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EP1000024A1 - Acides mercapto-acyl-amines utilises comme inhibiteurs des metallo-beta lactamases - Google Patents

Acides mercapto-acyl-amines utilises comme inhibiteurs des metallo-beta lactamases

Info

Publication number
EP1000024A1
EP1000024A1 EP98943877A EP98943877A EP1000024A1 EP 1000024 A1 EP1000024 A1 EP 1000024A1 EP 98943877 A EP98943877 A EP 98943877A EP 98943877 A EP98943877 A EP 98943877A EP 1000024 A1 EP1000024 A1 EP 1000024A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
alkyl
compound according
hydrogen
formula
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Withdrawn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
EP98943877A
Other languages
German (de)
English (en)
Inventor
John H. SmithKline Beecham Pharm. BATESON
Desmond John SmithKline Beecham Pharm. BEST
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.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9716224.2A external-priority patent/GB9716224D0/en
Priority claimed from GBGB9716221.8A external-priority patent/GB9716221D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP1000024A1 publication Critical patent/EP1000024A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • 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
    • 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

  • This invention relates to chemical compounds having metallo- ⁇ -lactamase inhibitory and antibacterial properties
  • the invention also relates to methods for the preparation of such compounds, to pharmaceutical compositions containing them, and to uses thereof.
  • Metallo- ⁇ -lactamases confer resistance to the vast majority of ⁇ -lactam based therapies, including carbapenems and jeopardise the future use of all such agents.
  • carbapenems and other ⁇ -lactam antibiotics the clinical climate is becoming more favourable for the survival of clinical strains which produce metallo- ⁇ -lactamases, and metallo- ⁇ -lactamases have now been identified m common pathogens such as Bacteroides fragilis, Klebsiella, Pseudomonas aeruginosa and Serratia marcescens.
  • R is hydrogen, a salt forming cation or an in vivo hydrolysable ester-forming group
  • R [ is hydrogen, (C ⁇ _g)alkyl optionally substituted by up to three halogen atoms or by a mercapto, (C ⁇ _6)alkoxy, hydroxy, amino, nitro, carboxy, (C ⁇ _ ) alkylcarbonyloxy, (C ] _6)alkoxycarbonyl, formyl or (C 1.5) alkylcarbonyl group, (C3_7)cycloalkyl, (C3_7)cycloalkyl(C2-6)alkyl. (C2-6) al kenyl, (C2-6)alkynyl, aryl, aryl(C ⁇ _5>alkyl, heterocyclyl or heterocyclyl(C ; _ ⁇ )alkyl or is selected from
  • A is a monocyclic aryl or heteroaryl ring and B is a monocyclic aryl, alicyclic or heterocyclic ring, C and D are independently -Zp-(CRgRc;)q- or -(CRgRoJq-Zpwhere p is 0 or 1 , q is 0 to 3 provided that p + q in C is not 0, Rg and R9 are independently hydrogen or (Ci _6)alkyl or together represent oxo and Z is O, NRJQ or S(O) x where R ⁇ j is hydrogen, (C ⁇ g)alkyl or aryl(C ⁇ _g)alkyl and x is 0-2, and wherein C and D are linked ortho to one another on each of rings A and B in formula (b); R2 is hydrogen, (C ⁇ _g)alkyl or aryl(C i.g)alkyl;
  • R3 is hydrogen, (C ⁇ _5)alkyl optionally substituted by up to three halogen atoms, (C3_7)cycloalkyl, fused aryl(C3_7)cycloalkyl, (C3_7)cycloalkyl(C2-6) a lkyl, (C2- g)alkenyl, (C2-6)al y yl, aryl, aryl-(C ⁇ _5)alkyl, heterocyclyl or heterocyclyl-(C ⁇ _6)alkyl; R4 is hydrogen, or an in vivo hydrolysable acyl group; and R5 and Rg are independently hydrogen and (C [ . )alkyl or together represent (CH2) r where r is 2 to 5.
  • the compound of formula (I) may exist in a number of isomeric forms, all of which, including E- and Z- geometric isomers and racemic and diastereoisomeric forms, are encompassed within the scope of the present invention.
  • stereochemistry at the carbon atom marked * is D-, particularly when R[ is selected from phenyl, (a) or (b).
  • the term 'aryl' includes phenyl and naphthyl, each optionally substituted with up to five, preferably up to three, groups selected from halogen, mercapto, (C ⁇ _6)alkyl optionally substituted by 1 -3 halo, phenyl, phenyl(C ⁇ _6)alkyl, phenyl(C ⁇ _6)alkoxy, (C ⁇ _ g)alkoxy optionally substituted by 1 -3 halo, hydroxy(C ⁇ .
  • alkyl mercapto(C ⁇ _6)alkyl, hydroxy, CO2 7, N(R7)2 or CON(R7)2 where each R7 is independently hydrogen.
  • Each alicyclic ring suitably has from 4 to 7, preferably 5 or 6, ring carbon atoms.
  • Alicyclic rings may be unsubstituted or substituted by, for example, up to five, preferably up to three, groups selected from those mentioned above for substitution on aryl
  • 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 those mentioned above for substitution on aryl and. for non-aromatic heterocyclic rings, oxo groups
  • Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms.
  • heteroaryl refers to heteroaromatic heterocyclic ring or ring system, suitably having 5 or 6 ring atoms in each ring
  • a fused heterocyclic ring system may include alicyclic rings and need include only one heterocyclic ring
  • heterocyclyl groups include py ⁇ dyl, t ⁇ azolyl, tetrazolyl, mdolyl, thienyl, isoimidazolyl, thiazolyl, furanyl, tetrahydrofuranyl, quinolmyl, lmidazolidinyl and benzothienyl
  • 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 tautome ⁇ c forms are included within the scope of the invention
  • 'lower alkyl', 'lower alkenyl', 'lower 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
  • examples of R ⁇ optionally substituted alkyl include methyl, isobutyl, carboxymethyl, mercaptomethyl and 1-hydroxyethyl
  • examples of R ⁇ aryl include phenyl optionally substituted with up to five, preferably up to three, groups selected from halogen, mercapto, (C ⁇ . ) alkyl optionally substituted by 1-3 halo, phenyl, (C ⁇ .g) alkoxy optionally substituted by 1-3 halo.
  • R j heteroaryl examples include indolyl, thienyl, isoimidazolyl, thiazolyl, furyl and benzothienyl, preferably 2- thienyl. 2-turyl or 2-benzoth ⁇ enyl
  • R ⁇ is formula (a)
  • ring A is selected from 2,5- thienyl. 2 5-turyl, 1 ,2-phenyl, 1 ,3-phenyl and 1 ,4-phenyl
  • ring B is selected from phenyl optionally substituted by one or two hydroxy or by methoxy, dimethylamino, carboxy, nitro, amino, acetylamino, t ⁇ fluoromethoxy or benzyloxy, 2-furyl, 2-, 3- or 4-py ⁇ dyl, 1 - tetrazolyl, 2-tetrazolyl 1 -t ⁇ azolyl 2-t ⁇ azolyl, 2 thienyl and ⁇ m ⁇ dazohn-2,5-d ⁇ one- l-yl and C is selected from CH2, O or OCH2.
  • R ⁇ is 4- benzyloxyphenyl 3- or 4-substituted in the benzyl group by asubstituent listed above for phenyl or naphthyl.
  • Preferred substituents are carboxy or dimethylamino.
  • R ⁇ examples include phenyl, (5-benzyl)thien-2-yl, (5-benzyl)furan-2- yl, 5-(l-tetrazolylmethyl)thien-2-yl, 5-(2-tetrazolylmethyl)thien-2-yl, 5-(imidazolin-2,5- dione- 1 -ylmethyl)thien-2-yl, 5-( 1 -t ⁇ azolylmethyl)th ⁇ en-2-yl, 5-(2-triazolylmethyl)th ⁇ en- 2-yl, 3-phenoxyphenyl, 2-phenoxyphenyl, 4-phenoxyphenyl, 3-(4-hydroxybenzyl)phenyl, 3-(4-methoxybenzyl)phenyl, 4-benzyloxyphenyl, 4-(2-thienylmethyloxy)phenyl, 1- fluorenyl, 3-(N-ethylcarbazolyl), 4-hydroxybenzyloxy-4-phenyl, 4-methoxybenzyloxy-4
  • R2 is preferably hydrogen.
  • R3 examples include methyl, isobutyl, phenyl-(CH2) i-5, 1- ⁇ ndanyl, 3,4- dihydroxybenzyl, 4-hydroxycarbonyl-phenylethyl, 2-trifluoromethylquinolin-6-yl, 4- difluoromethoxy-phenylethyl, 3-d ⁇ fluoromethoxyphenylethyl and 3-methyl-2,4,5- t ⁇ carbonyhm ⁇ dazolidin- 1-yl.
  • R3 is aryl or aryl-(C ⁇ _6)alkyl.
  • R3 is most preferably phenyl.
  • R 4 include hydrogen, lower alkylcarbonyl, optionally substituted benzoyl or optionally substituted phenyl lower alkyl carbonyl, more preferably hydrogen and acetyl.
  • R 4 is preferably hydrogen.
  • R 5 and R. are preferably independently hydrogen or methyl
  • Suitable pharmaceutically acceptable salts of the carboxylic acid group of the compound of formula (I) include those in which R is a metal ion e.g. aluminium salts, alkali metal salts (e g. sodium, lithium or potassium salts), alkaline earth metal salts (e.g calcium or magnesium salts), ammonium salts, and substituted ammonium salts, for example those with lower alkylamines (e g t ⁇ ethylamine), hydroxy-lower alkylamines (e.g.
  • 2-hydroxyethylamine bis-(2-hydroxyethyl)amine, tris-(2-hydroxyethyl) amine, lower-cycloalkylamines (e.g. dicyclohexyl-amine), or with procaine, dibenzylamine, ,N-dibenzyl- ethylenediamine, 1-ephenamine, N-methylmorpholine, N-ethylpiperidine, N-benzyl- ⁇ -phenethylamine, dehydroabietylamine, ethylenediamine, ,N'-bishydroabietylethylenediamine, bases of the pyridine type (e.g. pyridine, collidine and quinoline), and other amines which have been or can be used to form quaternary ammonium salts.
  • pyridine type e.g. pyridine, collidine and quinoline
  • other amines which have been or can be used to form quaternary ammonium salts.
  • Pharmaceutically acceptable salts may also be acid addition salts of any amino or substituted amino group(s) that may be present as optional substituents on the compound of formula (I), or of a heterocyclic group ring nitrogen atom.
  • Suitable salts include for example hydrochlorides, sulphates, hydrogen sulphates, acetates, phosphates etc. and other pharmaceutically acceptable salts will be apparent to those skilled in the art.
  • Suitable addition salts are the hydrochlorides and hydrogen sulphates.
  • Preferred salts are sodium salts.
  • suitable pharmaceutically acceptable in vivo hydrolysable ester- forming groups R include those forming esters which break down readily in the human body to leave the parent acid or its salt. Suitable groups of this type include those of part formulae (i), (ii), (iii), (iv) and (v): R a
  • R a is hydrogen, (C ⁇ . ) alkyl, (C3.7) cycloalkyl, methyl, or phenyl
  • R D is (C ⁇ . ) alkyl, (C j.g) alkoxy, phenyl, benzyl, (C3.7) cycloalkyl, (C3.7) cycloalkyloxy, (C ⁇ . ) alkyl (C3.7) cycloalkyl, 1 -amino (Ci .g) alkyl, or l-(C ⁇ .
  • R c represents (Ci .g) alkylene optionally substituted with a methyl or ethyl group and R ⁇ and R e independently represent (C ⁇ _6) alkyl
  • R ⁇ represents (C ⁇ . ) alkyl
  • R ⁇ represents hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (C 1.5) alkyl, or (C ⁇ . ) alkoxy
  • Q is oxygen or NH
  • R n is hydrogen or (Cj.g) alkyl
  • R 1 is hydrogen, (C ⁇ .
  • alkyl optionally substituted by halogen, (C2-6) alkenyl, (C ⁇ . ⁇ ) alkoxycarbonyl, aryl or heteroaryl, or R n and R 1 together form (C ⁇ . ⁇ ) alkylene
  • RJ represents hydrogen, (C i .g) alkyl or (C ⁇ . ) alkoxycarbonyl
  • R ⁇ represents (C g) alkyl, (C g) alkoxy, (Ci .g) alkoxy(Cj_6)alkoxy or aryl
  • suitable in vivo hydrolysable ester-forming groups include, for example, acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, ⁇ -acetoxyethyl, ⁇ -pivaloyloxyethyl, l-(cyclohexylcarbonyloxy)prop-l-yl, and ( l-am ⁇ noethyl)carbonyloxymethyl, alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl, ⁇ -ethoxycarbonyloxyethyl and propoxycarbonyloxyethyl, dialkylaminoalkyl especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylammoethyl, diethylaminomethyl or diethylammoethyl, 2-(alkoxycarbonyl)-2-alkenyl groups such as 2-( ⁇ sobutoxycarbonyl)pent-2
  • a further suitable pharmaceutically acceptable in vivo hydrolysable ester-forming group is that of the formula
  • R ⁇ is hydrogen, C [, alkyl or phenyl
  • R is preterably hydrogen
  • solvates mav be formed
  • This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of solvents such as water that may be produced by processes such as lyophilisation.
  • Compounds of formula (I) may be prepared in crystalline form by for example dissolution of the compound in water, preferably in the minimum quantity thereof, followed by admixing of this aqueous solution with a water miscible organic solvent such as a lower aliphatic ketone such as a di-(C ⁇ _6) alkyl ketone, or a (C ⁇ . ) alcohol, such as acetone or ethanol.
  • a water miscible organic solvent such as a lower aliphatic ketone such as a di-(C ⁇ _6) alkyl ketone, or a (C ⁇ . ) alcohol, such as acetone or ethanol.
  • the compounds of formula (I) are metallo- ⁇ -lactamase inhibitors and are intended for use in pharmaceutical compositions. Therefore it will readily be understood that they are preferably each provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85% pure, 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 59% of a compound of the formula (I) or salt, solvate or in vivo hydrolysable ester thereof.
  • the present invention also provides a process for the preparation of a compound of formula (I) as defined above, which comprises reacting a compound of formula (II)
  • Suitable ester-forming carboxyl-protecting groups R x other than in vivo hydrolysable ester forming groups are those which may be removed under conventional conditions.
  • Such groups for R ⁇ include methyl, ethyl, benzyl, p-methoxybenzyl, benzoylmethyl, p-nitrobenzyl, 4-pyridylmethyl. 2,2.2-t ⁇ chloroethyl, 2,2,2-tribromoethyl. t-butyl, t-amyl, allyl, diphenylmethyl, triphenylmethyl, adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl.
  • amino protecting groups include (C ⁇ . ) alkanoyl; benzoyl; benzyl optionally substituted in the phenyl ring by one or two substituents selected from (C1 -4) alkyl, (C 1-4) alkoxy, trifluoromethyl, halogen, or nitro; (C1 -4) alkoxycarbonyl; benzyloxycarbonyl or trityl substituted as for benzyl above; allyloxycarbonyl, trichloroethoxycarbonyl or chloroacetyl.
  • the compound of formula (III) is preferably presented as the anion prepared by treatment of the amine with an organic base such as triethylamine, pyridine or morpholine, and suitable examples of the leaving W group in the compound of formula (II) include halo such as chloro and mixed sulphonic anhydrides such as those where W is methanesulphonyloxy, toluene-p-sulphonyloxy or trifluoromethanesulphonyloxy in mixed sulphonic anhydrides.
  • the compound of formula (III) may be presented as the trimethylsilyl ester hydrochloride.
  • reaction of the compounds of formula (II) and (UI) is preferably carried out at ambient temperature, for example 15-25°C, in an inert solvent such as chloroform tetrahydrofuran, dichloromethane, dioxan or dimethylformamide.
  • the leaving group W in the compound of formula (II) is preferably SH and the reaction is carried out at elevated temperature, such as at reflux, in an inert solvent such as toluene.
  • Y convertible into R 'S examples include halo such as bromo which may be displaced by thiobenzoic acid or thioacetic acid
  • Examples of groups R ' R ', R ' R ' convertible to R. , R R ⁇ and R 4 include those where any carboxy or amino group is protected by carboxy or amino protecting groups. Additionally, examples of R ⁇ convertible to R ⁇ include those containing ring A substituted by hydroxy which can generate R j groups of formula (a) where linker C is of the form -0-(CRgRc)q- and where ring B is an aromatic ring or heterocycle, optionally substituted This may be effected, for example, by alkylation of the hydroxy substituent with a benzyl bromide derivative or with a heterocyclylalkyl bromide derivative.
  • the hydroxy group may be coupled with a benzyl alcohol derivative or with a heterocyclylalkyl alcohol derivative in established ways, for example in the presence of diethyl azodicarboxylate and triphenylphosphine (Mitsunobo et al, Bull. Chem. Soc. Jpn., 1967, 40, 2380).
  • R 4 ' in the compound of formula (II) is preferably other than hydrogen, such as an acyl protecting group as described above for carboxy protecting groups, for example acetyl.
  • the acid derivative of formula (II) is preferably prepared from the corresponding free acid by treatment with strong base such as sodium hydride followed by a source of the anion leaving group W, such as oxalyl chloride where W is Cl, or hydrogen sulphide where W is SH.
  • strong base such as sodium hydride
  • W oxalyl chloride
  • W hydrogen sulphide
  • Y is R 4 'S Compounds of formula (IV) where R 1 ' is -( A)-OH or -(A)-CH2OH may be converted to compounds with R ⁇ as defined in (a) where C is -OCH2- or -CH2O- using alcohols of formula (B')-CH2OH or (B')-OH, respectively under Mitsunobu conditions (Synthesis 1981, 1), using a coupling reagent such as t ⁇ phenyl phosphine and diethyl azodicarboxylate.
  • B' is B or a group convertible thereto, for example where a carboxy or amino substituent on B is protected.
  • the carboxy group -COOR x may be deprotected, that is to say, converted to a free carboxy, carboxy salt or carboxy ester group -COOR in a conventional manner, for example as described in EP0232966A.
  • Simultaneous deprotection of -COOR x and R4'S and any protecting group in R ⁇ may be achieved by treatment with sodium sulphide nonahydrate in water/methanol
  • this may be effected by chromatographic separation of the isomers of the product.
  • the desired isomer may then be deprotected to give the corresponding free acid or salt
  • *D isomer of formula (I) it is preferred to use the corresponding *D isomer of the intermediate of formula (III)
  • a carboxyl group may be regenerated from any of the above esters by usual methods appropriate to the particular R x 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
  • R x 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
  • acetonyl by hydrolysis in acetonit ⁇ le with 0 1M aqueous potassium hydroxide solution
  • compositions may be prepared from such acids by treatment with a base, after a conventional work-up if necessary Suitable bases include sodium hydrogen carbonate to form sodium salts
  • Crystalline forms of the compounds of formula (I) where R is a salt forming cation may for example be prepared by dissolving the compound (I) in the minimum quantity of water, suitably at ambient temperature, then adding a water miscible organic solvent such as a (Cj.g) alcohol or ketone such as ethanol or acetone, upon which crystallisation occurs and which may be encouraged for example by cooling or t ⁇ turation
  • a water miscible organic solvent such as a (Cj.g) alcohol or ketone such as ethanol or acetone
  • the ⁇ -keto ester is obtainable from the R ( -H, R . -CH 9 CO 9 R or R , '-CO 9 R x by routine methods (J March, vide infra)
  • the compounds of formula (III) may be prepared from the aldehyde intermediate R -CHO by the Strecker synthesis [cf Advanced Organic Chemistry; Mechanism and Structure, 4th Edn, by J.
  • a compound of formula (I) or a salt, solvate or in vivo hydrolysable ester thereof may be administered in the form of a pharmaceutical composition together with a pharmaceutically acceptable carrier and the invention also relates to such compositions.
  • the compounds of formula (I) have metallo- ⁇ -lactamase inhibitory properties, and are useful for the treatment of infections in animals, especially mammals, including humans, in particular in humans and domesticated (including farm)animals.
  • the compounds may be used, for example, for the treatment of infections of, inter alia, the respiratory tract, the urinary tract, and soft tissues and blood, especially in humans.
  • the invention further provides a method of treatment of bacterial infections in humans or animals which comprises administering, in combination with a ⁇ - lactam antibiotic, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof.
  • the compounds may be used in combination with an antibiotic partner for the treatment of infections caused by metallo- ⁇ -lactamase producing strains, in addition to those infections which are subsumed within the antibacterial spectrum of the antibiotic partner.
  • Metallo- ⁇ -lactamase producing strains include:- Pseudomonas aeruginosa, Klebsiella pneumoniae, Xanthomonas maltophilia, Bacteroides fragilis, Serratia marcescens, Bacteroides distasonis, Pseudomonas cepacia, Aeromonas hydrophila, Aeromonas sobria, Aeromonas salmonicida, Bacillus cereus, Legionella gormanii and Flavobacterium spp.
  • 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 compounds of formula (I) are particularly suitable for parenteral administration.
  • the compounds of formula (I) may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibiotics and other ⁇ -lactam antibiotic/ ⁇ -lactamase inhibitor combinations.
  • the composition may be formulated for administration by any route, such as oral, topical or parenteral.
  • 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 m unit dose presentation form, and may contain conventional exc ⁇ ients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrolhdone, fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycme, tabletting 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
  • 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 sterilisation 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.
  • a composition according to the invention may comprise a compound of formula (I) or a salt, solvate or in vivo hydrolysable ester thereof together with one or more additional active ingredients or therapeutic agents, for example a ⁇ -lactam antibiotic such as a carbapenem, penicillin or cephalosporin or pro-drug thereof.
  • a ⁇ -lactam antibiotic such as a carbapenem, penicillin or cephalosporin or pro-drug thereof.
  • Carbapenems, penicillins, cephalosporins and other ⁇ -lactam antibiotics suitable for co-administration with the compound of formula (I) - whether by separate administration or by inclusion in the compositions according to the invention - include both those known to show instability to or to be otherwise susceptible to metallo- ⁇ -lactamases and also those known to have a degree of resistance to metallo- ⁇ -lactamases.
  • a serine ⁇ -lactamase inhibitor such as clavulanic acid, sulbactam or tazobactam may also be co-administered with the compound of the invention and the ⁇ -lactam antibiotic, either by separate administration, or co-formulation with one, other or both of the compounds of the invention and the ⁇ -lactam antibiotic.
  • carbapenems examples include imipenem, meropenem, biapenem, BMS 18 1 139 ([4R- [4alpha,5beta,6beta(R*)]]-4-[2-[(aminoiminomethyl)amino]ethyl]-3-[(2-cyanoethyl)thio]- 6-( l -hydroxyethyl)-7-oxo- l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), BO2727 ([4R- 3[3S*,5S*(R*)],4alpha,5beta,6beta(R*)]]-6-(l-hydroxyethyl) -3-[[5-[l-hydroxy-3- (methylam ⁇ no)propyl]-3-pyrrohd ⁇ nyl]th ⁇ o]-4-methyl-7-oxo-l-aza
  • penicillins suitable for co-administration with the compounds according to the invention include benzylpenicil n, phenoxymethylpemcillin, carbenicil n, azidocilhn, propicil n, ampicillin, amoxycillin, epicilhn, ticarcil n, cyclacil n, pirbenicil n, azlocilhn, mezlocillm, sulbenicil n, piperacil n, and other known penicillins
  • the penicillins may be used in the form of pro-drugs thereof, for example as in vivo hydrolysable esters,for example the acetoxymethyl, pivaloyloxymethyl, ⁇ -ethoxycarbonyloxyethyl and phthahdyl esters of ampicillin.
  • benzylpenicilhn and amoxycillin as aldehyde or ketone adducts of penicillins containing a 6- ⁇ -am ⁇ noacetam ⁇ do side chain (for example hetacilhn, metampicilhn and analogous derivatives of amoxycillin), and as ⁇ -esters of carbenicilhn and ticarcilhn, for example the phenyl and indanyl ⁇ -esters
  • cephalosponns examples include, cefat ⁇ zme, cephalo ⁇ dme, cephalothin, cefazolin cephalex , cephacet ⁇ le, cephapi ⁇ n cephamandole nafate, cephradme, 4-hydroxycephalex ⁇ n, cephaloglycin.
  • cefoperazone cefsulodin, ceftazidime, cefuroxime cefmetazole, cefotaxime, ceftnaxone and other known cephalosponns, all of which may be used in the form of pro-drugs thereof
  • ⁇ -lactam antibiotics other than penicillins and cephalosponns include aztreonam, latamoxef (Moxalactam - Trade Mark), and other known ⁇ -lactam antibiotics, all of which may be used in the form of pro-drugs thereof
  • penicillins for co-administration with the compounds according to the invention include ampicillin amoxycillin, carbenicilhn, piperacilhn, azlocilhn mezlocillm, and ticarcilhn
  • Such penicillins may be used in the form of their pharmaceutically acceptable salts, for example their sodium salts
  • ampicillin or amoxycillin may be used in the form of fine particles of the zwitte ⁇ onic form (generally as ampicillin t ⁇ hydrate or amoxN Cilhn t ⁇ hydrate) for use in an injectable or infusable suspension, tor example, in the manner hereinbefore described in relation to the compounds according to the invention
  • Amoxycillin for example in the form of its sodium salt or the t ⁇ hydrate, is particularly preferred for use in synergistic compositions according to the invention
  • cephalosponns for co-administration with the compounds according to the invention include cefotaxime and ceftazidime, which may be used in the form of their pharmaceutically acceptable salts, for example their sodium salts
  • a compound of formula (I) may be administered to the patient in conjunction with a ⁇ -lactam antibiotic such as a carbapenem, penicillin or cephalosporin in a synergistically effective amount
  • the compounds of formula (I) may suitably be administered to the patient at a daily dosage of from 0 7 to 50 mg/kg of body weight
  • a daily dosage of from 0 7 to 50 mg/kg of body weight
  • 50 to 3000 mg, preferably from 100 to 1000 mg, of a compound according to the invention may be administered daily, suitably in from 1 to 6, preferably from 2 to 4, separate doses
  • Higher or lower dosages may, however, be used in accordance with clinical practice
  • each unit dose may suitably comprise from 25 to 1000 mg, preferably from 50 to 500 mg, of a compound according to the invention
  • Each unit dose may, for example, be 62 5, 100, 125, 150, 200 or 250 mg of a compound according to the invention
  • the ratio of the amount of the compound according to the invention to the amount of the other ⁇ -lactam antibiotic may vary within a wide range
  • the said ratio may, for example, be from 100 1 to 1 100, more particularly, it may, for example, be from 2 1 to 1 30
  • the amount of carbapenem, penicillin, cephalosporin or other ⁇ -lactam antibiotic in a synergistic composition according to the invention will normally be approximately similar to the amount in which it is conventionally used per se, for example from about 50 mg, advantageously from about 62 5 mg, to about 3000 mg per unit dose, more usually about 125, 250, 500 or 1000 mg per unit dose
  • the present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or in vivo hvdrolvsable ester thereof for use in the treatment of bacterial infections
  • the present invention also includes the use of a compound of formula (I) or a pharmaceutically acceptable salt solvate or in hvdrolvsable ester thereof in the manufacture of a medicament for the treatment of bacterial infections
  • the present invention also includes the use of a compound of formula (I) or a pharmaceutically acceptable salt solvate or in hvdrolvsable ester thereof as a metallo- ⁇ -lactamase inhibitor All the above compositions and methods may optionally include a serine ⁇ - lactamase inhibitor as above described.
  • the compounds of the present invention are active against metallo- ⁇ -lactamase enzymes produced by a wide range of organisms including both Gram-negative organisms and Gram-positive organisms.
  • the title compound was prepared from D-p-hydroxyphenylglycine by stirring in methanol, presaturated with hydrogen chloride gas, overnight. The methanol was removed under reduced pressure and the residue partitioned between ethyl acetate and an excess of saturated NaHCO3 solution. The organic layer was washed with water and dried and solvent removed.
  • the methyl ester (lOOmg; 0.2mmol) from Description 5 was suspended in methanol (3ml) and treated with a solution of sodium sulphide nonahydrate (200mg; 0.84mmol) in water (2ml). The suspension was stirred under argon for 3 hours. The reaction mixture was washed with ethyl acetate and the aqueous layer was acidified by addition of 5M hydrochloric acid solution (10 drops) and then extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO . Removal of the solvent afforded title compound as a foam (0. lmmol), APCI [M-H] " 476.
  • the inhibitory activity of the compounds of the invention is measured in 25mM PIPES pH 7 buffer at 10 concentrations (1000, 333, 111 , 37, 12.3, 4.1, 1.4, 0.46, 0.15 and 0.05 ⁇ M) at 37°C using nitrocefin (91 ⁇ M final concentration) as the reporter substrate.
  • the assays are performed with a 5 minute preincubation of enzyme and inhibitor and are conducted in the presence of added zinc sulphate (Zn 2* lOO ⁇ M, final concentration).
  • the methodology is described in detail in the following references: Payne et al (1991), I. Antimicrob. Chemother., 28:255; Payne et al (1994), Antimicrob. Agents and Chemother., 38:767.
  • Compounds of the invention may be tested and found to inhibit Bacteroides fragilis CfiA metallo- ⁇ -lactamase with 150 values ⁇ 1000 ⁇ M.
  • the compound of the Example 2 exhibits ah I 50 value against B. fragilis CfiA metallo- ⁇ -lactamase of ⁇ l ⁇ M and exhibited significant inhibition of the Stenotrophomonas maltophilia L-l (formerly Xanthomonas maltophilia L-l) and Bacillus cereus II metallo- ⁇ -lactamases, with I 50 values in the range 0.2 - 14 ⁇ M.

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Abstract

L'invention concerne des dérivés d'acides aminés représentés par la formule (I) et présentant des propriétés inhibitrices dirigéescontre les métallo-β-lactamases, propriétés qui sont utiles dans le traitement des infections chez l'animal. Dans la formule (I), R4S-C(R5R6)-C(=CHR3)-CON(R2)-CH(R1)-CO2R, les variables sont telles que définies dans la revendication 1.
EP98943877A 1997-07-31 1998-07-21 Acides mercapto-acyl-amines utilises comme inhibiteurs des metallo-beta lactamases Withdrawn EP1000024A1 (fr)

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GBGB9716224.2A GB9716224D0 (en) 1997-07-31 1997-07-31 Compounds
GB9716224 1997-07-31
GB9716221 1997-07-31
GBGB9716221.8A GB9716221D0 (en) 1997-07-31 1997-07-31 Compounds
PCT/EP1998/004974 WO1999006365A1 (fr) 1997-07-31 1998-07-21 Acides mercapto-acyl-amines utilises comme inhibiteurs des metallo-beta lactamases

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