EP0540606A1 - Cephalosporines et homologues, preparations et compositions pharmaceutiques - Google Patents

Cephalosporines et homologues, preparations et compositions pharmaceutiques

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Publication number
EP0540606A1
EP0540606A1 EP91913545A EP91913545A EP0540606A1 EP 0540606 A1 EP0540606 A1 EP 0540606A1 EP 91913545 A EP91913545 A EP 91913545A EP 91913545 A EP91913545 A EP 91913545A EP 0540606 A1 EP0540606 A1 EP 0540606A1
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EP
European Patent Office
Prior art keywords
formula
group
compound
alkyl
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP91913545A
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German (de)
English (en)
Inventor
John Hargreaves Smithkline Beecham Bateson
George Smithkline Beecham Pharmaceuticals Burton
Stephen Christopher Martin Fell
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Beecham Group PLC
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Beecham Group PLC
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Priority claimed from GB909016189A external-priority patent/GB9016189D0/en
Priority claimed from GB919109540A external-priority patent/GB9109540D0/en
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0540606A1 publication Critical patent/EP0540606A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D463/00—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D463/10—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D463/14—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hetero atoms directly attached in position 7
    • C07D463/16—Nitrogen atoms
    • C07D463/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
    • C07D463/20—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D463/22—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen further substituted by nitrogen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to novel ⁇ -lactam containing
  • GB 1 405 758 (Beecham Group Ltd) discloses the compound 3-(2-tetrahydropyranylmethyl)-7-(2-thienylacetamido)-3- cephem-4-carboxylic acid and records its in vitro activity (MIC) against five typical Gram-positive bacteria.
  • the present invention provides a compound of formula (I) or a salt thereof:
  • R 1 is hydrogen, methoxy or formamido
  • R 2 is an acyl group, in particular that of an
  • R 3 is a carboxy group or a carboxylate anion, or R 3 is a readily removable carboxy protecting group (such as a pharmaceutically acceptable in-vivo hydrolysable ester group);
  • R 4 represents up to four substituents selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, halogen, amino, alkylamino, acylamino, dialkylamino, CO 2 R, CONR 2 , SO 2 NR 2 (where R is hydrogen or C 1-6 alkyl), aryl and heterocyclyl, which may be the same or different and wherein any R 4 alkyl substituent is optionally substituted by any other R 4 substituent;
  • X is S,SO,SO 2 ,O or CH 2 ;
  • m is 1 or 2; and n is 1, subject to the proviso that when R 1 is hydrogen, X is S and the 3-position substituent is
  • R 3 is hydrogen, R 2 is not 2-thienylacetyl or
  • N-t-butoxycarbonyl-D- ⁇ -amino-phenylacetyl N-t-butoxycarbonyl-D- ⁇ -amino-phenylacetyl.
  • the bonding carbon atom of the cyclic ether moiety which links the ring to the cephalosporin nucleus is generally asymmetric.
  • the present invention includes either
  • the formamido group can exist in conformations wherein the hydrogen atoms of the -NH-CHO moiety are cis- or trans-; of these the cis conformation normally predominates.
  • the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for use as a therapeutic agent, and in particular an in vivo hydrolysable ester thereof for use as an orally administrable therapeutic agent.
  • the present invention further provides a compound of formula (Ia) or a pharmaceutically acceptable salt or in vivo
  • hydrolysable ester thereof for use in the treatment of bacterial infections, more particularly an in vivo
  • hydrolysable ester thereof for use in the oral treatment of bacterial infections.
  • the present invention also includes a method of treating bacterial infections in humans and animals which comprises the administration of a therapeutically effective amount of an antibiotic compound of this invention of the formula (Ia) or a pharmaceutically acceptable in vivo hydrolysable ester thereof, in particular the oral administration of a
  • the present invention includes the use of a compound of formula (Ia) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for the
  • pharmaceutically acceptable in vivo hydrolysable ester or which are in non-pharmaceutically acceptable salt form are primarily useful as intermediates in the preparation of compounds of the formula (Ia) or a pharmaceutically
  • Suitable readily removable carboxy protecting groups for the group R 3 include groups forming ester derivatives of the carboxylic acid, including in vivo hydrolysable esters.
  • the derivative is preferably one which may readily be cleaved invivo.
  • Suitable ester-forming carboxyl-protecting groups are those which may be removed under conventional conditions.
  • Such groups for R 3 include benzyl, p-methoxybenzyl,
  • R 7 is aryl or heterocyclic, or an in vivo hydrolysable ester radical such as defined below.
  • R 7 is aryl or heterocyclic, or an in vivo hydrolysable ester radical such as defined below.
  • 'aryl' includes phenyl and naphthyl, each optionally substituted with up to five, preferably up to three, groups selected from halogen, mercapto, C 1-6 alkyl, phenyl, C 1-6 alkoxy,
  • heterocyclyl' and 'heterocyclic' as used herein include aromatic and non-aromatic, single and fused, rings suitably containing up to four hetero-atoms in each ring selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or substituted by, for example, up to three groups selected from halogen, (C 1-6 ) alkyl, (C 1-6 ) alkoxy, halo (C 1-6 ) alkyl, hydroxy, carboxy, carboxy salts, carboxy esters such as (C 1-6 ) alkoxycarbonyl,
  • each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms.
  • the term 'heteroaryl' refers to
  • a fused heterocyclic ring system may include carbocyclic rings' and need include only one heterocyclic ring.
  • Compounds within the invention containing a heterocyclyl group may occur in two or more tautometric forms depending on the nature of the
  • heterocyclyl group all such tautomeric forms are included within the scope of the invention.
  • 'alkyl' alkenyl, alkynyl and 'alkoxy' include straight and branched chain groups
  • containing from 1 to 6 carbon atoms such as methyl, ethyl, propyl and butyl.
  • a particular alkyl group is methyl.
  • 'halogen' refers to fluorine, chlorine, bromine and iodine.
  • a carboxyl group may be regenerated from any of the above esters by usual methods appropriate to the particular R 3 group, for example, acid- and base- catalysed hydrolysis, or by enzymically-catalysed hydrolysis, or by hydrogenolysis under conditions wherein the remainder of the molecule is substantially unaffected.
  • suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt. Suitable ester groups of this type include those of part formulae (i), (ii), (iii), (iv) and (v):
  • R a is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, methyl, or phenyl
  • R b is C 1-6 alkyl, C 1-6 alkoxy, phenyl, benzyl, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, C 1-6 alkyl C 3-7
  • R a and R b together form a 1,2-phenylene group optionally substituted by one or two methoxy groups
  • R c represents C 1-6 alkylene optionally substituted with a methyl or ethyl group and R d and R e independently represent C 1-6 alkyl
  • R f represents C 1-6 alkyl
  • R g represents hydrogen or phenyl optionally substituted by up to three groups selected from halogen, C 1-6 alkyl, or C 1-6 alkoxy
  • Q is oxygen or NH
  • R h is hydrogen or C 1-6 alkyl
  • R i is hydrogen, C 1-6 alkyl optionally substituted by halogen, C 2-6 alkenyl, C 1-6 alkoxycarbonyl, aryl or heteroaryl
  • R h and R i together form C 1-6 alkylene
  • R j represents hydrogen, C 1-6 alkylene
  • alkoxycarbonyloxyalkyl groups such as
  • dialkylaminoalkyl especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl
  • 2-(alkoxycarbonyl)-2-alkenyl groups such as
  • esters linked to a second ⁇ -lactam antibiotic or to a ⁇ -lactamase inhibitor are phthalidyl and dimethoxyphthalidyl; and esters linked to a second ⁇ -lactam antibiotic or to a ⁇ -lactamase inhibitor.
  • a preferred in vivo hydrolysable ester group is the
  • hydrolysable ester group is that of the formula:
  • R 5 is hydrogen, C 1-6 alkyl or phenyl.
  • Suitable pharmaceutically acceptable salts of the carboxy group of the compound of formula (I) include metal salts, eg aluminium, alkali metal salts such as sodium or potassium, especially sodium, alkaline earth metal salts such as calcium or magnesium, and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy-lower alkylamines such as
  • Other useful salts include the lithium salt and silver salt. Salts within compounds of formula (I), may be prepared by salt exchange in conventional manner.
  • the group X may be sulphur or an oxidised sulphur atom, i.e. a sulphoxide (SO) or sulphone (SO2) group.
  • SO sulphoxide
  • SO2 sulphone
  • X is sulphur
  • R 1 is hydrogen
  • cephalosporin nucleus is unsubstituted or substituted by up to three substituents, R 4 , selected from C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkoxycarbonyl C 1-6 alkoxy C 1-6 alkyl, and C 1-6 alkanoyloxy C 1-6 alkyl.
  • R 4 selected from C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkoxycarbonyl C 1-6 alkoxy C 1-6 alkyl, and C 1-6 alkanoyloxy C 1-6 alkyl.
  • the cyclic ether at the 3-position of the cephalosporin nucleus is unsubstituted.
  • m is 1.
  • cyclic ether is bonded to the cephalosporin nucleus at a ring carbon adjacent to the oxygen heteroatom.
  • Suitable acyl groups R 2 include those of formulae (a) - (f) :
  • a 1 is C 1-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, cyclohexenyl, cyclohexadienyl, an aromatic (including heteroaromatic) group, such as phenyl, substituted phenyl, thienyl, pyridyl, or an optionally substituted thiazolyl group, a C 1-6 akylthio group or C 1-6 alkyloxy;
  • X 1 is a hydrogen or halogen atom, a carboxylic acid, carboxylic ester, sulphonic acid, azido, tetrazolyl, hydroxy, acyloxy, amino, ureido,
  • a 2 is an aromatic group, for example a phenyl
  • X 2 is a -CH 2 OCH 2 -, -CH 2 SCH 2 - or alkylene group
  • X 3 is an oxygen or sulphur atom
  • a 3 is an aryl or heteroaryl group such as phenyl, substituted phenyl, furyl, aminothiazolyl or
  • a 4 is hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl (C 1-6 ) alkyl, C 1-6 alkoxycarbonyl (C 1-6 ) alkyl, C 2-6 al'cenylr carboxy (C 1-6 ) alkyl, C 2-6 alkynyl, aryl or C 1-6 alkyl substituted by up to three aryl groups.
  • the term 'heteroaryl' as used herein means a heteroaromatic heterocyclic ring or ring system, suitably having 5 or 6 ring atoms in each ring.
  • R 2 is a group (a)
  • a 1 is C 1-6 alkyl, C 3-6 cycloalkyl, cyclohexenyl, cyclohexadienyl, phenyl,
  • substituted phenyl such as hydroxyphenyl, thienyl or
  • pyridyl and X 1 is a hydrogen or halogen atom, or a carboxy, carboxylic ester, azido, tetrazolyl, hydroxy, acyloxy, optionally protected amino, ureido, guanidino or acylureido group.
  • R 2 is a group of formula (d)
  • a 2 is phenyl
  • X 3 is oxygen and p is O.
  • R 2 is a group of formula (e) or (f) suitable values for the group A 3 include those commonly found in antibacterially active cephalosporins containing a hydroxyimino, substituted hydroxyimino or vinyl group in the side chain attached to position 7 of the cephalosporin nucleus, for example phenyl, thien-2-yl, thien-3-yl, fur-2-yl, fur-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 5-amino-l, 2, 4-thiadiazol-3-yl and 2-aminothiazol-4-yl in each of which the amino group is optionally protected.
  • suitable values for the group A 3 include those commonly found in antibacterially active cephalosporins containing a hydroxyimino, substituted hydroxyimino or vinyl group in the side chain attached to position 7 of the cephalosporin nucleus, for example phenyl, thien-2-y
  • Preferred groups for A3 include phenyl, 2-aminothiazol-4-yl, fur-2-yl, thien-2-yl, 2-(2-chloroacetamido)thiazol-4-yl, 2-tritylamino-thiazol-4-yl, 5-amino-1,2,4-thiadiazol-3-yl and 4-aminopyrimid-2-yl.
  • a particularly preferred group for A 3 is 2-aminothiazol-4-yl.
  • Suitable values for the group A 4 include hydrogen, methyl, ethyl, cyclopropylmethyl, triphenylmethyl (trityl),
  • Preferred values for A 4 in compounds of formula (Ia) include methyl and hydrogen.
  • R 2 is a group of formula (e) (or (f)) can exist as syn and anti (or E and Z) isomers or mixtures thereof. Both isomers are encompassed within the scope of this invention.
  • the compounds of the invention wherein R 2 is a group of formula (e) have the syn configuration (i.e. have the group OA 4 syn to the amide linkage) or are enriched in that isomer.
  • R 2 is a group of formula (f)
  • the group A 4 is preferably cis to the amide linkage, i.e. when group (f) is 2-amino-thiazol-4-yl, the Z-configuration is preferred.
  • Certain compounds of the invention include an amino group which may be protected. Suitable amino protecting groups are those well known in the art which may be removed under conventional conditions without disruption of the remainder of the molecule.
  • amino protecting groups include C 1-6 alkanoyl; benzoyl; benzyl optionally substituted in the phenyl ring by one or two substituents selected from C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, halogen, or nitro; C 1-4
  • alkoxycarbonyl benzyloxycarbonyl or trityl substituted as for benzyl above; allyloxycarbonyl, trichloroethoxycarbonyl or chloroacetyl.
  • solvates may be formed.
  • This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as
  • the antibiotic compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 95% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 49% of a compound of the formula (I) or salt thereof.
  • Specific compounds within this invention of formula (Ia) include the following pharmaceutically acceptable carboxylic acids, salts and in-vivo hydrolysable esters: sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(RS)-tetrahydrofuran-2-ylmethyl]ceph-3-em-4-carboxylate; and pivaloyloxymethyl (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(RS)-tetrahydrofuran-2-ylmethyl]ceph-3-em-4-carboxylate.
  • the present invention further provides a process for the preparation of a compound of formula (I), which process comprises treating a compound of formula (II) or a salt thereof:
  • R 1 , CO 2 R 3 , R 4 , m, n and X are as hereinbefore defined, wherein any reactive groups may be protected, and wherein the amino group is optionally substituted with a group which permits acylation to take place; with an
  • Acids of formula (III) may be prepared by methods known in the art, or methods analogous to such processes. Suitable processes include those described, for example, in UK Patent 2 107 307 B, UK Patent Specification No. 1,536,281, and U.K. Patent Specification No. 1,508,064.
  • Suitable groups which permit acylation to take place and which are optionally present on the amino group of the starting material of the formula (II) include N-silyl,
  • N-stannyl and N-phosphorus groups for example trialkylsilyl groups such as trimethylsilyl, trialkyltin groups such as tri-n-butyltin, groups of formula -P.R 20 R 21 wherein R 20 is an alkyl, haloalkyl, aryl, aralkyl, alkoxy, haloalkyl, aryl, aralkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy or dialkylamino group, R 21 is the same as R 20 or is halogen or R 20 and R 21 together form a ring; suitable such phosphorus groups being -P(OC 2 H 5 ) 2 , -P(C 2 H 5 ) 2 ,
  • a group which may optionally be introduced onto the amino group in the compound of formula (II) is triraethylsilyl.
  • silylation reaction may be carried out in situ, prior to the acylation reaction, with a silylating agent that does not require concomitant addition of base.
  • Suitable silylating agents include, for example,
  • N,O-bis(trimethylsilyl)carbamate A preferred silylating agent is N,O-bis (trimethylsilyl) acetamide.
  • the silylation reaction may suitably be carried out in an inert, anhydrous organic solvent such as dichloromethane at room temperature or at an elevated temperature, for example 30 - 60°C, preferably 40 - 50°C.
  • the above process may optionally be carried out in the presence of a small quantity, for example 0.1 equivalents, of a silyl halide, for example a tri (C 1-6 ) alkylsilyl halide, especially trimethylsilyl chloride.
  • a silyl halide for example a tri (C 1-6 ) alkylsilyl halide, especially trimethylsilyl chloride.
  • a reactive N-acylating derivative of the acid (III) is employed in the above process.
  • the choice of reactive derivative will of course be influenced by the chemical nature of the substituents of the acid.
  • Suitable N-acylating derivatives include an acid halide, preferably the acid chloride or bromide or alternatively a symmetrical or mixed anhydride.
  • the acylation may be effected in the presence of an acid binding agent for example, tertiary amine (such as pyridine or
  • the acylation reaction using an acid halide may be carried out at a temperature in the range -50°C to +50°C, preferably -20°C to +20°c, in aqueous or non-aqueous media such as water, acetone, tetrahydrofuran, ethyl acetate,
  • reaction may be carried out in an
  • acylation with acid halide or anhydride is suitably carried out in the presence of a basic catalyst such as pyridine or 2,6-lutidine.
  • Acid halides may be prepared by reacting the acid (III) or a salt or a reactive derivative thereof with a halogenating (eg chlorinating or brominating) agent such as phosphorus pentachloride, thionyl chloride, oxalyl chloride or
  • Suitable mixed anhydrides are anhydrides with, for example, carbonic acid monoesters, trimethyl acetic acid, thioacetic acid, diphenylacetic acid, benzoic acid, phosphorus acids (such as phosphoric, phosphorous, and phosphinic acids) or aromatic or aliphatic sulphonic acids (such as
  • N-acylating derivatives of acid (III) are the acid azide, or activated esters such as esters with
  • N-acylphthalimides or an alkylidene iminoester prepared by reaction of the acid (III) with an oxime.
  • reactive N-acylating derivatives of the acid (III) include the reactive intermediates formed by reaction in situ with a condensing agent such as a carbodiimide, for example, N,N'-diethyl-, dipropyl- or
  • diisopropylcarbodiimide N,N'-di-cyclohexyl-carbodiimide, or N-ethyl-N'-[3-(dimethylamino)propyl]- carbodiimide; a suitable carbonyl compound, for example,
  • Other condensing agents include Lewis acids (for example BBr 3 - C 6 H 6 );
  • the condensation reaction is preferably carried out in an organic reaction medium, for example, methylene chloride, dimethylformamide,
  • a further method of forming the N-acylating derivative of the acid of formula (III) is to treat the acid of formula (III) with a solution or suspension preformed by addition of a carbonyl halide, preferably oxalyl chloride, or a
  • phosphoryl halide such as phosphorus oxychloride
  • a halogenated hydrocarbon solvent preferably dichloromethane, containing a lower acyl tertiary amide, preferably
  • N,N-dimethylformamide N,N-dimethylformamide.
  • the N-acylating derivative of the acid of formula (III) so derived may then be caused to react with a compound of formula (II).
  • the acylation reaction may conveniently be carried out at -40° to +30°C, if desired in the presence of an acid binding agent such as pyridine.
  • a catalyst such as 4-dimethylaminopyridine may optionally also be added.
  • a preferred solvent for the above acylation reaction is dichloromethane.
  • the optional reduction step, the optional conversion of R 2 to a different R 2 , CO 2 R 3 to a different CO 2 R 3 and X to a different X, and the optional formation of a salt may be carried out using methods well known in the art of
  • cephalosporin and penicillin chemistry when the group X is S, SO, or SO 2 , the group X may be converted into a different group X by methods of oxidation or reduction well known in the art of
  • cephalosporin and penicillin synthesis as described, for example, in European Patent Application Publication No. 0 114 752.
  • sulphoxides in which X is SO
  • a suitable oxidising agent for example an organic peracid such as m-chloroperbenzoic acid.
  • a reduction step is generally effected by processes well known in the art of ⁇ -lactam chemistry, for example using phosphorus trichloride in dimethylformamide.
  • the cyclisation reaction is an intramolecular Wittig-type reaction and is typically carried out by heating the
  • the phosphorus residue, P' is typically a
  • trialkylphosphoranylidene residue for example a C 1-6 trialkylphosphoranylidene residue such as
  • R 2 side-chain may be removed by the Delft procedure commonly used in ⁇ -lactam chemistry. Suitable reaction conditions include treatment with phosphorus pentachloride and N-methylmorpholine at reduced temperature.
  • a compound of formula (IV) may be prepared from a compound of formula (V):
  • halogenating agent suitably a chlorinating agent such as thionyl chloride, which reaction displaces the formula (V) hydroxyl group by halogen, suitably chloride, and is typically carried out at reduced temperature in an inert solvent, for example in
  • a base typically a pyridine derivative such as 2,6-lutidine. Formation of the phosphorane may be effected by treatment of the
  • a compound of formula (V) may be prepared by reaction of a compound of formula (VI) :
  • R 1 and R 2 are as hereinbefore defined.
  • a leaving group Y is halogen, for example chloro.
  • the reaction may be carried out at ambient temperature in an inert solvent, for example acetone or dimethylformamide, in the presence for a base, for example potassium carbonate.
  • a compound of formula (V) may also be prepared by reaction of a compound of formula (IX) :
  • R 1 , R 2 and CO 2 R 3 are as hereinbefore defined and X' is an X-group precursor, with a compound of formula (VII) as hereinbefore defined.
  • the reaction may be carried out at ambient temperature in an inert solvent, for example acetone, with the addition of base, for example potassium carbonate, before work-up.
  • Azetidin-2-one compounds of formulae (VIII) and (IX) may be prepared according to known methods in heterocyclic
  • a compound of formula (VIII) may be prepared according to the method of Osborne N.F. et al., J. Chem. Soc, Perkin Trans. I, 146, 1980.
  • a compound of formula (IX) in which X' is a mercapto group may be prepared by ring opening of a 4-thia-2,6-diazabicyclo [3.2.0]-hept-2-ene-7-one derivative according to the method of Masayuki Narisada et al., Tetrahedron Lett., 1755 (1978).
  • compounds of formula (I) may be prepared directly by organo-cuprate displacement of a leaving group at the 3-position of a compound of formula (X) :
  • R 1 , R 2 , CO 2 R 3 and X are as hereinbefore defined and
  • L is a leaving group, suitably a halogen, mesylate, triflate or fluorosulphonate leaving group, by reaction with a compound of formula (XI) :
  • Z is an organo-cuprate group and R 4 and m are as hereinbefore defined.
  • a compound with a halogen 3-position leaving group, for example chloro, in which X is sulphur may be prepared by the procedure of Fujumoto K. et al., J. Antibiotics, 40, 370, (1987).
  • a compound with a 3-position leaving group, L, in which X is CH 2 may be prepared from the hydroxy intermediate, prepared as described by S. Uyeo and H. Ona, Chem. Pharm. Bull., 28, 1563, (1980).
  • ⁇ 2 -cephems may function as intermediates, in the
  • the present invention also provides a pharmaceutical composition which comprises a compound of formula (Ia) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof and a pharmaceutically acceptable carrier.
  • the compositions of the invention include those in a form adapted for oral, topical or parenteral use and may be used for the treatment of bacterial infection in mammals
  • the antibiotic compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibiotics.
  • compositions may be formulated for administration by any route, such as oral, topical or parenteral, especially oral.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional
  • excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or
  • polyvinylpyrollidone for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine;
  • tabletting lubricants for example magnesium stearate, talc, polyethylene glycol or silica
  • disintegrants for example potato starch
  • acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired,
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic
  • preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
  • the compound can be
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient.
  • the dosage as employed for adult human treatment will preferably range from 100 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration.
  • Such a dosage corresponds to 1.5 to 50 mg/kg per day.
  • the dosage is from 5 to 20 mg/kg per day.
  • the compound of formula (Ia) may be the sole therapeutic agent in the compositions of the invention or a combination with other antibiotics or with a ⁇ -lactamase inhibitor may be employed.
  • compositions also comprise a compound of formula (XIII) or a pharmaceutically acceptable salt or ester thereof:
  • A is hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, mono- or di-hydrocarbyl- substituted amino, or mono- or di-acylamino; an optionally substituted triazolyl group; or an optionally substituted tetrazolyl group as described in EP-A-0 053 893.
  • a further advantageous composition comprises a compound of formula (Ia) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof together with a compound of formula (XIV) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof:
  • B represents hydrogen, halogen or a group of formula:
  • R 8 and R 9 are the same or different and each represents hydrogen, C 1-6 alkoxycarbonyl or carboxy, or a pharmaceutically acceptable salt thereof.
  • ⁇ -lactamase inhibitors include 6-alkylidene penems of formula (XV):
  • R 10 and R 11 are the same or different and each represents hydrogen, or a C 1-10 hydrocarbon or heterocyclic group optionally substituted with a functional group; and R represents hydrogen or a group of formula R 13 or -SR 13 where R 13 is an optionally substituted C 1-10 hydrocarbon or heterocyclic group, as described in EP-A-0 041 768.
  • ⁇ -lactamase inhibitors include
  • compositions of this invention which include a
  • ⁇ -lactamase inhibitory amount of a ⁇ -lactamase inhibitor are formulated in a conventional manner using techniques and procedures per se known in the art.
  • the antibiotic compounds of the present invention are active against a wide range of organisms including both
  • Gram-negative organisms such as E.coli and Gram-positive organisms such as S.aureus.
  • dichloromethane 50ml was treated with oxalyl chloride (6.7g, 4.6ml) and then 2-3 drops of dimethylformamide (DMF). After the initial effervescence had subsided the solution was left at ambient temperature for 1.5h. The solvent and excess oxalyl chloride were removed in vacuo and the
  • Lutidine (0.828g, 0.898ml) was added followed by the dropwise addition of a solution of thionyl chloride (0.921g, 0.557ml) in THF (5ml). A white precipitate was formed which slowlychanged to yellow on warming to 0°C.
  • N-methylmorpholine (0.408g, 0.443ml) was added followed by a solution of phophorus pentachloride (0.497g) in dry
  • N,N-diisopro ⁇ ylethylamine (0.357g, 0.481ml) followed by methanesulphonyl chloride, (0.159g, 0.107ml).
  • methanesulphonyl chloride (0.159g, 0.107ml).
  • the homogeneous solution was treated with the amino cephalosporin from (g), (0.428g) and pyridine (0.099g,
  • Peak serum concentration of the compound from Example 1 was 33.0 ⁇ g/ml, obtained at 30 minutes following oral dosing of the compound from Example 2 to mice at a dose equivalent to 50 mg/kg.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés correspondant à la formule (I) ou un de leurs sels, procédés de préparation, leur utilisation comme antibiotiques et leurs intermédiaires. Dans la formule, R1 représente hydrogène, méthoxy ou formamido; R2 représente un groupe acyle, en particulier celui d'une céphalosporine à efficacité antibactérienne; CO2R3 représente un groupe carboxy ou un anion de carboxylate, ou R3 représente un groupe de protection carboxy pouvant se retirer instantanément; R4 représente jusqu'à quatre substituants qui peuvent être semblables ou différents; m représesnte 1 ou 2 et n représente 1.
EP91913545A 1990-07-24 1991-07-22 Cephalosporines et homologues, preparations et compositions pharmaceutiques Withdrawn EP0540606A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9016189 1990-07-24
GB909016189A GB9016189D0 (en) 1990-07-24 1990-07-24 Novel compounds
GB9109540 1991-05-02
GB919109540A GB9109540D0 (en) 1991-05-02 1991-05-02 Novel compounds

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Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9125645D0 (en) * 1991-12-03 1992-01-29 Smithkline Beecham Plc Novel compounds
EP0624160B1 (fr) * 1992-01-22 2001-10-31 Pfizer Inc. Derives de 2-isocephem et d'oxacephem, procedes de preparation, les intermediaires de ceux-ci et leur utilisation comme agents antibacteriens
GB9212609D0 (en) * 1992-06-13 1992-07-29 Smithkline Beecham Plc Novel compounds
GB9213567D0 (en) * 1992-06-26 1992-08-12 Smithkline Beecham Plc Novel compounds
GB9424847D0 (en) * 1994-12-09 1995-02-08 Smithkline Beecham Plc Novel process
GB2300856A (en) * 1995-05-16 1996-11-20 Pfizer Ltd Beta-lactam preparation
AU4398297A (en) * 1996-10-02 1998-04-24 Daiichi Pharmaceutical Co., Ltd. Method for esterifying carboxylic compounds
FR2776292B1 (fr) 1998-03-20 2004-09-10 Oncopharm Cephalotaxanes porteurs de chaine laterale et leur procede de synthese
GB0019124D0 (en) 2000-08-03 2000-09-27 Pfizer Novel process
HUP0400642A3 (en) * 2000-12-04 2010-03-29 Pfizer Prod Inc Coupling process and intermediates useful for preparing cephalosphorins
ATE319719T1 (de) * 2000-12-04 2006-03-15 Pfizer Prod Inc Verfahren und esterderivate zur herstellung von cephalosphorinen
US7378408B2 (en) * 2001-11-30 2008-05-27 Pfizer Inc. Methods of treatment and formulations of cephalosporin
KR100710555B1 (ko) 2001-12-04 2007-04-24 에스케이 주식회사 광학적으로 순수한 (ｒ)-폼 또는 (ｓ)-폼의테트라히드로퓨라닐 케톤의 제조방법
MX356509B (es) 2011-12-22 2018-05-30 Alios Biopharma Inc Nucleósidos sustituidos, nucleótidos y análogos de los mismos.
US9441007B2 (en) 2012-03-21 2016-09-13 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
USRE48171E1 (en) 2012-03-21 2020-08-25 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US9422323B2 (en) 2012-05-25 2016-08-23 Janssen Sciences Ireland Uc Uracyl spirooxetane nucleosides
PT2935303T (pt) 2012-12-21 2021-04-30 Alios Biopharma Inc 4'-fluoro-nucleósidos, 4'-fluoro-nucleótidos e seus análogos para o tratamento de hcv
CN105254648B (zh) * 2015-11-13 2018-04-03 广东温氏大华农生物科技有限公司 一种头孢维星及其钠盐的合成方法
GB2575261B (en) 2018-07-02 2022-03-09 Norbrook Lab Ltd Intermediates in the synthesis of C3-substituted cephalosporins
JP2021534196A (ja) 2018-08-23 2021-12-09 シージェン インコーポレイテッド 抗ｔｉｇｉｔ抗体
IL293592A (en) 2019-12-06 2022-08-01 Vertex Pharma Transduced tetrahydrofurans as sodium channel modulators
TW202322824A (zh) 2020-02-18 2023-06-16 美商基利科學股份有限公司 抗病毒化合物
CN111620893B (zh) * 2020-06-08 2021-12-14 重庆医药高等专科学校 C-3位四氢呋喃取代的头孢菌素-铁载体耦合物及其制备方法和应用
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
AU2022284886A1 (en) 2021-06-04 2023-11-30 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2197573A1 (en) * 1972-09-07 1974-03-29 Roussel Uclaf 7-substd-phenylacetamido-cephalosporin derivs - - antibiotics active against streptococci and staphylococci
BE793448A (fr) * 1971-12-31 1973-06-28 Roussel Uclaf Procede de preparation de nouveaux derives des cephalosporines et produits obtenus
BE791161A (fr) * 1972-01-03 1973-05-09 Beecham Group Ltd Procede pour la preparation d'analogues des cephalosporines
BE791160A (fr) * 1972-01-03 1973-05-09 Beecham Group Ltd Nouveaux cephemes substitues
NL7305936A (fr) * 1972-05-05 1973-11-07
JPS5849382A (ja) * 1981-09-18 1983-03-23 Kyowa Hakko Kogyo Co Ltd β−ラクタム化合物
GB8821797D0 (en) * 1988-09-16 1988-10-19 Beecham Group Plc Novel compounds
DE69032681T2 (de) * 1989-03-30 1999-02-25 Pfizer Cephalosporine und ihre Homologen, Verfahren zu ihrer Herstellung und pharmazeutische Präparate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9201695A1 *

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NO930226D0 (no) 1993-01-22
CA2359744A1 (fr) 1992-02-06
DE69131714T2 (de) 2000-02-24
DK0540609T3 (da) 1999-12-27
FI930270A0 (fi) 1993-01-22
DE122006000065I1 (de) 2007-03-01
CZ6493A3 (en) 1994-04-13
WO1992001695A1 (fr) 1992-02-06
IL98909A0 (en) 1992-07-15
ES2137162T3 (es) 1999-12-16
EP0540609B1 (fr) 1999-10-13
LU91290I2 (fr) 2007-01-22
HUT63628A (en) 1993-09-28
CN1223859A (zh) 1999-07-28
JPH05509089A (ja) 1993-12-16
CA2087967A1 (fr) 1992-01-25
PT98426A (pt) 1992-05-29
NO930226L (no) 1993-03-23
IE912569A1 (en) 1992-01-29
MY106399A (en) 1995-05-30
JP2851428B2 (ja) 1999-01-27
GR3031711T3 (en) 2000-02-29
MX9100317A (es) 1992-02-28
ATE185567T1 (de) 1999-10-15
AU648329B2 (en) 1994-04-21
NZ239061A (en) 1993-11-25
AP832A (en) 2000-05-03
CN1061046C (zh) 2001-01-24
YU129691A (sh) 1994-01-20
AU8222491A (en) 1992-02-18
DE69131714D1 (de) 1999-11-18
KR100189075B1 (ko) 1999-06-01
KR930701456A (ko) 1993-06-11
NL300249I1 (nl) 2007-02-01
FI930270A (fi) 1993-03-22
WO1992001696A1 (fr) 1992-02-06
HU9300177D0 (en) 1993-04-28
EP0540609A1 (fr) 1993-05-12
CN1060469A (zh) 1992-04-22
AP9100305A0 (en) 1991-07-31
CN1111410C (zh) 2003-06-18
JPH05509305A (ja) 1993-12-22
CA2087967C (fr) 2002-09-10
CA2359744C (fr) 2007-02-13
DE122006000065I2 (de) 2007-09-13

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