand the tranformations referred to under (ii) annd (iii) and still can be removed under selective and mild conditions. Typical R5 groups are acid sensitive groups such as tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, trityl, 1-adamantyloxycarbonyl and so on (which can be removed under mild conditions in the presence of organic or inorganic acids e.g. formic acid, trifluoroacetic acid, p-toluensulfonic acid, methansulfonic acid, aluminum
trichloride, boron trifluoride...) or groups that can be removed under neutral conditions such as p-nitrobenzyloxycarbonyl, benzyloxycarbonyl (removable by hydrogenolysis); allyloxycarbonyl (removable in the presence of palladium catalysts or equivalent catalysts). The diazotation reaction can usually be carried out either in an aprotic organic solvent (e.g. ethyl acetate,
dichloromethane, chloroform, tetrahydrofuran,
acetonitrile...) in the presence of organic nitrites (e.g. alkyl nitrites such as butyl nitrite, tert-butylnitrite, amyl nitrite, propyl nitrite and so on) with or without an acid catalyst (e.g. formic acid, trifluoroacetic acid, p-toluensulfonic acid, acetic acid, methanesulfonic acid) or in a biphasic system in the presence of nitrous acid
(usually in situ generated by interaction of an inorganic nitrite (e.g. alkaline metal, alkaline-earth metal or ammonium nitite) and an organic or inorganic acid (e.g. p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, perchloric acid, hydrochloric acid and the like).
Compounds of formulae (III), (IV) and (V) arer known compounds or can be prepared from known compounds by known processes. The potentialities of protease inhibitor therapy in the treatment of conditions resulting from the destruction of connective tissues have recently received particular attention. Much effort has been devoted to the search for inhibitors of human leukocyte elastase (HLE), which is the primary destructive agent in pulmonary emphysema and is probably involved in rheumatoid arthritis (J.C. Power, Am. Rev. Resp. Diseases 127, S54-S58, 1983; C.H. Hassal et al, FEBS Letters, 183, n. 2, 201, 1985, G. Weinbaum and V.V. Damiano, TIPS, 8, 6, 1987; M. Velvart, Rheumatol. Int. 1, 121, 1981) . Low molecular weight
inhibitors appear to have a number of advantages over natural high molecular weight protease inhibitors from either plant or animal sources: 1) they can be obtained in quantities; 2) they can be rationally designed or
optimised; 3) they are not antigenic; and 4) they may be used orally or in aerosols. Many low molecular weight elastase inhibitors discovered so far contain reactive functional groups (chloromethyl ketones, isocyanates, etc); they may react with functional groups of proteins, and therefore they may be quite toxic. In this respect, jβ-lactam compounds are of potential interest because, though reactive towards serine protease, they are, as it is known, non-toxic at very high concentrations.
The compounds of the present invention are
characterized by high inhibitory activity on elastases, especially human leukocyte elastase (HLE) and in particular can possess improved chemical and/or biological stability, making them suitable for systemic (i.v. or oral)
administration.
When tested as inhibitors of human leukocyte elastase (HLE), representative compounds of formula (I) showed good "potency" (low value of apparent dissociation constant of the HLE-inhibitor complex at steady state, Ki ss) and
"efficiency" (high value of rate of formation of the HLE-inhibitor complex, k5/Ki) :
Figure imgf000031_0001
wherein
Figure imgf000032_0004
E = enzyme (HLE)
S = substrate (see Protocol)
P = product (see Protocol)
I = inhibitor
El = Michaelis complex
EI*= covalent complex (inactivated enzyme)
I*= inactivated inhibitor
Protocol
Kinetic parameters of HLE (Calbiochem) were determined at 37° C., 0.027M pH 7.4 phosphate buffer, 1% DMSO, 1% MeCN, NaCl (1=0.15), by monitoring the release of 7-amino-4-methylcoumarin (fluorescence detection) from N-methoxysuccinyl-alanyl-prolyl-valyl-7-amido-4-methylcoumarin as the substrate, according to the
equations:
Figure imgf000032_0001
Figure imgf000032_0002
Figure imgf000032_0003
wherein[P], [I], [S]=product, inhibitor, and substrate concentration Vs=steady state rate
Vz=zero time rate
Vo=rate at [I] =0
Km=Michaelis constant for the enzyme substrate pair
(independently determined under the same experimental conditions).
Full details of the Experimental Protocol are reported in M. Alpegiani et al., Eur. J. Med. Chem. 1992, 27, 875-890.
For example, the compounds prepared respectively in examples 5 and 8 have a Kon of 3000 and 3400 M-1 sec-1, Ki SS 0.1 and 6μM. Moreover the compound of example 8 showed a chemical stability, expressed as half-life in aqueous buffer at 37°C, of 410 hours at pH 7.4 and of 3000 hours at pH 1.2. Owing to their high elastase-inhibiting activity and their quite negligible toxicity, (the orientative acute toxicity by i.v., oral or aerosol route is almost always greater than 500 mg/kg in rat) the compounds of the present invention can be used in the treatment of inflammatory and degenerative diseases caused by proteolytic enzymes in mammals including humans. The compounds can be used to make medicaments useful to prevent or arrest the progression of diseases caused by proteolytic degradation of lungs and connective tissues, reduce inflammation and fever, and relieve pain. Such diseases are emphysema, acute
respiratory distress syndrome, bronchial inflammation, rheumatoid arthritis, osteoarthritis, infectious arthritis, rheumatic fever, spondylitis, gout, lupus, psoriasis, or in the control of tumour invasion and the like. Accordingly, the present invention also provides pharmaceutical and veterinary compositions containing a suitable carrier and/or diluent and, as an active principle, a
4-alk(en)ylcephem sulfone of formula (I) or a
pharmaceutically or veterinarily acceptable salt thereof. The pharmaceutical or veterinary compositions containing a compound of formula I or salt thereof may be prepared in a conventional way by employing conventional non-toxic pharmaceutical carriers or diluents in a variety of dosage forms and ways of administration. In particular, the compounds of formula I can be administered:
A) Orally, for example, as tablets, troches,
lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such
compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable
preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be
uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
Formulation for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium
carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium
carboxymethylcellulose, methylcellulose, hydroxy
propylmethylcellulose, sodium alginate,
polyvinylpyrrolidone gum tragacanth and gum acacia;
dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation
products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol
anhydrides , for example polyoxyethylene sorbitan
monooleate. The said aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, or one or more sweetening agents, such as sucrose or saccharin. Oily suspension may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an
antioxidant such as ascorbic acid. Dispersible powders and granules suitable for peparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present . The pharmaceutical compositions of the invention may also be in the form of oil-in-water
emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol
anhydrides, for example sorbitan mono-oleate, and
condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents . Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
B) Parenterally, either subcutaneously, or
intravenously, or intramuscularly, or intrasternally, or by infusion techniques, in the form of sterile injectable aqueous or olagenous suspensions. TheT pharmaceutical compositions may be in the form of a sterile injectable aqueous or olagenous suspension.
This suspension may be formulated according to the known art using those suitable dispersing of wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic
parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides . In addition fatty acids such as oleic acid find use in the preparation of injectables; C) By inhalation, in the form of aerosols or
solutions for nebulizers;
D) Rectally, in the form of suppositories prepared by mixing the drug with a suitable non-irratating excipient which is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and poly-ethylene glycols;
E) Topically, in the form of creams ointments, jellies, solutions or suspensions.
Still a further object of the present invention is to provide a method fo controlling inflammatory and
degenerative diseases by administering a therapeutically effective amount of one or more of the active compounds encompassed by the formula I in humans or mammalians in need of such treatment .
Daily dose are in the range of about 0.1 to about 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the
disease, and the frequency and route of administration;
preferably, daily dosage levels for humans are in the range of 20 mg to 2 g. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans, may contain from 5 mg to 2 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 5 mg to about 500 mg of active ingredient .
Compounds of formula (VI) are known compounds or can be prepared from known compounds by known methods.
The following preparations and examples illustrate but do not limit the invention. PREPARATION 1
7β - tert - Butoxycarbonylamino - 3 - desacetoxy
cephalosporanic acid
Trietylamine (56 ml) was added dropwise to a mixture of 7β-amino-3-deacetoxy cephalosporanic acid (42.8 g) in dioxane (800 ml) and water (400 ml). tert -Butylpercarbonate (66 g) was then added and the resulting mixture was vigorously stirred at room temperature for 6 hours, thence poured into water/diethyl ether (ratio 3:1; 800 ml). The aqueous phase was acidified with 8%
hydrochloric acid (300 ml) and extracted twice with ethyl acetate. Following drying over Na2SO4 and evaporation of the solvent, a foamy solid was obtained which upon
treatment with petroleum ether turned into a white powder (53 g).
IR (KBr) ʋ max 3600-2500, 1780, 1710 cm-1
NMR (200 MHz, DMSO-d6) δ 2.00 (3H, s), 3.33 (1H, d, J=
17.8 Hz), 3.49 (1H, d, J= 17.8 Hz), 4.98 (1H, d, J= 4.6 Hz), 5.34 (1H, dd, J= 4.6 and 8.9 Hz),
7.95 (1H, d, J= 8.9 Hz, exch. D2O) .
PREPARATION 2
7β-tert-Butoxycarbonylamino-4-tert-butylcarbonyl-3-methyl- 3-cephem 1.1-dioxide
Step A. 7β-tert-Butoxycarbonylamino-3-desacetoxy
cephalosporanyl chloride
A solution of 7β-tert-butylamino-3-desacetoxy
cephalosporanic acid (40.8 g) in dry tetrahydrofuran (400 ml) was cooled to 0°C. Under nitrogen, oxalyl chloride (16.8 ml) was added, soon followed by 0.7 ml of N,N-dimethylformamide.
The resulting solution was stirred for 2 hours at 0-5°C, then it was rotoevaporated to dryness. Dry toluene (60 ml) was added and the mixture was evaporated again to dryness, giving a brownish solid (42.34 g), used as such in the following step. Step B. 7β-tert-Butoxycarbonyl amino-4-tert-butyl carbonyl-3-methyl-3-cephem
To a solution of copper (I) iodide (31.5 g) and lithium chloride (140.2 g) in dry THF (200 ml) cooled to - 70°C and, under nitrogen atmosphere, a 1M solution of tert-butyl magnesium chloride (165 ml) was added dropwise . To this mixture, a solution of crude 7β- tert-butoxycarbonylamino-3-deacetoxy cephalosporanyl chloride (42.34 g) in dry THF (400 ml), was dropped slowly always keeping the temperature at -70°C. The reaction mixture was stirred till temperature rose to 20°C, then was poured into diethyl ether (600 ml) and 20% aqueous NH4Cl (600 ml). The etheral extracts were collected, washed with aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated. The crude residue was purified by silica gel chromatography to yield the title compound as a white powder (41.89 g)
IR (KBr) ʋ max 3320, 1780, 1725 (sh), 1695 cm-1
NMR (CDCl3, 200 MHz) δ 1.21 (9H,s), 1.45 (9H, s), 1.75
(3H, d, J= 0.5 Hz), 3.09 (1H, d, J= 17.5 Hz), 3.52 (1H, br.d, J= 17.5 Hz), 4.97 (1H, d, J= 4.6 Hz), 5.20 (1H, d, J= 9.1 Hz, exch. D2O), 5.51 (1H, dd, J= 4.6 and 9.2 Hz) .
Step C. 7β-tert-Butoxycarbonylamino-4-tert-butylcarbonyl-3- -methyl-3-cephem 1.1-dioxide
7β-tert-Butoxycarbonylamino-4-tert-butylcarbonyl-3-methyl-3-cephem (41.89 g) was dissolved in methylene chloride (600 ml) . The solution was cooled to -10°C and 55% 3-chloroperbenzoic acid (92.7 g) was added portionwise. The resulting mixture was stirred for 4 hours at room
temperature. The precipitated 3-chlorobenzoic acid was filtered off and the filtrate was sequentially washed with 1M aqueous NaHSO3 and saturated aqueous NaHCO3.
Upon drying over Na2SO4, the solvent was rotoevaporated. Treatment of the residue with dichloromethane/diethyl ether gave the title product as a white solid (39.3 g).
IR (KBr) ʋ max 3400, 1780, 1700 cm-1
NMR (200 MHZ, CDCl3) δ 1.23 (9H, s), 1.45 (9H, s), 1.72 ( 3H, s), 3 . 54 ( 1H, d, J= 18 . 2 Hz), 3 . 88 ( 1H, br . d, J= 18 . 2 Hz), 4 . 79 ( 1H, br . d, J= 3 . 7 Hz), 5 . 81 ( 2H , m) .
PREPARATION 3
7β-Amino-4-tert-butylcarbonyl-3-methyl-3-cephem 1,1-dioxide To a suspension of 24 g of 7β-tert-butoxycarbonylamino-4-tert-butylcarbonyl-3-methyl-3-cephem 1,1-dioxide in methylene chloride (50 ml) were added 2 ml of anisole and 140 ml of trifluoroacetic acid. After stirring for 0.5 h, the TFA was evaporated in vacuo . The residue was taken up in ethyl acetate and washed with saturated aqueous NaHCO3 and eventually with brine. Upon drying over Na2SO4, the solvent was rotoevaporated and treatment of the residue with a mixture of
dichloromethane/diisopropyl ether gave the title product as a white powder (13.9 g) .
IR (KBr) ʋ max 1785, 1690 cm-1
NMR (200 MHz, CDCl3) δ 1.23 (9H, s), 1.7 1 (3H, s), 3.48
(1H, d, J= 18.2 Hz), 3.87 (1H, br.d, J= 18.2 Hz), 4.71 (1H, br.d, J= 4.7 Hz), 4.80 (1H, br.d. J= 4.7 Hz).
PREPARATION 4
4-tert-Butylcarbonyl-7-diazo-3-methyl-3-cephem 1,1-dioxide To a solution of 13.9 g of 7β-amino-4-tert-butylcarbonyl-3-methyl-3-cephem 1,1 dioxide in methylene chloride (700 ml) were added acetic acid (1ml) and tertbutylnitrite (11 ml). The reaction mixture was stirred for 0.5 h at room temperature, thence poured into a 1M solution of aqueous NaHCO3. The organic layer was separated, washed with water and dried over Na2SO4. Removal of the solvent in vacuo, left an oily residue which upon treatment with petroleum ether turned into a yellow powder (14.1 g).
IR (CHCl3) ʋ max 2100, 1790, 1700 cm-1
NMR (200 MHz, CDCl3) δ 1.25 (9H, s), 1.78 (3H, s), 3.66 (1H, d, J= 17.1 Hz), 3.86 (1H, br.d, J= 17.1 Hz), 5.50 (1H, s). PREPARATION 5
3-bromomethyl-7β-tert-butoxycarbonylamino-4-tert-butylcarbonyl-3-methyl-3-cephem 1,1-dioxide
A solution of 7β-tert-butoxycarbonylamino-4-tert-butylcarbonyl-3-methyl-3-cephem 1,1-dioxide (2.7 g) in carbon tetrachloride (150 ml) and methylene chloride (100 ml) was refluxed for 4 h in the presence of N-bromosuccinimide (NBS; 1.5 g) and α,α'-azoisobutyronitrile (AIBN; 100 mg). Removal of the solvent and silica gel chromatography of the residue afforded the title compound (2.8 g; plus 0.4 g of 2-bromo derivative) as a white solid. IR (KBr) ʋ max 1805, 1725, 1685 cm-1
NMR (200 MHz, CDCl3) δ 1.27 (9H, s), 1.46 (9H, s),
3.57 (1H, d, J= 18 Hz), 4.26 (1H, br.d, J= 18
Hz), 3.77 (1H, d, J= 11.4 Hz), 4.02 (1H, d, J=
11.4 Hz), 4.88 (1H, br.d, J= 4.6 Hz), 5.85 (2H, m).
PREPARATION 6
7β-tert-Butoxycarbonylamino-4-tert-butylcarbonyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem 1,1-dioxide.
A solution of 3-bromomethyl 7β-tert-butoxycarbonylamino-4-tert-butylcarbonyl-3-cephem 1,1-dioxide (2.8 g) was treated, in dry acetonitrile (150 ml), with triethylamine (1 ml) and 2-mercapto-5-methyl-1,3,4-thiadiazole (1.05 g). After 30 min the reaction mixture was diluted with ethyl acetate, washed with brine and dried over Na2SO4. Removal of the solvent and flash
chromatography of the residue afforded the title product as a white powder (3.1 g).
IR (KBr) ʋ max 1800, 1730, 1700 cm-1
NMR (200 MHz, CDCl3) δ 1.24 (9H, s), 1.46 (9H, s),
3.81 (1H, d, J= 14.5 Hz), 4.15 (1H, d, J= 14.5
Hz), 3.96 (1H, d, J= 18.3 Hz), 4.20 (1H, br.d, J= 18.3 Hz), 4.87 (1H, m), 5.85 (2H, m) . PREPARATION 7
7β-Amino-4-tert-butylcarbonyl-3-(5-methyl-1,3,4-thiadiazol- 2-yl)thiomethyl-3-cephem 1,1-dioxide
To a suspension of 7β-tert-butoxycarbonylamino-4-tert-butylcarbonyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem 1,1-dioxide (3.1 g) in methylene chloride (15 ml) were added anisole (0.15 ml) and trifluoroacetic acid (10 ml) . In about 10 min the reaction was over. TFA was completely removed in vacuo and the residue taken up in ethyl acetate and washed with aqueous NaHCO3. Upon drying over NA2SO4, the solvent was rotoevaporated and the residue taken up in methylene chloride/isopropyl ether (1/2).
Collection of the precipitate by filtration afforded the pure title product as a light yellow powder (2 g).
IR (KBr) ʋ max 1780, 1690 cm-1
NMR (200 MHz, DMSO-d6) δ 1.14 (9H, s), 2.45 (2H, m),
2.67 (3H, s), 3.80 (1H, d, J= 13.3 Hz), 3.95 (1H, d, J= 13.3 Hz), 3.98 (1H, d, J= 17.5 Hz), 4.39
(1H, br.d, J= 17.5 Hz), 5.01 (1H, m), 5.27 (1H, d, J= 4.6 Hz).
PREPARATION 8
4-tert-Butylcarbonyl-7-diazo-3-(5-methyl-1.3.4-thiadiazol- 2-yl)thiomethyl-3-cephem 1,1-dioxide
To a suspension of 7β-amino-4-tert-butylcarbonyl-3-(5-methyl-1,3,4-thyadiazol-2-yl)thiomethyl-3-cephem 1,1-dioxide (2 g) in methylene chloride (60 ml) were added tert-butylnitrite (1.1 ml) and a catalytic amount of acetic acid (0.06 ml) . The reaction mixture was stirred for 4 h at room temperature ( clear and yellow solution), thence poured into a 1M solution of NaHCO3. The organic layer was collected, washed with water and dried over Na2SO4.
Removal of the solvent and flash chromatography of the crude product left an oily residue which, upon treatment with petroleum ether, turned into a yellow solid (1.22 g). IR (CHCl3) ʋ max 2100, 1790, 1700 cm-1
NMR (200 MHz, CDCl3) δ 1.27 (9H, s), 2.75 (3H, s), 3 . 83 ( 1H, d , J= 14 . 2 Hz), 4 . 17 ( 1H, d , J= 14 . 2
Hz), 4 . 05 ( 1H, d, J= 17 . 4 Hz), 4 . 21 ( 1H, br . d, J= 17 . 4 Hz), 5 . 58 ( 1H, br . s ) . PREPARATION 9
7β-tert-Butoxycarbonylamino-3-methyl-4-phenylcarbonyl-cephem 1,1-dioxide
Step A. 7β-tert-butoxycarbonylamino-3-methyl-4-phenylcarbonyl-3-cephem
To a solution of copper (I) iodide (22.2 g) and lithium chloride (9.9 g) in dry THF (150 ml), cooled to - 50°C and under nitrogen atmosphere, a 1.9M solution of phenyl magnesium chloride (61.5 ml) was added dropwise. To this mixture, a solution of crude 7β-tert-butoxycarbonylamino-3-deacetoxy cephalosporanyl chloride (30 g, prepared according to the procedure described in PREPARATION 2, step A) in dry THF (150 ml) and diglyme (90 ml), was dropped slowly always keeping the temperature at - 50°C. After stirring for 1 h at the same temperature, the reaction mixture was poured into diethyl ether (1 l) and 20% aqueous NH4Cl (1.6 l). The organic layer was
separated, washed twice with aqueous NH4Cl and eventually wiyh brine. Upon drying over NaSO4, the solvent was removed in vacuo and the resultant crude residue was passed through a silica gel column to give the purified title compound as a light yellow solid (12.3 g).
IR (KBr) ʋ max 1770, 1700, 1670 cm-1
NMR (200 MHz, CDCl3) δ 1.45 (9H, s), 1.77 (3H, s),
3.22 (1H, d, J= 18 Hz), 3.60 (1H, br.d, J= 18Hz), 5.08 (1H, d, J= 4.6 Hz), 5.24 (1H, br.d, J= 9.5
Hz), 5.52 (1H, dd, J= 4.6 and 9.5 Hz), 7.30-8.00
(5H, m).
Step B. 7β-tert-butoxycarbonylamino-3-methyl-4-phenylcarbonyl-3-cephem 1,1-dioxide
To a solution of 7β-tert-butoxycarbonylamino-3-methyl- 3-cephem (12.3 g) in ethyl acetate (500 ml), cooled to - 10°C, 55% 3-chloroperbenzoic acid (25.7 g) was added portionwise. The resulting mixture was stirred for 6 h at room temperature and then sequentially washed with 1M aqueous NaHSO3 and saturated aqueous NaHCO3. Upon drying over NaSO4, the solvent was rotoevaporated to a small volume. Following addition of cyclohexane gave the title compound which was collected by filtration as white
crystals (11.7 g) .
IR (KBr) ʋ max 1770, 1720, 1670 cm-1
NMR (200 MHz, DMSO-dJ δ 1.38 (9H, s), 1.64 (3H, s),
4.11 (1H, d, J= 18.2 Hz), 4.36 (1H br.d, J= 18.2 Hz), 5.44 (1H, d, J= 4.6 Hz), 5.65 (1H, dd, J=
4.6 and 9.7 Hz), 7.20 (1H, d, J= 9.7 Hz), 7.4-7.9 (5H, m).
PREPARATION 10
7β-Amino-3-methyl-4-phenylcarbonyl-3-cephem 1,1-dioxide
To a suspension of 7β-tert-butoxycarbonylamino-3-methyl-4-phenylcarbonyl-3-cephem 1,1-dioxide (11.7 g) in methylene chloride (40 ml), trifluoroacetic acid (45 ml) and a catalytic amount of anisole (1 ml) were added. After stirring for 30 min., TFA was evaporated in vacuo and the residue taken up in ethyl acetate. Following washing with saturated aqueous NaHCO3 afforded the precipitation of the a white solid from the organic layer. The aqueous phase was discarded and the precipitate was collected by
filtration, washed with a mixture of ethyl acetate/hexane and eventually dried in vacuo to give the title compound as a white powder (8.4 g).
IR (KBr) ʋ max 1770, 1670 cm-1
NMR (200 MHz, DMSO-d6) δ 1.62 (3H, s), 4.03 (1H, d,
J= 18.2 Hz), 4.31 (1H, br.d, J= 18.2 Hz), 4.83
(1H, m), 5.27 (1H, d, J= 4.2 Hz), 7.5-8.0 (5H, m). PREPARATION 11
7-Diazo-3-methyl-4-phenylcarbonyl-3-cephem 1,1-dioxide
A suspension of 7β-amino-3-methyl-4-phenylcarbonyl-3-cephem 1,1-dioxide (8.4 g) in methylene chloride (400 ml) was treated with tert-butylnitrite (6.5 ml) and a
catalytic amount of acetic acid. The reaction mixture was stirred for 0.5 h at room temperature thence poured into a 1M solution of aqueous NaHCO3.
The organic layer was separated, washed with water and dried over NaSO4. Removal of the solvent in vacuo left an oily residue which upon treatment with petroleum ether turned into a yellow solid (6.5 g).
IR (CHCl3) ʋ max 2090, 1790, 1670 cm-1
NMR (200 MHz, CDCl3) δ 1.66 (3H, s), 3.66 (1H, d, J=
17.8 Hz), 4.02 (1H, br.d, J= 17.8 Hz), 5.66 (1H, s), 7.4-8.0 (5H, m).
EXAMPLE 1
7,7-Dibromo-4-tert-butylcarbonyl-3-methyl-3-cephem 1,1-dioxide
To a solution of 4-tert-butylcarbonyl-7-diazo-3-methyl-3-cephem 1,1-dioxide (4.6 g) in methylene chloride (400 ml) at -20°C was added bromine (15.2 ml). In the reaction mixture was let rise to 0°C and after about 30 min. the reaction was over (TLC monitoring).
The solvent was rotoevaporated and the residue was taken up in CH2CL2/ET2O (1/1). Collection by filtration of the precipitate afforded the title product as a light yellow powder (4.7 g).
IR (CHCl3) ʋ max 1820, 1700 cm-1
NMR (200MHz, CDCl3) δ 1.26 (9H, s), 1.75 (3H, s), 3.56 (1H, d, J= 17.8 Hz), 3.92 (1H, d, J= 17.8 Hz), 5.14 (1H, s). EXAMPLE 2
7,7-Diallyl-4-tert-butylcarbonyl-3-methyl-3-cephem 1,1-dioxide
To a solution of 4.3 g of 7,7-dibromo-4-tert-butylcarbonyl-3-methyl-3-cephem 1,1-dioxide in acetonitrile (150 ml), prepared as described in example 1, were added α,α-azoisobutyronitrile (100 mg) and allyltributyltin (9.3 ml).
The reaction mixture was let stand at reflux for 2 h, then poured into water-ethyl acetate. The organic layer was collected, dried over Na2SO4 and concentrated in vacuo.
Flash chromatography of the residue gave the pure title product as a white solid (2.46 g) .
IR (KBr) ʋ max 1760, 1690 cm _1
NMR (200 MHz, CDCl3) δ 1.26 (9H, s), 1.68 (3H, s), 2.55
(2H, m), 2.8-3.1 (2H, m), 3.39 (1H, d, J= 17.6 Hz),
3.90 (1H, br.d, J= 17.6 Hz), 4.45 (1H, br.s), 5.1-5.3
(4H, m), 5.7-6.0 (2H, m) .
EXAMPLE 3
7 , 7-Diallyl-2-bromo-4-tert-butylcarbonyl-3-methyl-3-cephem
1.1-dioxide
To a solution of 2 g of 7,7-diallyl-4-tert-butylcarbonyl-3-methyl-3-cephem 1,1-dioxide in acetonitrile
(40 ml) were added trietylamine (0.87 ml) and N-bromosuccinimide (1.22 g). After 30 min. the reaction mixture was poured into ethyl acetate / 4% aqueous HaHSO3.
The organic layer was collected and sequentially washed with saturated NaHCO3 and water. After drying over Na2SO4, removal of the solvent left a crude residue which was then purified by flash chromatography affording the pure title product as a white solid (2.2 g) .
IR (KBr) ʋ max 1795, 1705 cm-1
NMR (200 NMR, CDCl3) δ 1.23 (9H, s), 1.80 (3H, s), 2.59
(2H, m), 2.8-3.1 (2H, m), 4.86 (1H, s), 5.17 (1H, s), 5.2-5.4 (4H, m), 5.6-6.0 (2H, m). EXAMPLE 4
7,7-Diallyl-4-tert-butylcarbonyl-3-methyl-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-3-cephem 1,1-dioxide
Procedure A
To a solution of 215 mg of 7,7-diallyl-2-bromo-4-tert-butylcarbonyl-3-methyl-3-cephem 1,1-dioxide, prepared as described in example 3, in dimethylformamide (2ml) was added sodium 1-methyl-1,2,3,4-tetrazolyl-5-mercaptide (160 mg). After 15 min. the reaction mixture was diluted with ethyl acetate and sequentially washed with saturated NaHCO3 and brine. Upon drying over Na2SO4 and removal of the organic solvent in vacuo, the crude residue was passed through a silica gel column affording the pure title product as a white powder (180 mg).
Procedure B
A solution of 350 mg of 7,7-diallyl-4-tert-butylcarbonyl-3-methyl-3-cephem 1,1-dioxide in acetonitrile (6 ml) was sequentially treated with toluene-4-thiosulfonic acid S-(1-methyl-1H-tetrazol-5-yl) ester (300 mg) and 1,5-diazabicyclo [4.3.0]non-5-ene (0.25 ml). The reaction mixture was stirred for 1 h at room temperature and then poured into ethyl acetate / 2% aqueous HCl . The organic phase was washed with brine, dried over Na2SO4 and
concentrated. Flash chromatography of the residue gave the title product as a white solid (300 mg).
IR (KBr) ʋ max 1785, 1700 cm-1
NMR (200MHz, CDCl3) δ 1.25 (9H, s), 1.94 (3H, s), 2.6
(2H, m), 2.8-3.1 (2H, m), 4.09 (3H, s), 4.87 (1H, s), 4.98 (1H, s), 5.1-5.4 (4H, m), 5.7-5.9 (2H, m).
EXAMPLE 5
7,7-Diallyl-4-tert-butylcarbonyl-3-methyl-2-(5-methyl- 1,3,4-thiadiazol-2-yl)thio-3-cephem 1,1-dioxide
215 mg of 7,7-diallyl-2-bromo-4-tert-butylcarbonyl-3- methyl-3-cephem 1,1-dioxide, prepared according the procedure described in example 3, were dissolved in dimethylformamide (2ml) and treated with triethylamine (0.07 ml) and 2-mercapto-5-methyl-1,3,4 thiadiazole (70 mg) . After 15 min. the reaction mixture was diluted with ethyl acetate then sequentially washed with saturated
NaHCO3 and brine and eventually dried over Na2SO4. The organic layer was concentrated in vacuo and the resulting residue was chromatographed on a flash column affording the pure title product as a white powder (185 mg) .
IR (KBr) ʋ max 1790, 1700 cm -1
NMR (200 MHz, CDCl3) δ 1.22 (9H, s), 1.91 (3H, s), 2.58 (2H, m), 2.79 (3H, s), 2.7-3.1 (2H, m), 5.01 (1H, s), 5.1-5.4 (4H, m), 5.2 (1H, s), 5.7-5.9 (2H, m).
EXAMPLE 6
7,7-Diallyl-4-tert-butylcarbonyl-2-(4-carboxybenzoyl)oxy-3-methyl-3-cephem 1,1 dioxide
430 mg of 7,7-diallyl-2-bromo-4-tert-butylcarbonyl-3-methyl-3-cephem 1,1-dioxide were dissolved in acetonitrile (25 ml) and treated with silver (4-methoxybenzyloxycarbonyl)-4-benzoate (400 mg). The reaction mixture was let stir at room temperature for 2 h. Solid AgBr was removed by filtration and the remaining solution was diluted with ethyl acetate, washed with saturated brine and eventually dried over Na2SO4. Flash chromatography of the concentrated residue afforded the pure protected compound (390 mg) which was then dissolved in
dichloromethane (5 ml) and treated with anisole (0.0050 ml) and trifluoroacetic acid (2 ml) . After 20 min., TFA was removed in vacuo and the resulting residue taken up in dichloromethane (2 ml). Addition of isopropylether afforded the title compound as a white powder (250 mg).
IR (KBr) ʋ max 1790, 1745, 1705 cm-1
NMR (200 MHz, CDCl3) δ 1.31 (9H, s), 1.77 (3H, s), 2.59 (2H, m), 2.8-3.1 (2H, m), 4.64 (1H, s), 5.2-5.4 (4H, m), 5.7-5.9 (2H, m) . EXAMPLE 7
7α-Allyl-7β-bromo-4-tert-butylcarbonyl-3-methyl-cephem 1,1-dioxide
To a solution of 2.1 g of 7,7-dibromo-4-tert-butylcarbonyl-3-methyl-3-cephem 1,1-dioxide in acetonitrile (70 ml), prepared as described in example 1, were added o;,α-azoisobutyronitrile (50 mg) and allyltributyltin (2,1 ml) . The reaction mixture was let stand at reflux for 1 h, then was allowed to warm to room temperature and poured into water/ethyl acetate. The organic layer was collected, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed a on a flash column to yield the title compound as a white powder (1.5 g) .
IR (KBz) ʋ 1800, 1700 cm-1
NMR (200 MH2, CDCl3) δ 1.27 (9H, s), 1.73 (3H, s), 2.95- 3.00 (2H, m), 3.51 (1H, d, J= 17.4 Hz), 3.86 (1H, br.d, J= 17.4 Hz), 4.65 (3H, s), 5.3-5.4 (2H, m), 5.7- 5.9 (1H, m) . EXAMPLE 8
7β-Bromo-4-tert-butylcarbonyl-7α-methoxy-3-methyl-3-cephem 1,1-dioxide
To a solution of 4.6 g of 4-tert-butylcarbonyl-7-diazo-3-methyl-3-cephem 1,1-dioxide in methylene chloride (100 ml) was added methanol (70 ml) and then solid N-bromosuccinimide (2.75 g) in small portions to control N2 evolution.
After stirring for 1.5 h at room temperature, the reaction mixture was diluted with CH2Cl2. The organic layer was washed with brine and dried over Na2SO4. Removal of the solvent in vacuo left a residue which was purified by flash chromatography (n-hexane/EtOAc 2/1) affording the title product as a light yellow solid (4.45 g) .
IR (KBr) ʋ max 17800, 1690 cm-1
NMR (200 NHz, CDCl3) δ 1.27 (9H, s), 1.78 (3H, s), 3.60
(1H, d, J= 17.1 Hz), 3.85 (1H, br.d, J= 17.1 Hz), 3.66 (3H, s), 4.76 (1H, br.s). EXAMPLE 9
7α-Allyl-4-tert-butylcarbonyl-7β-methoxy-3-methyl-3-cephem
1,1-dioxide
To a solution of 4.4 g 7-bromo-4-tert-butylcarbonyl-7-methoxy-3-methyl-3-cephem 1,1-dioxide in acetonitrile (160 ml) were added α,α'-azoisobutyronitrile (100 mg) and allyltributyltin (7.7 ml).
The reaction mixture was let stand at reflux for 4 h, then poured into water/ethyl acetate. The organic layer was collected, dried over Na2SO4 and concentrated in vacuo.
Flash chromatography of the residue gave the purified title product as a white solid (2.9 g).
IR (CHCl3) ʋ max 1790, 1700 cm-1
NMR (200 MHz, CDCl3) δ 1.25 (9H, s), 1.72 (3H, s), 2.6-2.9 (2H, m), 3.43 (1H, d, J= 17.7 Hz), 3.83 (1H, br.d, J= 17.7 Hz), 3.63 (3H, s), 4.50 (1H, br.s), 4.3-5.4 (2H, m), 5.7-5.9 (1H, m).
EXAMPLE 10
7α-Allyl-4-tert-butylcarbonyl-7β-methoxy-3-methyl-2-(5-methyl-1,3,4-thiadiazol-2-yl)thio-3-cephem 1,1-dioxide
To a solution of 7α-allyl-2-bromo-4-tert-butylcarbonyl-7β-methoxy-3-methyl-3-cephem 1,1-dioxide (160 mg) prepared as described in Example 3, starting from the compound of example 9, were added triethylamine (0.07 ml) and 2-mercapto-5-methyl-1,3,4 thiadiazole (70 mg). In about
15 min. the reaction was over.
The reaction mixture was diluted with ethyl acetate, sequentially washed with saturated NaHCO3 and brine and dried over Na2SO4. Removal of the solvent in vacuo left the crude product which was obtained pure as a white solid by silica gel chromatography (120 mg).
IR (KBr) ʋ max 1810, 1700 cm-1
NMR (200 MHz, CDCl3) δ 1.20 (9H, s), 1.92 (3H, s), 2.79 (3H, S), 2.7-2.9 (2H, m), 3.61 (3H, s), 5.11 (1H, s), 5.12 (1H, S), 5.35 (2H, m), 5.8-5.9 (1H, m). EXAMPLE 11
7α-Allyl-4-tert-butylcarbonyl-7β-methoxy-3-methyl-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-3-cephem 1,1-dioxide
Following the procedure described in Example 10 and using 2-mercapto-1-methyl-1,2,3,4-tetrazole instead of 2-mercapto-5-methyl-1,3,4-thiadiazole the title product was obtained as a white powder.
IR (KBr) ʋ max 1790, 1700 cm-1 EXAMPLE 12
7α-Allyl-2- (6-hydroxy-2-methyl-5-oxo-2.5-dihydro-1,2.4-triazin-3-yl)thio-4-tert-butylcarbonyl-7β-methoxy-3-methyl-3-cephem 1,1-dioxide
A solution of 7α-allyl-4-tert-butylcarbonyl-7β-methoxy-3-methyl-3-cephem 1,1-dioxide (130 mg) in
acetonitrile (5 ml) was sequentially treated with N-bromosuccinimide (100 mg) and triethylamine (0.06 ml).
After 5 minutes at room temperature a solution of 6-benzhydryloxy-3-mercapto-2-methyl-5-oxo-2,5-dihydro-1,2,4-triazine (140 mg) and triethylamine (0.06 ml) in DMF (1 ml) was added. The reaction mixture was stirred for 15 minutes, then partitioned between EtOAc and water. The organic layer was sequentially washed with 2% aqueous HCl, 4% aqueous NaHCO3 and brine, then dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in dichloromethane (1 ml) and treated with anisole (0.2 ml) and trifluoroacetic acid (1 ml). After 30 minutes, TFA was removed in vacuo; the residue was dissoved in EtOAc and extracted with saturated aqueous NaHCO3. Upon careful acidification with concentrated hydrochloric acid, the aqueous phase was back extracted with EtOAc. Following drying (Na2SO4) and removal of the solvent, a waxy solid was obtained which was treated with diisopropyl ether to afford the title compound as a white powder
IR (KBr) ʋ max 1790, 1700, 1620-1660 cm-1
NMR (200 MHz, CDCl3) 6 1.25 (9H, s), 1.85 (3H, s), 2.79 (3H, s), 2.6-3.0 (2H, m), 3.62 (3H, s), 3.82 (3H, s), 4.73 (1H, S), 5.2-5.5 (2H, m), 5.7-5.9 (1H, m), 5.94 (1H, s) . EXAMPLE 13
7α-Allyl-2-benzoyloxy-4-tert-butylcarbonyl-7β-methoxy-3-methyl-3-cephem 1,1-dioxide
7α-allyl-2-bromo-4-tert-butylcarbonyl-7β-methoxy-3-methyl-3-cephem 1,1-dioxide (200 mg), prepared as described in Example 3, starting from the compound of example 9, was dissolved in dry acetonitrile (5 ml) and treated with silver benzoate (210 mg) . After stirring for 30 min. at room temperature, the reaction mixture was partitioned between ethyl acetate and water.
Following drying over Na2SO4, the organic phase was rotoevaporated. The residue was passed through a silica gel column affording the pure title product as a white solid (140 mg)
IR (KBr) ʋ max 1815, 1785, 1740, 1705 cm-1
NMR (200 NHz, CDCl3) δ 1.30 (9H, s), 1.76 (3H, s), 2.7-2.9 (2H, m), 3.63 (3H, s), 4.67 (1H, s), 5.35 (2H, m), 5.8-5.9 (1H, m), 6.03 (1H, s).
EXAMPLE 14
4-tert-Butylcarbonyl-7-methoxy-3-methyl-7-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-3-cephem 1,1-dioxide
To a solution of 7β-bromo-4-tert-butylcarbonyl-7α-methoxy-3-methyl-3-cephem 1,1-dioxide (200 mg) in
acetonitrile (5 ml) was added sodium 1-methyl 1,2,3,4-tetrazolyl-5-mercaptide (200 mg). After stirring for 5 h at room temperature, the reaction mixture was partitioned between ethyl acetate/saturated NaHCO3. The organic phase was collected, washed with water and dried over Na2SO4.
Removal of the solvent in vacuo left a residue which was taken up in dichloromethane. Because of its poor solubility in such a solvent, the residue was first triturated and eventually filtered to give the title product as a light yellow powder (170 mg) .
IR (KBr) ʋ max 1800, 1700 cm-1
NMR (200 MHz, CDCl3) δ 1.23 (9H, s), 1.73 (3H, s), 3.47 (1H, d, J= 18 Hz), 3.97 (1H, br.d, J= 18 Hz), 3.81 (3H, s), 4.12 (3H, s), 5.48 (1H, s) .
EXAMPLE 15
7β-Bromo-7α-methoxy-3-methyl-4-phenylcarbonyl-3-cephem 1,1-dioxide
To a solution of 7-diazo-3-methyl-4-phenylcarbonyl-3-cephem 1,1-dioxide (2.1 g) in methylene chloride (50 ml) was added methanol (30 ml) and then solid N-bromosuccinimide (NBS; 1.41 g) in small portions to control N2 evolution. After stirring for 1.5 h at room
temperature, the reaction mixture was diluted with CH2Cl2. The organic layer was washed with brine and dried over Na2SO4. Removal of the solvent in vacuo left a residue which was chromatographed on a flash column (n-hexane/ethyl acetate 2/1) affording the title product as a yellow solid (2.12 g).
IR (KBr) ʋ max 1790, 1670 cm-1
NMR (200 MHz, CDCl3) δ 1.69 (3H, s), 3.61 (3H, s),
3.59 (1H, d, J= 17.7 Hz), 3.99 (1H br.d, J= 17.7
Hz), 4.95 (1H, br.s), 7.5-8.0 (5H, m).
EXAMPLE 16
7α-Allyl-7β-methoxy-3-methyl-4-phenylcarbonyl-3-cephem 1,1-dioxide
To a solution of 7-bromo-7-methoxy-3-methyl-4-phenylcarbonyl-3-cephem 1,1-dioxide (1.1 g) in acetonitrile (40 ml) were added α,α'-azoisobutyronitrile (AIBN; 30 mg) and allyl tributyltin (1.8 ml). The reaction mixture was let stand at reflux for 4 h, then poured into water/ethyl acetate. The collected organic layer was dried over Na2SO4 and concentrated in vacuo. Flash chromatography of the residue gave the purified title compound as a light yellow solid (645 mg). IR (KBr) ʋ max 1780, 1670 cm-1
NMR (200 MHz, CDCl3) δ 1.68 (3H, s), 2.6-2.9 (2H, m),
3.61 (3H, s), 3.50 (1H, d, J= 17.9 Hz), 3.88 (1H, br.d, J= 17.9 Hz), 4.62 (1H, br.s), 5.2-5.4 (2H, m), 5.6-5.8 (1H, m), 7.4-8.0 (5H, m).
EXAMPLE 17
7α-Allyl-7β-methoxy-3-methyl-2-(1-methyl-1,2,3,4-tetrazol- 5-yl)thio-4-phenylcarbonyl-3-cephem 1,1-dioxide
A solution of 7α-allyl-7β-methoxy-3-methyl-4-phenylcarbonyl-3-cephem 1,1-dioxide (480 mg) in
acetonitrile (10 ml) was sequentially treated with toluene-4-thiosulfonic acid S-(1-methyl-1H-tetrazol-5-yl) ester (395 mg) and 1,5-diazabicyclo [4.3.0] non-5-ene (DBN; 0.32 ml). The reaction mixture was stirred for 0.5 h at room temperature, then poured into ethyl acetate/2% aqueous HCl. The organic layer was collected, washed with brine, dried over Na2SO4 and concentrated to dryness. Flash
chromatography of the residue gave the title product as a light yellow solid (380 mg).
IR (KBr) ʋ max 1790, 1675 cm-1
NMR (200 MHz, CDCl3) δ 1.93 (3H, s), 2.6-2.9 (2H, m),
3.58 (3H, S), 4.10 (3H, s), 5.01 (1H, s), 5.09
(1H, s), 5.3-5.4 (2H, m), 5.6-5.8 (1H, m), 7.5- 8.0 (5H, m) .
EXAMPLE 18
4-tert-Butylcarbonyl-7β-methoxy-3-methyl-7α-propyl-3-cephem 1,1-dioxide
A mixture of 7α-allyl-4-tert-butylcarbonyl-7β-methoxy-3-methyl-3-cephem 1,1-dioxide (1.02 g), cyclohexadiene (3 ml) and 10% Pd/C (250 mg) was heated at reflux for 90 minutes. Upon removal of the catalyst by filtration, the filtrate was partitioned between EtOAc and water and the organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography affording the title product as a white solid (835 mg). IR (CHCl3) ʋ max 1780, 1695 cm-1
NMR (200 MHz, CDCl3) δ 1.02 (3H, t, J= 7.2 Hz), 1.25
(9H, s), 1.4-1.7 (2H, m), 1.72 (3H, s), 1.8-2.1
(2H, m), 3.47 (1H, d, J= 17.5 Hz), 3.59 (3H, s), 3.81 (1H, br.d, J= 17.5 Hz), 4.45 (1H, m).
EXAMPLE 19
4-tert-Butylcarbonyl-7β-methoxy-3-methyl-2-(1-methyl- 1,2,3,4-tetrazol-5-yl)thio-7α-propyl-3-cephem 1,1-dioxide A solution of 4-tert-butylcarbonyl-7β-methoxy-3-methyl-7α-propyl-3-cephem 1,1-dioxide (50 mg) and toluene-4-thiosulfonic acid S-(1-methyl-1H-tetrazol-5-yl) ester (45 mg) was treated with 1,5-diazabicyclo[4,3,0]non-5-ene (0.045 ml) and left stand at room temperature for 15 minutes. The reaction mixture was partitioned between EtOAc and water. The upper layer was sequentially washed with 2% aqueous HCl, 4% aqueous NaHCO3 and brine. Drying over
Na2SO4, removal of the solvent and purification of the residue by flash chromatography allowed the isolation of the title product as a white powder (39 mg)
IR (KBr) ʋ max 1785, 1695 cm-1
NMR (200 MHz, CDCl3) δ 1.04 (3H, t, J= 7.2 Hz), 1.24
(9H, s), 1.4-1.8 (2H, m), 1.8-2.2 (2H, m), 1.94
(3H, s), 3.57 (3H, s), 4.10 (3H, s), 4.90 (1H, s), 4.92 (1H, s) .
EXAMPLE 20
2-Bromo-3-bromomethyl-4-tert-butylcarbonyl-7β-methoxy-7α-propyl-3-cephem 1,1-dioxide and 3-bromomethyl-4-tert-butylcarbonyl-7β-methoxy-7α-propyl-3-cephem 1,1-dioxide A solution of 4-tert-butylcarbonyl-7β-methoxy-3-methyl-7α-propyl-3-cephem 1,1-dioxide (800 mg) in
dichloromethane/carbon tetrachloride 1:4 (100 ml) was treated with NBS (1.3 g) and AIBN (70 mg). The mixture was heated at reflux for 2 hours then concentrated under vacuum. The residue was flash chromatographed over SiO2 (eluting with EtOAc/n-hexane mixtures). The first eluted product was shown to be the 2,3'-dibromocephem derivative (600 mg) :
IR (CHCl3) ʋ max 1800, 1705 cm -1
NMR (200 MHz, CDCl3) δ 1.04 (3H, t, J= 7.2 Hz), 1.31
(9H, s), 1.3-1.7 (2H, m), 1.8-2.2 (2H, m), 3.60
(3H, s), 3.79 (1H, d, J= 11.7 Hz), 4.10 (1H, dd, J= 0.5 and 11.7 Hz), 5.17 (1H, d, J= 0.5 Hz),
5.44 (1H, s).
The second eluted product was the 3'-bromo cephem derivative (250 mg):
IR (KBr) ʋ max 1785, 1695 cm-1.
NMR (200 MHz, CDCl3) δ 1.03 (3H, t, J= 7.2 Hz), 1.29
(9H, s), 1.3-1.7 (2H, m), 1.8-2.2 (2H, m), 3.50
(1H, dd, J= 0.8 and 17.7 Hz), 3.59 (3H, s), 3.81 and 3.95 (2H, ABq, J= 11.3 Hz), 4.18 (1H, dd, J=
1.5 and 17.7 Hz), 4.57 (1H, dd, J= 0.8 and 1.5
Hz).
EXAMPLE 21
4-tert-Butylcarbonyl-7β-methoxy-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-7α-propyl-3-cephem 1,1-dioxide
A solution of 3-bromomethyl-4-tert-butylcarbonyl-7β-methoxy-7α-propyl-3-cephem 1,1-dioxide (120 mg) in CH3CN (12 ml) was treated with sodium 1-methyl-1,2,3,4-tetrazolyl-5-mercaptide (120 mg) and stirred for 15 minutes at room temperature, then poured into EtOAc/4% aqueous NaHCO3. The organic layer was dried (Na2SO4) and
rotoevaporated. The residue was purified by flash
crhomatography yielding the title product as a white powder (100 mg).
IR (KBr) ʋ max 1790, 1695 cm-1
NMR (200 MHz, CDCl3) δ 1.03 (3H, t, J= 7.2 Hz), 1.25
(9H, s), 1.4-1.6 (2H, m), 1.8-2.2 (2H, m), 3.59
(3H, s), 3.77 and 4.07 (2H, ABq, J= 13.3 Hz),
3.82 (1H, dd, J= 0.5 and 17.5 Hz), 3.95 (3H, s), 4.10 (1H, dd, J= 1.4 and 17.5 Hz), 4.55 (1H, dd, J= 0.5 and 1.4 Hz) . EXAMPLE 22
4-tert-Butylcarbonyl-7β-methoxy-3-(6-hydroxy-2-methyl-5-oxo-2,5-dihydro-1.2.4-triazin-3-yl)thiomethyl-7α-propyl-3-cephem 1,1-dioxide
Starting from 3-bromomethyl-4-tert-butylcarbonyl-7βmethoxy-7α-propyl-3-cephem 1,1-dioxide and following a procedure similar to that described in Example 12 the title product was obtained as a light pink powder.
IR (KBr) ʋ max 1790, 1695, 1620-1660 cm-1
EXAMPLE 23
4-tert-Butylcarbonyl-7β-methoxy-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-7α-propyl-3-cephem 1,1-dioxide
A solution of 2-bromo-3-bromomethyl-4-tert-butylcarbonyl-7β-methoxy-7α-propyl-3-cephem 1,1-dioxide (100 mg) in CH3CN (10 ml)
was treated with sodium 1-methyl-1,2,3,4-tetrazolyl-5-mercaptide (150 mg) and stirred at room temperature for 30 minutes, then partitioned between EtOAc and water. The upper phase was washed with brine, then dried (Na2SO4) and rotoevaporated. Following purification by flash
chromatography, the title product was obtained as a white powder (80 mg) .
IR (KBr) ʋ max 1795, 1695 cm-1
NMR (200 MHz, CDCl3) δ 1.03 (3H, t, J= 7.2 Hz), 1.25
(9H, s), 1.3-1.8 (2H, m), 1.8-2.2 (2H, m), 3.57
(3H, s), 3.70 and 4.33 (2H, ABq, J= 14.0 Hz),
3.96 (3H, S), 4.14 (3H, s), 4.91 (1H, s), 5.41
(1H, s, exch. D2O) .
EXAMPLE 24
4'-tert-Butyl-7ι8-methoxy-7α-propyl-furo[3,4-clcephem 1,1- dioxide
A solution of 3-bromomethyl-4-tert-butylcarbonyl-7β- methoxy-7α-propyl-3-cephem 1,1-dioxide (125 mg) in
acetonitrile (10 ml) was treated with triethylamine (0.08 ml) and let stand at room temperature for 1 hour. The reaction mixture was partitioned between EtOAc and 1% aqueous HCl; the organic layer was dried (Na2SO4) and rotoevaporated. The residue was passed through a short pad of SiO2 eluting with n-hexane/EtOAc 3:1. The title product was obtained as a whitish powder.
IR (KBr) ʋ max 1790 cm-1.
NMR (200 MHz, CDCl3) δ 1.03 (3H, t, J= 7.2 Hz), 1.37
(9H, s), 1.4-1.7 (2H, m), 1.9-2.2 (2H, m), 3.64
(3H, S), 4.14 (2H, m), 4.57 (1H, s), 7.14 (1H, t, J= 1.4 Hz) .
EXAMPLE 25
Pharmaceutical composition for intramuscular injection:
Figure imgf000058_0001
Procedure:
Step 1. Dissolve the active ingredient in the buffer
solution.
Step 2. Aseptically filter the solution from step 1. Step 3. The sterile solution is aseptically filled into sterile ampoules
Step 4. The ampoules are sealed under aseptic conditions

Claims

1. A compound of formula (Ia) or (Ib) or a
pharmaceutically or veterinarily acceptable salt thereof
Figure imgf000059_0001
Figure imgf000059_0002
wherein A is an organic radical which is optionally
substituted and is selected from straight or branched C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C7-C22 alkaryl, C7-C22 aralkyl, C8-C14 alkenylaryl, C8-C14 aralkenyl, C8-C14
alkynylaryl, C8-C14 aralkynyl, (cycloalkyl)alkyl,
(cycloalkyl)alkenyl, heterocyclyl, (heterocyclyl)alkyl,
(heterocyclyl)alkenyl;
Q and W, each independently, represent
(1) chloro, fluoro, bromo or iodo;
(2) A as defined above
(3) hydroxy or an ether OA wherein A is as defined above (4) a thioether, sulfoxide or sulfone -S(O)mA wherein m is either zero, one or two and A is as defined above;
(5) a selenoether, selenoxide or selenone -Se(O)mA
wherein m is either zero, one or two and A is as defined above;
(6) acyl -C(O)A wherein A is as defined above; (7) formyloxy -OC(O)H or acyloxy -OC(O)A wherein A is as defined above;
(8) sulfonyloxy -OS(O)2A wherein A is as defined above;
(9) formamido -NHC(O)H or an acylamino group -NHC(O)A
wherein A is as defined above or acylamino -NH-Z wherein Z is a mono, di- or tripeptide composed of D or L α-aminoacids chosen from Ala, Gly, Val, Leu, Ile, Phe and with the terminal amino group either free or acylated by a group -C(O)A or -C(O)OA wherein A is as defined above;
(10) azido, nitro or cyano;
or Q and W taken together constitute an oxo group (=O) or a group of formula =CHA, =CHC(O)A, =CHC(O)OA or =CHS(O)2A wherein A is as defined above;
or Q and W taken together with the carbon atom to which they are attached constitute an oxirane or cyclopropyl group; and where appropriate Q and W are optionally substituted;
with the proviso that in the compounds of formula (Ia) Q and W do not both represent chloro or fluoro atoms;
R1 is either hydrogen or an optionally substituted straight or branched C1-C12 alkyl or a C2-C12 alkenyl group, or a C7-C14 aralkyl group, or a (heterocyclyl) alkyl group;
R2 represents:
(1) hydrogen;
(2) A as defined above;
(3) halo;
(4) a sulfenyl, sulfinyl or sulfonyl group -S(O)mA wherein A and m are as defined above;
(5) an acyloxy group -OC(O)A wherein A is as defined
above;
or R1 and R2 taken together constitute a methylene group or a group of formula =CHA, =CHC(O)A or =CHC(O)OA wherein A is as defined above;
or R1 and R2 taken together with the carbon atom to which they are attached constitute a carbocyclic or heterocyclic group; where appropriate R1 and/or R2 are optionally substituted; R3 represents:
(1) A as defined above;
(2) chloro or fluoro or hydrogen;
(3) a sulfenyl, sulfinyl or sulfonyl group -S(O)mA wherein A and m are as defined above;
(4) hydroxy or an oxy group -O-A wherein A is as defined above;
(5) formyl -C(O)H, carboxy -CO2H, or an acyl group -C(O)A or C(O)OA wherein A is as defined above;
(6) on oxymethyl group -CH2-OA wherein A is as defined
above;
(7) a thiomethyl group or a derivative thereof of formula -CH2S(O)mA wherein m and A are as defined above;
(8) formyloxymethyl -CH2OC(O)H or an acyloxymethyl group - CH2OC(O)A or -CH2O-Z wherein A and Z are as defined above;
(9) an acylthiomethyl group -CH2SC(O)A wherein A is as
defined above;
(10) an aminomethyl group -CH2-N(A)A' wherein A is as
defined above and A', being the same or different, is as defined above for A; or A and A' taken together with the nitrogen atom to which they are attached represent a heterocyclic ring;
(11) ammoniomethyl -CH2N+(A) (A' )A'' wherein A and A' are as defined above and A'', being the same or different, is as defined for A; or A is alkyl and A' and A'' together with the nitrogen atom to which they are attached represent a heterocyclic ring, or A and A' and A'' together with the nitrogen atom to which they are attached represent a heterocyclic ring;
(12) formamidomethyl -CH2NHC(O)H or an acylaminomethyl
group -CH2NH-C(O)A or -CH2NH-Z wherein A and Z are as defined above;
where appropriate R3 is optionally substituted;
and X represents O, NR or S, wherein R is hydrogen or straight or branched C1-C12 alkyl, C3-C8 cycloalkyl, C6- C14 aryl or C7-C22 aralkyl group; or an isomer thereof which is a stereoisomer, diastereoisomer, epimer, geometrical isomer or tautomer, or a mixture of any of these isomers.
2. A compound or salt according to claim 1 wherein A is selected from straight or branched C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-C10 aryl, C7-C13 aralkal, C7-C13 alkaryl, C3-C8 cycloalkyl and heterocyclyl, and is
optionally substituted by one or more of halo, sulfo, carboxy, C1-C5 alkylcarbonyloxy, C1-C5 alkoxy, C1-C5
alkoxycarbonyl, C1-C5 carbamoyl, sulfamoyl, C1-C5
carbamoyloxy, C1-C5 alkylcarboxamido, C1-C5
haloalkylcarboxamido, nitro, cyano, diazo, hydroxy, benzhydryloxy, amino, C6-C10 arylcarbonyl, C6-C10 aryloxy, C7-C13 aralkyloxy, C7-C13 alkaryloxy, C1-C5 alkanoyl, C1-C5 alkanoyloxy, C1-C5 alkylsulfonyl, C6-C10 arylcarbonyloxy, C6-C10 arylcarboxy, C7-C13 alkarylcarboxy, C7-C13
aralkylcarbonyloxy, C7-C13 aralkanoyloxy, C7-C13
alkarylcarbonyloxy, C7-C13 alkarylcarboxy, C1-C5
halocarbamoyl, C1-C5 alkylcarboxy, C1-C5 alkanoyl amido;
Q and W, each independently, are
(1') chloro, fluoro or bromo;
(2') straight or branched C1-C5 alkyl or C1-C5 alkenyl;
(3') C1-C5 alkyloxy, C1-C5 alkenyloxy, C6-C10 aryloxy, C7-C10 aralkyloxy, heterocyclyloxy;
(4') C1-C5 alkylthio, C2-C5 alkenylthio, C6-C10 arylthio, C7-C10 aralkylthio, heterocyclylthio;
(5') C1-C5 alkylsulfinyl, C2-C5 alkenylsulfinyl, C6-C10 arylsulfinyl, C7-C10 aralkylsulfinyl, heterocyclylsulfinyl; (6') C1-C5 alkylsulfonyl, C2-C5 alkenylsulfonyl, C6-C10 arylsulfonyl, C7-C10 aralkylsulfonyl, heterocyclylsulfonyl; (7') phenylselenyl, phenylseleninyl, phenylselenonyl;
(8') C1-C5 alkylcarbonyl, C2-C5 alkenylcarbonyl, C6-C10 arylcarbonyl, C7-C10 aralkylcarbonyl, heterocyclylcarbonyl; (9')C1-C5 alkylcarbonyloxy, C2-C5 alkenylcarbonyloxy, C6-C10 arylcarbonyloxy, C7-C10 aralkylcarbonyloxy,
heterocyclylcarbonyloxy; (10') C1-C5 alkylsulfonyloxy, C2-C5 alkenylsulfonyloxy, C6-C10 arylsulfonyloxy, C7-C10 aralkylsulfonyloxy,
heterocyclylsulfonyloxy;
(11') C1-C5 alkylcarboxamido, C2-C5 alkenylcarboxamido, C6-C10 arylcarboxamido, C7-C10 aralkylcarboxamido,
heterocyclylcarboxamido;
(12') nitro, azido, cyano, formyloxy, formamido;
or Q and W taken together constitute an oxo group, or a methylene group, or an optionally substituted cyclopropyl or oxirane group, or a group of formula =CHY or =CHC(O)Y or =CHC(O)OY or =CHS(O)2Y, wherein Y is C1-C5 alkyl, C1-C5 alkenyl, C6-C10 aryl, C7-C10 aralkyl or heterocyclyl;
and, where appropriate, are optionally substituted by one or more substituents for the groups defined under (1')- (11') being selected from halo, sulfo, carboxy, C1-C5 alkylcarbonyloxy, C1-C5 alkoxy, C1-C5 alkoxycarbonyl, C1-C5 carbamoyl, sulfamoyl, C1-C5 carbamoyloxy, C1-C5
alkylcarboxamido, C1-C5 haloalkylcarboxamido, nitro, cyano, diazo, hydroxy, benzhydryloxy, amino, C6-C10 arylcarbonyl, C6-C10 aryloxy, C7-C13 aralkyloxy, C7-C13 alkaroloxy, C1-C5 alkanoyl, C1-C5 alkanoyloxy, C1-C5 alkylsulfonyl, C6-C10 arylcarbonyloxy, C6-C10 arylcarboxy, C7-C13 alkarylcarboxy, C7-C13 aralkylcarbonyloxy, C7-C13 alkarylcarbonyloxy, C7-C13 aralkanoyloxy, C7-C13 aralkylcarboxy, C1-C5 halocarbamoyl, C1-C5 alkylcarboxy, C1-C5 alkanoylamido,
C7-C13 alkarylcarbonyl, C7-C13 aralkylcarbonyl, C1-C5
alkylthio, C6-C10 arylthio, C1-C5 alkylsulfonyl, C6-C10 arylsulfonyl, sulfo C1-C5 alkyl, carboxy C1--5 alkylthio, C1-C5 alkylcarbonyloxy C1-C5 alkylthio, C2-C10 secondary amino, C3-C15 tertiary amino, di-C1-C5 alkylamino, di-C1-C5- alkylamino C1-C5 alkyl, oxo, halo C1-C5 alkanoyl, straight or branched C1-C5 alkyl and straight or branched C2-C5 alkenyl;
R1 is either hydrogen or halogen, or an optionally
substituted straight or branched C2-C5 alkyl or C1-C5 alkenyl, or an optionally substituted C7-C10 aralkyl or (heterocyclyl)alkyl; optional substituents being selected from nitro, cyano, carbamoyl, hydroxy, carboxy, amino, methoxycarbonyl, benzhydryloxycarbonyl, tert-butoxycarbonyl, acetyl,
acetoxy, formamido, methoxy, sulfonyl, methylthio, phenoxy, halogen;
R2 is either
(1') hydrogen;
(2') halogen
(3') an optionally substituted straight or branched C1-C5 alkyl, C1-C5 alkenyl or C7-C10 aralkyl;
(4') optionally substituted C6-C10 arylthio, or
heterocyclylthio;
(5') a group OC(O)R4 wherein R4 is hydrogen, or an
optionally substituted C1-C5 straight or branched alkyl or alkenyl or an optionally substituted C3-C6 cycloalkyl, C6-C14 aryl C7-C14 aralkyl, heterocyclyl;
the optional substituents being selected from halo, sulfo, carboxy, C1-C5 alkylcarbonyloxy, C1-C5 alkoxy, C1-C5 alkoxycarbonyl, C1-C5 carbamoyl, sulfamoyl, C1-C5
carbamoyloxy, C1-C5 alkylcarboxamide, C1-C5
haloalkylcarboxamido, nitro, cyano, diazo, hydroxy,
benzhydryloxy, amino, C6-C10 arylcarbonyl, C6-C10 aryloxy, C7-C13 aralkyloxy, C7-C13 alkaryloxy, C1-C5 alkanoyl, C1-C5 alkanoyloxy, C1-C5 alkylsulfonyl, C6-C10 arylcarbonyloxy, C6-C10 arylcarboxy, C7-C13 alkarylcarboxy, C7-C13
aralkylcarbonyloxy, C7-C13 alkarylcarboxy, C7-C13
alkarylcarbonyloxy, C7-C13 aralkanoyloxy, C1-C5
halocarbanoyl, C1-C5 alkylcarboxy, C1-C5 alkanoylamido, C7-C13 alkarylcarbonyl, C7-C13 aralkylcarbonyl, C1-C5 alkylthio, C6-C10 arylthio, C1-C5 alkylsulfonyl, C6-C10 arylsulfonyl, sulfo C1-C5 alkyl, carboxy C1-C5 alkylthio, C2-C10 secondary amino, C3-C15 tertiary amino, di-C1-C5-alkylamino, di-C1-C5-alkylamino-C1-C5 alkyl, oxo, C1-C5 haloalkanoyl, straight or branched C1-C5 alkyl and straight or branched C2-C5 alkenyl;
R3 is either hydrogen or
(1') methyl, chloromethyl, bromomethyl, benzyl, ethyl, propyl, phenyl
(2') chloro
(3') methoxy or benzyloxy
(4') methylthio
(5') formyl, acetyl, benzoyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl;
(6') methoxymethyl, ethoxymethyl, isopropoxymethyl; or benzyloxymethyl, phenoxymethyl, 3-pyridyloxymethyl wherein the phenyl and pyridyl rings are either unsubstituted or substituted by one group or two equal or different groups chosen from hydroxy, carboxy, amino, halogen and C1-C4 alkoxycarbonyl;
(7') a heterocyclylthiomethyl group wherein the
heterocyclyl ring either unsubstituted or substituted by one group or two equal or different groups chosen from the following: hydroxy, carboxy, amino, sulfo,
dimethylaminomethyl, carboxymethyl, carboxymethylthio, cyano, cyanomethyl, nitro, methoxy, methylthio, acetoxy, halogen or C1-C4 alkyl or alkenyl;
(8') acetoxymethyl, benzoyloxymethyl, phenylacetoxymethyl or C3-C6 alkanoyloxymethyl wherein the above groups are either unsubstituted or substituted by one or more groups selected from carboxy, hydroxy, C1-C3 alkoxy;
(9') trialkylammoniomethyl wherein the alkyl group is chosen from methyl, ethyl or propyl; N-methylpyrrolidiniomethyl, N-methylpiperidimiomethyl, N-methylmorpholiniomethyl;
(10') pyridiniomethyl which is either unsubstituted or substituted on the heterocyclic ring by fluoro, clhoro, methoxy, hydroxy, carboxy or carbamoyl;
(11') carbamoyloxymethyl;
(12') carboxy;
and X represents O, S or NR, wherein R is as defined in claim 1.
3. A compound or salt according to claim 1 or 2 wherein A is a group selected from methyl, tert-butyl, 2- phenyl-2-propyl, benzyl and diphenylmethyl, which groups are optionally substituted by one or more substituents selected from carboxy, carbamoyl, methanesulfonyl, methoxy, ethoxy, tert-butoxy, benzyloxy, acetoxy, pivaloyoxy, benzoxy, carboxymethyl,
-C6H4-COOH, C6H5COO-, -CH2-C6H4-COOH, CH3-C6H4-COO- , C6H5-CH2-COO-, -C6H4-CH2COOH, benzoyl, pivaloyl, formamido,
acetamido, trifluoroacetamido and pivalamido;
Q and W, which are as defined in claim 1 or 2, are independently each optionally substituted, where
appropriate, by one or more substituents selected from fluoro, chloro, bromo, carboxy, tetrazolyl, carbamoyl, methanesulfonyl, benzyloxy, benzoxy, acetoxy, pivaloyloxy, methylthio, phenylthio, benzenesulfonyl, sulfomethyl, carboxymethyl, carboxyethyl, carboxypropyl,
carboxymethylthio, -C6H4-COOH, C6H5COO-, -CH2-C6H4-COOH, CH3-C6H4-COO-, C6H5-CH2-COO-, -C6H4CH2COOH, acetyl,
trifluoroacetyl, benzoyl, pivaloyl, dimethylamino,
diethylamino, dimethylaminoethyl, formamido, acetamido, trifluoroacetamido, pivalamido, vinyl and allyl; and
R2, which is as defined in claim 1 or 2, is optionally substituted where appropriate by one or more substituents selected from fluoro, chloro, bromo, carboxy, tetrazolyl, carbamoyl, methanesulfonyl, benzyloxy, benzoxy, acetoxy, pivaloyloxy, methylthio, phenylthio, benzenesulfonyl, sulfomethyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxymethylthio, -C6H4-COOH, C6H5COO-, -CH2-C6H4-COOH, CH3-C6H4-COO-, -OCOCH2C6H5, HOCOCH2C6H4-, acetyl, trifluoroacetyl, benzoyl, pivaloyl, dimethylamino, diethylamino,
dimethylaminoethyl, formamido, acetamido,
trifluoroacetamido, pivalamido, vinyl and allyl.
4. A compound selected from
7,7-Dibromo-4-tert-butylcarbonyl-3-methyl-3-cephem 1,1-dioxide
7,7-Diallyl-4-tert-butylcarbonyl-3-methyl-3-cephem 1,1-dioxide
7,7-Diallyl-2-bromo-4-tert-butylcarbonyl-3-methyl-3-cephem 1,1-dioxide 7,7-Diallyl-4-tert-butylcarbonyl-3-methyl-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-3-cephem 1,1-dioxide
7,7-Diallyl-4-tert-butylcarbonyl-3-methyl-2-(5-methyl-1,3,4-thiadiazol-2-yl)thio-3-cephem 1,1-dioxide
7,7-Diallyl-4-tert-butylcarbonyl-2-(4-carboxybenzoyl)oxy-3-methyl-3-cephem 1,1 dioxide
7α-Allyl-7β-bromo-4-tert-butylcarbonyl-3-methyl-cephem 1,1-dioxide
7β-Bromo-4-tert-butylcarbonyl-7α-methoxy-3-methyl-3-cephem 1,1-dioxide
7α-Allyl-4-tert-butylcarbonyl-7β-methoxy-3-methyl-3-cephem 1,1-dioxide
7α-Allyl-4-tert-butylcarbonyl-7β-methoxy-3-methyl-2-(5-methyl-1,3,4-thiadiazol-2-yl)thio-3-cephem 1,1-dioxide 7α-Allyl-4-tert-butylcarbonyl-7β-methoxy-3-methyl-2- (1- methyl-1,2,3,4-tetrazol-5-yl)thio-3-cephem 1,1-dioxide
7α-Allyl-2-(6-hydroxy-2-methyl-5-oxo-2,5-dihydro-1,2, 4-1riazin-3-yl)thio-4-tert-butylcarbonyl-7β-methoxy-3-methyl-3-cephem 1,1-dioxide
7α-Allyl-2-benzoyloxy-4-tert-butylcarbonyl-7β-methoxy-3-methyl-3-cephem 1,1-dioxide
4-tert-Butylcarbonyl-7-methoxy-3-methyl-7-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-3-cephem 1,1-dioxide
7β-Bromo-7α-methoxy-3-methyl-4-phenylcarbonyl-3-cephem 1,1-dioxide
7α-Allyl-7β-methoxy-3-methyl-4-phenylcarbonyl-3-cephem 1,1-dioxide
7α-Allyl-7β-methoxy-3-methyl-2-(1-methyl-1,2,3,4-tetrazol- 5-yl)thio-4-phenylcarbonyl-3-cephem 1,1-dioxide
4-tert-Butylcarbonyl-7β-methoxy-3-methyl-7α-propyl-3-cephem 1,1-dioxide
4-tert-Butylcarbonyl-7β-methoxy-3-methyl-2-(1-methyl- 1,2,3,4-tetrazol-5-yl)thio-7α-propyl-3-cephem 1,1-dioxide 2-Bromo-3-bromomethyl-4-tert-butylcarbonyl-7,3-methoxy-7α- propyl-3-cephem 1,1-dioxide and 3-bromomethyl-4-tert- butylcarbonyl-7β-methoxy-7α-propyl-3-cephem 1,1-dioxide 4-tert-Butylcarbonyl-7β-methoxy-3-(1-methyl-1,2, 3,4- tetrazol-5-yl)thiomethyl-7α-propyl-3-cephem 1,1-dioxide 4-tert-Butylcarbonyl-7β-methoxy-3-(6-hydroxy-2-methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-7α-propyl-3-cephem 1,1-dioxide
4-tert-Butylcarbonyl-7β-methoxy-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-7α-propyl-3-cephem 1,1-dioxide
4'-tert-Butyl-7β-methoxy-7α-propyl-furo[3,4-c]cephem 1,1-dioxide; and pharmaceutically or veterinarily acceptable salts thereof; and the stereoisomers, diastereoisomers, geometrical isomers, and tautomers thereof, and their mixtures.
5. A compound according to any one of the preceding claims, or a pharmaceutically or veterinarily acceptable salt thereof, of the formula (lc) or (Id);
Figure imgf000068_0001
Figure imgf000068_0002
6. A process for preparing a compound as defined in claim 1, or a pharmaceutically or veterinarily acceptable salt thereof, which process comprises:
(i) reacting a compound of formula (II)
Figure imgf000068_0003
wherein A, R1, R2 and R3 are as defined in claim 1 with either (ia) a reagent of formula (III)
Q-W (III)
wherein Q and W, being the same or different, are as defined in claim 1; or
(ib) reagents of formulae (IV) and (V)
Q-H (IV)
W-L (V)
wherein Q and W are as defined above and L is a leaving group (ii) if needed, subjecting a compound of formula
(Ia), wherein A, Q, W, R1 and R3 are as above defined, to known processes and/or conventional reactions which entail the transformation of any of the groups A,Q,W,R1, R2 and R3 of a compound of formula (Ia) to afford a different
compound of formula (Ia) wherein A, Q, W, R1, R2 and R3 are as above defined or a compound of the formula (Ib), (iii) if desired, converting the resulting compound of formula (Ia) or (Ib) into a pharmaceutical or veterinarily
acceptable salt thereof.
7. A pharmaceutical or veterinary composition comprising a suitable carrier and/or diluent and, as an active principle, a compound according to any one of claims 1 to 5 or a pharmaceutically or veterinarily acceptable salt thereof.
8. A compound or salt as defined in any one of claims 1 to 5 for use in a method of treatment of the human or animal body by therapy.
9. A compound or salt as claimed in claim 8, for use in the treatment of inflammatory or degenerative diseases caused by proteolytic enzymes in mammals including humans.
10. A compound or salt as claimed in claim 8 for use in the treatment of emphysema, adult respiratory distress syndrome, rheumatic fever, spondylitis, gout, lupus or psoriasis, or in the control of tumor invasion.
PCT/EP1996/002883 1995-07-06 1996-07-02 7,7-disubstituted cephem-4-ketones WO1997002268A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0934944A1 (en) * 1997-12-30 1999-08-11 PLIVA farmaceutska, kemijska, prehrambena i kozmeticka industrija, dionicko drustvo 7-bromo- and 7,7-dibromo-cepham and cephem derivatives and their use as protease inhibitors
US6143742A (en) * 1997-12-11 2000-11-07 Fuisz Technologies Ltd Treatment for necrotizing infections

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0124081A2 (en) * 1983-05-02 1984-11-07 Merck & Co. Inc. New substituted cephalosporin sulfones as antiinflammatory and antidegenerative agents, pharmaceutical compositions containing the same and processes for making them
US5077286A (en) * 1988-04-13 1991-12-31 Farmitalia Carlo Erba S.R.L. Beta-lactam derivatives of the 4-acylcephem sulphone and 3-acylpenam sulphone-type
WO1992018474A2 (en) * 1991-04-08 1992-10-29 Synphar Laboratories, Inc. Novel 2-spirocyclopropyl cephalosporin sulfone derivatives and processes for the preparation thereof
EP0564835A2 (en) * 1992-04-08 1993-10-13 PHARMACIA S.p.A. 2,2-Disubstituted cephem sulphones
WO1994020504A1 (en) * 1993-03-04 1994-09-15 Farmitalia Carlo Erba S.R.L. 2-acyloxycephem derivatives as elastase inhibitors
WO1994028003A1 (en) * 1993-05-20 1994-12-08 Pharmacia S.P.A. Tricyclic defem sulphones as elastase inhibitors
WO1995002603A2 (en) * 1993-07-14 1995-01-26 Pharmacia S.P.A. Use of cephem derivatives as anti-metastatic agents
GB2291425A (en) * 1994-07-20 1996-01-24 Pharmacia Spa 7-Diazo-1,1-dioxo-cephem-4-ketone derivatives

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0124081A2 (en) * 1983-05-02 1984-11-07 Merck & Co. Inc. New substituted cephalosporin sulfones as antiinflammatory and antidegenerative agents, pharmaceutical compositions containing the same and processes for making them
US5077286A (en) * 1988-04-13 1991-12-31 Farmitalia Carlo Erba S.R.L. Beta-lactam derivatives of the 4-acylcephem sulphone and 3-acylpenam sulphone-type
WO1992018474A2 (en) * 1991-04-08 1992-10-29 Synphar Laboratories, Inc. Novel 2-spirocyclopropyl cephalosporin sulfone derivatives and processes for the preparation thereof
EP0564835A2 (en) * 1992-04-08 1993-10-13 PHARMACIA S.p.A. 2,2-Disubstituted cephem sulphones
WO1994020504A1 (en) * 1993-03-04 1994-09-15 Farmitalia Carlo Erba S.R.L. 2-acyloxycephem derivatives as elastase inhibitors
WO1994028003A1 (en) * 1993-05-20 1994-12-08 Pharmacia S.P.A. Tricyclic defem sulphones as elastase inhibitors
WO1995002603A2 (en) * 1993-07-14 1995-01-26 Pharmacia S.P.A. Use of cephem derivatives as anti-metastatic agents
GB2291425A (en) * 1994-07-20 1996-01-24 Pharmacia Spa 7-Diazo-1,1-dioxo-cephem-4-ketone derivatives

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6143742A (en) * 1997-12-11 2000-11-07 Fuisz Technologies Ltd Treatment for necrotizing infections
EP0934944A1 (en) * 1997-12-30 1999-08-11 PLIVA farmaceutska, kemijska, prehrambena i kozmeticka industrija, dionicko drustvo 7-bromo- and 7,7-dibromo-cepham and cephem derivatives and their use as protease inhibitors

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