EP0651755A1 - Cephalosporines et 1-carba-1-dethia cephalosporines - Google Patents

Cephalosporines et 1-carba-1-dethia cephalosporines

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Publication number
EP0651755A1
EP0651755A1 EP93917875A EP93917875A EP0651755A1 EP 0651755 A1 EP0651755 A1 EP 0651755A1 EP 93917875 A EP93917875 A EP 93917875A EP 93917875 A EP93917875 A EP 93917875A EP 0651755 A1 EP0651755 A1 EP 0651755A1
Authority
EP
European Patent Office
Prior art keywords
formula
group
compound
pharmaceutically acceptable
vivo hydrolysable
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Withdrawn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
EP93917875A
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German (de)
English (en)
Inventor
George Burton
Brian Charles Gasson
Antoinette Naylor
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Inc
Original Assignee
SmithKline Beecham Ltd
Pfizer Inc
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Filing date
Publication date
Application filed by SmithKline Beecham Ltd, Pfizer Inc filed Critical SmithKline Beecham Ltd
Publication of EP0651755A1 publication Critical patent/EP0651755A1/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Withdrawn legal-status Critical Current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
    • 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 compounds, their preparation and their use, and in particular to a novel class of cephalosporins. These compounds have antibacterial properties, and are therefore of use in the treatment of bacterial infections in humans and animals caused by a wide range of organisms.
  • R a , and R D arc various substituents, and R c is a ring system selected from:
  • cephems and carbacephems bearing a bicyclic substituent at the 3-position of the cephem nucleus, which includes a 5- or 6- membered cyclic ether or cyclic thio-ether moiety.
  • the present invention provides a compound of formula (I) or a salt thereof:
  • R! is hydrogen, methoxy or formamido
  • R2 is an acyl group, in particular that of an antibacterially active cephalosporin
  • CO2R3 is a carboxy group or a carboxylate anion, or R ⁇ is a readily removable carboxy protecting group or a pharmaceutically acceptable salt-forming group or in vivo hydrolysable ester group;
  • X is S, SO, SO2 orCH2;
  • R is a bicyclic group where m is 1 or 2; wherein one of Y or Z is O, S, SO or SO2 and the other is CH2, and wherein R ⁇ may be unsubstituted or may have one or more optional substituents R ⁇ , which may be present on any of the carbon atoms in the bicyclic ring system shown, selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, halogen, amino, alkylamino, acylamino, dialkylamino, CO2R, OCOR, CONR2, SO2NR2 nere R is hydrogen or alkyl; aryl and heterocyclyl, which may be the same or different and wherein any R ⁇ alkyl substituent is optionally substituted by one or more substituents selected from the list from which R ⁇ is selected, in place of any of the hydrogen atoms in the bicyclic system.
  • the bonding carbon atom of the heterocyclic moiety of R ⁇ which links R ⁇ to the cephalosporin nucleus is generally asymmetric.
  • the present invention includes either stereoisomer, as well as mixtures of both isomers.
  • the formamido group can exist in conformations wherein the hydrogen atoms of the -NH-CHO moiety are cis- or trans-: of these the cj conformation normally predominates.
  • Rl, R ⁇ , and R ⁇ are as defined with respect to formula (I) and the group CO2R * is CO2R where CO2R ⁇ is a carboxy group or a carboxylate anion.
  • the present invention provides a compound of formula (la) 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 (la) 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 the formula (la) or a pharmaceutically acceptable in vivo hydrolysable ester thereof, in particular the oral administration of a therapeutically effective amount of an in vivo hydrolysable ester.
  • the present invention includes the use of a compound of formula (la) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for the 0 manufacture of a medicament for the treatment of bacterial infections, in particular the use of an in vivo hydrolysable ester for the manufacture of a medicament for the oral treatment of bacterial infections.
  • the term 'aryl' includes phenyl and naphthyl, each optionally substituted with up to five, preferably up to three, groups selected from 5 halogen, mercapto, (C ⁇ _g) alkyl, phenyl, dC ⁇ . ⁇ ) alkoxy, hydroxy(C ⁇ _6)alkyl, mercapto(C ⁇ _6)alkyl, halo(C ⁇ _(5) alkyl. hydroxy, amino, nitro, carboxy, (Cj. 6)alkylcarbonyloxy, (C ⁇ _ j)alkoxycarbonyl, formyl, or (C ⁇ _6)alkylcarbonyl groups.
  • heterocyclyl' and 'heterocyclic' as used herein include aromatic and non-aromatic, single and fused, rings suitably containing up to four hetero-atoms in 0 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 ⁇ _g)alkyl, (C ⁇ _6)alkoxy, halo(C ⁇ _.6)alkyl, hydroxy, carboxy, carboxy salts, carboxy esters such as (C ⁇ _6)alkoxycarbonyl, (C ⁇ _6)alkoxyca ⁇ bonyl(C ⁇ _ _ ..
  • Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms.
  • Tieteroaryl' refers to heteroaromatic heterocyclic rings.
  • 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 3 Q depending on the nature of the heterocyclyl group; all such tautomeric forms are included within the scope of the invention.
  • heteroaryl as used herein means a heteroaromatic heterocyclic ring or ring system, suitably having 5 or 6 ring atoms in each ring.
  • 'alkyl', 'alkenyl', 'aikynyl' 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.
  • Those compounds of the formula (I) wherein R ⁇ is a readily removable hydrolysable ester or which are in non-pharmaceutically acceptable salt form are primarily useful as intermediates in the preparation of compounds of the formula (la) or a pharmaceutically acceptable salt or pharmaceutically acceptable in vivo hydrolysable ester thereof.
  • Suitable readily removable carboxy protecting groups for the group R-- include groups forming ester derivatives of the carboxylic acid, including in vivo hydrolysable esters. The derivative is preferably one which may readily be cleaved in vivo.
  • salts and carboxy-protected derivatives including in vivo hydrolysable esters, of any carboxy groups that may be present as optional substituents in compounds of formula (I) or (la).
  • acid addition salts of any amino group or substituted amino group that may be present as optional substituents in compounds of formula (I) or (la).
  • Suitable ester-forming carboxyl-protecting groups are those which may be removed under conventional conditions.
  • a carboxyl group may be regenerated from any of the above esters by usual methods appropriate to the particular R ⁇ 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 which R-- may comprise 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 ⁇ . ) alkyl, (C3.7) cycloalkyl, methyl, or phenyl
  • R D is (C ⁇ _6) alkyl, (Cj_6) alkoxy, phenyl, benzyl, (C3.7) cycloalkyl, (C3.7) cycloalkyloxy, (C ⁇ _6) alkyl (C3.7) cycloalkyl, 1-amino (C ⁇ .
  • R a and R* 3 together form a 1,2-phenylene group optionally substituted by one or two methoxy groups;
  • R c represents (Cj.g) alkylene optionally substituted with a methyl or ethyl group and R ⁇ and R e independently represent (Cj.g) alkyl;
  • R ⁇ represents (C . ⁇ ) alkyl;
  • RS represents hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (C ⁇ . ) alkyl, or (C ⁇ .
  • R n is hydrogen or (Cj.g) alkyl
  • R* is hydrogen, (Cj.g) alkyl optionally substituted by halogen, (C2-6) alkenyl, (C ⁇ . ) alkoxycarbonyl, aryl or heteroaryl; or R n and R* together form (Cj. ⁇ ) alkylene
  • R represents hydrogen, (C ⁇ . ) alkyl or (C ⁇ _6) alkoxycarbonyl
  • R ⁇ represents (C ⁇ _s) alkyl, (Cj. ) alkoxy, (C ⁇ _6) alkoxy((C ⁇ _6))alkoxy or aryl.
  • suitable in vivo hydrolysable ester groups include, for example, acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, ⁇ -acetoxyethyl, ⁇ -pivaloyloxyethyl, l-(cyclohexylcarbonyloxy)prop- 1 - yl, and (l-aminoethyl)carbonyloxymethyl; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl, ⁇ -ethoxycarbonyloxyethyl and propoxycarbonyloxyethyl; dialkylaminoalkyl especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; 2-(alkoxycarbonyl)-2-alkenyl groups such as
  • R m is hydrogen, (Cj.g) alkyl or phenyl.
  • a preferred in vivo hydrolysable ester group is the pivaloyloxymethyl ester.
  • 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 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)- amine, cycloalkylamines such as dicyclohexylamine, or with procaine, dibenzylamine, £LN-dibenzylethylene- diamine, 1-ephenamine, N-methylmorpholine, N-ethylpiperidine, N-benzyl- ⁇ -phenethylamine, dehydroabietyl
  • the group X may be an oxidised sulphur atom, i.e. a sulphoxide (SO) or sulphone (SO2) group.
  • SO sulphoxide
  • SO2 sulphone
  • X is a sulphoxide group it will be understood that ⁇ - and ⁇ -isomers may exist; both such isomers are encompassed within the scope of the present invention.
  • X is S or CH2.
  • R* is hydrogen.
  • Suitable acyl groups R ⁇ include those of formulae (a) - (f): A,(CH 2 ) p -CH-(CH 2 )m-C ⁇
  • a 1 is (C ⁇ . ) alkyl, substituted (Cj.g) alkyl wherein the substituents may be as for R ⁇ above, (C3.6) cycloalkyl, cyclohexenyl, cyclohexadienyl, an aryl (including heteroaryl) group, such as phenyl, substituted phenyl, thienyl, pyridyl, or an optionally substituted thiazolyl group, a (Cj.g) akylthio group or (Cj.g) alkyloxy;
  • X ⁇ is a hydrogen or halogen atom, a carboxy lie acid, carboxylic ester, sulphonic acid, azido, tetrazolyl, hydroxy, acyloxy, amino, ureido, acylamino, heterocyclylamino, guanidino or acyl
  • R 2 is a group (a)
  • A is (C ⁇ . ) alkyl, (C3..6) cycloalkyl, cyclohexenyl, cyclohexadienyl, phenyl, substituted phenyl (eg substituted as for "aryl” above) such as hydroxyphenyl, thienyl or pyridyl; and
  • X ⁇ 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)
  • A2 is phenyl
  • X3 is oxygen
  • p is O
  • suitable values for the group A3 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.
  • 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-l,2,4-thiadiazol-3-yl and 4-aminopyrimid-2-yl.
  • a preferred acyl group R-- is one of formula (e), having a group, A3 which is 2-aminothiazol-4-yl.
  • Suitable values for the group A4 include hydrogen, methyl, ethyl, cyclopropylmethyl, triphenylmethyl (trityl), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, carboxymethyl, carboxypropyl and i-butoxycarbonylmethyl.
  • Preferred values for A4 in compounds of formula (la) include methyl and hydrogen.
  • one of Y or Z is preferably O or S.
  • groups R ⁇ include dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrothianaphtiiyl and dihydrooxanaphthyl, and such groups may be linked to the cephalosporin nucleus by any of the available ring positions on the 5- or 6- membered heterocyclic ring of R ⁇ .
  • R ⁇ may be linked to the nucleus at a ring position adjacent to the O or S atom of the heterocyclic ring.
  • a suitable example of such a group R ⁇ is dihydrobenzofuran-2-yl.
  • R ⁇ may carry up to three substituents R ⁇ .
  • R ⁇ is unsubstitued.
  • R 2 is a group of formula (e) or (f) can exist as ⁇ y_n and ami (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 sy configuration (i.e. have the group OA4 ⁇ yn to the amide linkage) or are enriched in that isomer.
  • R 2 is a group of formula (f)
  • the group A4 is preferably cjs 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 (Cj.g) alkanoyl; benzoyl; benzyl optionally substituted in the phenyl ring by one or two substituents selected from (C1.4) alkyl, (C1.4) alkoxy, trifluoromethyl, halogen, or nitro; (C1.4) alkoxycarbonyl; benzyloxycarbonyl or trityl (ie triphenylmethyl) 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 lyophilisation.
  • 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, particularly at least 98% 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 (la) include the following pharmaceutically acceptable carboxylic acids, and salts and in-vivo hydrolysable esters thereof: (6R,7S)-7-[2-(2-Aminothiazol-4-yl)-2-(Z)-methyoxyiminoac ⁇ tamido]-3-[(S)- dihydrobenzofuran-2-yl]ceph-3-em-4-carboxylic acid.
  • the present invention provides a process for the preparation of a compound of formula (I) or (la) as defined above in which -CO2R ⁇ is a carboxy group or carboxylate anion or R ⁇ is a pharmaceutically acceptable salt-forming group or in- vivo hydrolysable ester group, wherein a compound of formula (I) as defined above in which R3 is a carboxy protecting group has its group CC ⁇ R ⁇ replaced by a group CO2R which is a carboxy group or a carboxylate anion, or in which R ⁇ is a pharmaceutically acceptable salt-forming group or in-vivo hydrolysable ester group.
  • 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 2 is the acyl group as defined with respect to formula (I) and wherein any reactive groups may be protected; and thereafter, if necessary or desired, carrying out one or more of the following steps: i) removing any protecting groups; ii) converting the group CO2R ⁇ into a different group CO2R ⁇ ; iii) converting the group R 2 into a different group R 2 ; iv) converting the group X and/or Y and/or Z into a different group X and/or Y and/or Z, for example S into SO or SO2; v) converting the product into a salt or ester.
  • 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
  • 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 ⁇ RS wherein R? is an alkyl, haloalkyl, aryl, aralkyl, alkoxy, haloalkyl, aryl, aralkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy or dialkylamino group, R° is the same as R ' or is halogen or R and R** 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 trimethylsilyl.
  • 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, ⁇ -(trimethylsilyl)-acetamide, ⁇ , ⁇ -bis-( methylsilyl)acetamide, H»Q-bis(trimethylsilyl)- trifluoroacetamide, ⁇ -methyl-M-trimethylsilylacetamide, N-methyl-N-trimethylsilyl-trifluoroacetamide, £LN'-bis(trimethylsilyl)urea, and H»_Q-bis(trimethylsilyl)carbamate.
  • a preferred silylating agent is MQ-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 ⁇ _ 6)alkylsilyl halide, especially trimethylsilyl chloride.
  • a silyl halide for example a tri(C ⁇ _ 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 dimethylaniline), molecular sieves, an inorganic base (such as calcium carbonate or sodium bicarbonate) or an oxirane, which binds hydrogen halide liberatec' in the acylation reaction.
  • the oxirane is preferably a (C ⁇ _6)-l,2-alkylene oxide - jch as ethylene oxide or propylene oxide.
  • 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, dimethylacetamide, dimethylformamide, acetonitrile, dichloromethane, 1,2-dichloroethane, or mixtures thereof.
  • the reaction may be carried out in an unstable emulsion of water-immiscible solvent, especially an aliphatic ester or ketone, such as methyl isobutyl kietone or butyl acetate.
  • the 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 phosgene.
  • a halogenating agent such as phosphorus pentachloride, thionyl chloride, oxalyl chloride or phosgene.
  • 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 phosphi e acids) or aromatic or aliphatic sulphonic acids (such as p.-toluenesulphonic acid or methanesulphonic acid).
  • Alternative EJ-acylating derivatives of acid (III) are the acid azide, or activated esters such as esters with 2-mercaptopyridine, cyanomethanol, ⁇ -nitrophenol, 2,4-dinitrophenol, thiophenol, halophenols, including pentachlorophenol, monomethoxyphenol, M-hydroxy succinimide, H-hydroxybenzotriazole, or
  • reactive M-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, £LN'-diethyl-, dipropyl- or diisopropylcarbodiimide, N-N'-di-cyclohexyl-carbodiimide, or H-ethyl-H'-[3-(dimethylamino)propyl]- carbodiimide; a suitable carbonyl compound, for example, N,N'-carbonyldiimidazole or N,N'-carbonyldi- triazole; an isoxazolinium salt, for example, N-ethyl-5-phenylisoxazolinium-3-sulphonate or N-t-butyl-5- methylisoxazolinium perchlorate; or an N-alkoxycarbonyl 2-alkoxy-l,2-dihydroquinoline, such as
  • condensing agents include Lewis acids (for example BBr3 - C ⁇ Hg); or a phosphoric acid condensing agent such as diethylphosphorylcyanide.
  • the condensation reaction is preferably carried out in an organic reaction medium, for example, methylene chloride, dimethylformamide, acetonitrile, alcohol, benzene, dioxan or tetrahydrofuran.
  • a further method of forming the N-acylating derivative of the acid of formula (HI) 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, to a halogenated hydrocarbon solvent, preferably dichloromethane, containing a lower acyl tertiary amide, preferably 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.
  • CO2R ( ⁇ ) the optional conversion (iii) of R 2 to a different R 2 , CC ⁇ R ⁇ to a different C I ⁇ R ⁇ and (iv), X and/or Y and/or Z to a different X and/or Y, and/or Z and (v) the optional formation of a salt or ester, may be carried out using methods well known in the art of cephalosporin and penicillin chemistry.
  • the group X, Y or Z is S, SO, or SO2
  • the group X, Y or Z may be converted into a different group Y 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.
  • sulphoxides in which X or Y 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.
  • removal of protecting groups may be carried out by any convenient method known in the art such that unwanted side reactions are minimised.
  • R-- is the protecting group p-methoxybenzyl
  • this group may suitably be removed by treatment of the protected compound with aluminium chloride in the presence of anisole. Separation of unwanted by-products may be carried out using standard methods.
  • Compounds of formula (II) in which X is S, SO or SO2 may be prepared starting from known compounds of formula (IV):
  • R 2 * is an amino protecting group, for example as discussed above.
  • a suitable group R 2 is phenoxyaetyl.
  • Compounds of formula (IV) may be reacted with compounds of formula R ⁇ -CO-CH2-X where R ⁇ is as defined above and X is a halogen, suitably chlorine, to form a compound of formula (V):
  • R 2 and R 22 are amino-protecting groups, for example as discussed above.
  • a suitable group R 2 * is phenylacetyl, and a suitable group R 22 is 4-methoxyphenyl.
  • Compounds of formula (Nil) may be reduced, e.g by Pd/C:H2 and the protecting group R 22 removed to form compounds of formula (Nm):
  • R31 is a group R ⁇ or a group which can be converted into or replaced by R ⁇ .
  • R ⁇ l may be a carboxyl protecting group, for example as discussed above, suitably 4-methoxybenzyl.
  • Compounds of formula (IX) may for example be prepared by reaction of the compound (V) or (VIII) with the corresponding R ⁇ l-glyoxylate.
  • R is an organic hydrocarbon group such as alkyl or phenyl, suitably n-butyl, by replacement of the hydroxy group shown in (IX) by halogen, e.g. by treatment of (IX) with a thionyl halide such as thionyl chloride, followed by reaction with a compound PR ⁇ .
  • R is an organic hydrocarbon group such as alkyl or phenyl, suitably n-butyl
  • the compound (X) then be cyclised, typically by heating, e.g. under refluxs to form a compound of formula (XI):
  • Deprotection of the 7-amino group i.e. removal of R 2
  • the deprotection may for example be carried out using the knowing Delft procedure, e.g. using phosphorus pentachloride in the presence of N- methylmorpholine
  • Deprotection of the 4-acyl group i.e. removal of R ⁇ l may be carried out using standard procedures, and known procedures may be used for formation of compounds of formula (I) which are salts or esters.
  • Compounds of formula (I) in which X is other then sulphur may be prepared by analogous routes which will be apparent to those skilled in the art.
  • the compound may be isomerically resolved if necessary to separate compounds containing the R and S isomers of the 5- or 6- membered heterocyclic ring of R ⁇ . This may conveniently be done with compounds of formula (XI).
  • the present invention also provides a pharmaceutical composition which comprises a compound of formula (la) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof and a pharmaceutically acceptable carrier.
  • 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 including humans.
  • 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.
  • suitable 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 polyvinylpyroUidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablctting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or 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 reconstitution with water or other suitable vehicle before use.
  • 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, i desired, conventional flavouring or colouring agents.
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter o other glyceride.
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
  • the compound dependin 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 bufferin 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 sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • 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. Suitably the dosage is from 5 to 20 mg/kg per day.
  • the compound of formula (la) 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 (XII) 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-0053 893.
  • a further advantageous composition comprises a compound of formula (la) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof together with a compound of formula (XIII) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof:
  • B represents hydrogen, halogen or a group of formula:
  • R x and Ry are the same or different and each represents hydrogen, (C ⁇ . ) alkoxycarbonyl or carboxy, or a pharmaceutically acceptable salt thereof.
  • ⁇ -lactamase inhibitors include 6-alkylidene penems of formula (XIN):
  • R m and R n are the same or different and each represents hydrogen, or a (Cj.io) hydrocarbon or heterocyclic group optionally substituted with a functional group; and RP represents hydrogen or a group of formula R 3 or -SR 1 ⁇ where R - ⁇ is an optionally substituted (C ⁇ _ ⁇ o) hydrocarbon or heterocyclic group, as described in EP-A-0041 768.
  • ⁇ -lactamase inhibitors include 6 ⁇ -bromopenicillanic acid and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof and 6 ⁇ -iodopenicillanic acid and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof described in, for example, EP-A-0410768 and EP-A-0 154 132 (both Beecham Group).
  • 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.
  • Oxalyl chloride (2.68ml) was added to a stirred mixture of 2,3-dihydro-2- benzofurancarboxylic acid (3.28g) and dichloromethane (48ml). Dimethyl- formamide (2 drops) was added and the mixture stirred at room temperature for 50 min. and then at reflux for a further 10 min. The solvent was evaported and chloroform was evaporated from the residue twice. The residue was dissolved in dichloromethane (200ml) and the solution cooled in an ice bath. A stream of diazomethane in argon was then passed into the solution until all the acid chloride was consumed, and then air was passed through the solution to remove excess diazomethane.
  • Methanesulphonyl chloride (7 ⁇ l, 0.090mmol) was added to 2-(2-thiazol-4-yl)- 2-(Z)-methoxyiminoacetic acid (19mg, 0.095mmol) and NN-diisopropylethylamine (16 ⁇ l, 0.092mmol) in DMF (2ml) at -30°C.
  • Aluminium chloride 22mg, 0.17mmol was added to anisole (0.9ml) and dry dichloromethane (0.5ml) at -20°C and stirred for 15min. The temperature of the cooling bath was then lowered to -40°C before addition of 4-methoxybenzyl (6R,7S)- 7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxy-iminoacetamido]-3-[(2S)-2,3- dihydrobenzofi ⁇ ran-2-yl] - 1 -carba- 1 -dethiaceph-3-em-4-carboxylate (33mg, 0.055mmol) in dichloromemane (2ml).

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Abstract

Composé de formule (I) ou sel dudit composé, où: R1 représente hydrogène, méthoxy ou formamido; R2 représente un groupe acyle; CO¿2R?3 représente un groupe carboxy ou un anion de carboxylate ou R3 représente un groupe protecteur carboxy facilement séparable ou un groupe acceptable pharmaceutiquement et formant un sel ou un groupe ester hydrolysable in vivo; X représente S, SO, SO¿2? ou CH2; R?4¿ représente un groupe bicyclique: (a), où m est 1 ou 2; où un élément parmi Y ou Z représente O, S, SO ou SO¿2? et l'autre représente CH2 et où R?4¿ peut être insubstitué ou posséder un ou plusieurs substituants R5 éventuels. Les composés de la formule (I) présentent une efficacité antibactérienne. L'invention décrit des procédés de préparation desdits composés, ainsi que des formulations comprenant lesdits composés.
EP93917875A 1992-07-23 1993-07-23 Cephalosporines et 1-carba-1-dethia cephalosporines Withdrawn EP0651755A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB929215631A GB9215631D0 (en) 1992-07-23 1992-07-23 Novel compounds
GB9215631 1992-07-23
PCT/GB1993/001523 WO1994002489A1 (fr) 1992-07-23 1993-07-23 Cephalosporines et 1-carba-1-dethia cephalosporines

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EP0651755A1 true EP0651755A1 (fr) 1995-05-10

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EP (1) EP0651755A1 (fr)
JP (1) JPH07509455A (fr)
GB (1) GB9215631D0 (fr)
WO (1) WO1994002489A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4037841A1 (de) * 1990-11-28 1992-06-04 Bayer Ag Neue 3-substituierte cephalosporine, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9402489A1 *

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WO1994002489A1 (fr) 1994-02-03
GB9215631D0 (en) 1992-09-09

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