EP1192128A1 - Derives de thiol servant d'inhibiteurs des metallo-beta-lactamases - Google Patents

Derives de thiol servant d'inhibiteurs des metallo-beta-lactamases

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Publication number
EP1192128A1
EP1192128A1 EP00941349A EP00941349A EP1192128A1 EP 1192128 A1 EP1192128 A1 EP 1192128A1 EP 00941349 A EP00941349 A EP 00941349A EP 00941349 A EP00941349 A EP 00941349A EP 1192128 A1 EP1192128 A1 EP 1192128A1
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EP
European Patent Office
Prior art keywords
group
optionally substituted
formula
compound
groups
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Withdrawn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
EP00941349A
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German (de)
English (en)
Other versions
EP1192128A4 (fr
Inventor
James M. Balkovec
Mark L. Greenlee
Milton L. Hammond
James V. Heck
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Merck and Co Inc
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Merck and Co Inc
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Publication of EP1192128A1 publication Critical patent/EP1192128A1/fr
Publication of EP1192128A4 publication Critical patent/EP1192128A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • 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
    • 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
    • C07C323/56—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 the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • Carbapenems such as imipenem and meropenem
  • ⁇ -lactam antibiotics that are widely used to treat a variety of serious infections.
  • carbapenems resist inactivation by most active-site serine ⁇ - lactamases and retain their activity against strains producing these enzymes.
  • carbapenems, as well as penicillin and cephalosporin members of the ⁇ -lactam family are efficiently hydrolyzed by the zinc- dependent molecular class B metallo- ⁇ -lactamases (MBLs).
  • MBLs zinc- dependent molecular class B metallo- ⁇ -lactamases
  • MBLs have now been identified in a number of pathogenic bacterial species including Bacillus cereus, Bacteroides fragilis, Aeromonas hydrophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Serratia marcescens, Stenotrophomonas maltophilia and Shigella flexneri. MBLs are not inactivated by currently available inhibitors of the active-site serine ⁇ -lactamases such as clavulanic acid or sulbactam. Consequently, there is a critical need for metallo- ⁇ -lactamase inhibitors that, when administered in combination with a ⁇ -lactam antibiotic, overcome MBL- mediated resistance in bacteria.
  • the present invention relates to novel thiol derivative compounds, pharmaceutically acceptable salts, and biolabile esters thereof, useful for inhibiting the activity of metallo- ⁇ -lactamases and treating bacterial infections, characterized by the general formula (I):
  • R 1 is selected from straight, branched, unsaturated or alicyclic alkyl, optionally substituted with from 1 to 3 R x groups; and (CH 2 ) n Ar, where Ar is an aryl selected from the group consisting of phenyl, furanyl, thienyl, pyridyl, naphthyl, biphenyl, dibenzofuranyl, dibenzothienyl, fluorenyl and fluorenonyl, where n is 0, 1, 2 or 3, and where Ar is optionally substituted with 1 to 3 R x groups;
  • R 2 is selected from hydrogen; and a group of formula II:
  • R is selected from hydrogen; straight, branched, unsaturated or alicyclic alkyl, optionally substituted with from 1 to 3 R x groups; (CH 2 ) n Ar, where Ar is an aryl selected from phenyl, furanyl, thienyl, pyridyl, naphthyl, biphenyl dibenzofuranyl, dibenzothienyl, fluorenyl and fluorenonyl, where Ar is optionally substituted with 1 to 3 R x groups, and where n is 0, 1, 2 or 3; and a group of formula III:
  • R is selected from hydrogen; and straight or branched alkyl
  • R 5 is selected from hydrogen; straight, branched, unsaturated or alicyclic alkyl, optionally substituted with 1 to 3 R x groups, where the alkyl group is optionally interrupted by X, where X is selected from O, S, NH and N(COCH 3 ); allyloxy and 9-fluorenylmethyloxy; and (CH 2 ) n Ar, where Ar is selected from phenyl, furanyl, thienyl, pyridyl, naphthyl, biphenyl, dibenzofuranyl, dibenzothienyl, fluorenyl and fluorenonyl, where n is 0, 1, 2 or 3, and where Ar is optionally substituted with 1 to 3 R x groups; and
  • R x is selected from OR, CN, C(O)NH 2 , C(O)NHR, C(O)N(R) 2 , OC(O)NH 2 , OC(O)R, CHO, SO 2 NH 2 , SOR, CF 3 , C(O)R, COOR, F, Cl, Br, I, OCH 2 Ph, NHR, N(R) 2 , NHCOR, NHCO 2 t-Bu, NHCO 2 allyl, NH 2 , and R, where R is hydrogen, Ci to C 15 alkyl, or aryl.
  • the invention is further directed to a pharmaceutical composition containing the thiol derivative compound, as well as a method of treating bacterial infections in animals or humans, wherein the composition is administered in combination with a ⁇ -lactam antibiotic.
  • alkyl is defined as monovalent alkane derivatives containing from about 1 to about 15 carbon atoms, interconnected by single or multiple bonds, including straight, branched, unsaturated and alicyclic which are optionally substituted with 1 to 3 R x .
  • straight alkyl refers to Cj to C 15 alk ls having one continuous chain of hydrocarbons. Examples of straight alkyl groups include, but is not limited to, methyl, ethyl, propyl, butyl, pentyl and hexyl.
  • branched alkyl is defined as monovalent hydrocarbons have one or more non-continuous hydrocarbons linked to a main hydrocarbon chain.
  • branched alkyl groups include, but is not limited to, isopropyl, isobutyl, t-butyl, isopentyl and neopentyl.
  • alicyclic alkyl refers to hydrocarbon compounds which contain a saturated ring in its structure. Examples of alicyclic alkyls include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentenyl, methylcyclopentyl and cyclohexyl.
  • unsaturated alkyl refers to hydrocarbon compounds containing one or more elements of which the total valence is unsatisfied or is satisfied by union with another atom of the same element.
  • Aryl is defined as an aromatic ring substituents, including heteroaryls, having a hydrogen atom removed therefrom as well as fused ring compounds thereof.
  • aryls include, but is not limited to, benzyl, furanyl, thienyl, pyridyl, naphthyl, biphenyl, dibenzofuranyl, dibenzothienyl, fluorenyl and fluorenonyl.
  • Heteroatoms are independently defined as oxygen, sulfur and nitrogen atoms.
  • Alkylcarbonyl and arylcarbonyl are defined as alkyl and aryl groups bonded to a carbonyl group, C(O).
  • stereoisomers of the thiol derivative compound, pharmaceutically acceptable salts, and biolabile esters thereof can be utilized to effectively inhibit the activity of metallo- ⁇ -lactamases.
  • the stereoisomers of the compound are characterized by formulae la and la':
  • R 1 , R 2 , R 3 , R 4 , R 5 , R x and all other variables are as originally defined.
  • stereoisomera are of formulae la and la';
  • R is selected from straight, branched, unsaturated or alicyclic alkyl, optionally substituted with from 1 to 3 R x groups; and (CH 2 ) n Ar, where Ar is an aryl selected from the group consisting of phenyl, furanyl, thienyl, pyridyl, naphthyl, biphenyl, dibenzofuranyl, dibenzothienyl, fluorenyl and fluorenonyl, where n is 0, 1, 2 or 3, and where Ar is optionally substituted with 1 to 3 R ⁇ groups; and R is hydrogen; wherein, the thiol derivatives are characterized by the formulae:
  • R can be selected from:
  • R , R , R x and all other variables are as originally defined.
  • a more preferred R 1 is (CH 2 ) n Ar, where Ar is an aryl selected from biphenyl and dibenzofuranyl, where n is 1, 2 or 3, and where Ar is optionally substituted with 1 R ⁇ group; and R 3 is selected from methyl, and (CH 2 ) n Ar, where Ar is selected from phenyl, naphthyl, pyridyl, thienyl and furanyl, where n is 0, and where Ar is optionally substituted with 1 ⁇ group.
  • Suitable combinations of R 1 and R 3 may be selected as follows:
  • R 1 and R 3 combinations can be selected as follows:
  • R 1 , R 4 , R , R ⁇ and all other variables are as originally defined.
  • R is methyl
  • suitable combinations of R and R may be selected as follows:
  • a more preferred R is (CH 2 ) n Ar, where Ar is aryl selected from biphenyl and dibenzofuranyl, where n is 1, 2 or 3; and where Ar is optionally substituted with 1 R x group; and R 4 is selected from hydrogen and methyl.
  • R 1 is bipehnyl
  • the thiol derivative is of the formula:
  • R and R combinations are selected from the group consisting of:
  • the invention is further directed to a pharmaceutical composition useful for treating bacterial infections in humans and animals, wherein the composition is characterized as containing a therapeutically effective amount of the inventive thiol derivative, pharmaceutically acceptable salts, and biolabile esters thereof.
  • composition can include forms for oral, topical and parenteral treatment.
  • suitable composition forms include but are not limited to, tablets, capsules, lozenges, granules, powders, creams and liquid preparations, i.e. oral or parenteral solutions or suspensions.
  • the composition When prepared for oral administration via capsules and tablets, the composition may contain conventional binders such as sorbitol, gelatin, syrups, acasia and other ingredients known in the art. Liquid preparations may include emulsions, syrups, elixirs and aqueous and oil suspensions.
  • Topical compositions may be prepared utilizing creams, lotions, powders and ointments of aqueous, alcoholic and oleaginous liquids in combination with the inventive compound, pharmaceutically acceptable salts or biolabile esters thereof.
  • compositions may be prepared using the compound, salts, or esters by suspending or dissolving the derivative in a suitable carrier.
  • the derivative may be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule. Buffering, preservative, anesthetic agents, surfactants and wetting agents may also be dissolved in the carrier as desired.
  • the composition can contain from about 0.1 to about 99.9 weight percent, based on 100 total weight percent, of the compound, pharmaceutically acceptable salts, or biolabile esters thereof.
  • the composition can contain from about 2 to about 70 weight percent, and preferable about 20 weight percent, based on 100 total weight percent of the compound.
  • the composition, salt or ester can contain compatible carriers known in the art, in an amounts from about 1 to about 98 weight percent, based on 100 total weight percent.
  • the composition, salt or ester can contain carriers in an amount from about 98 to about 30 weight percent; preferably, about 80 weight percent, based on 100 total weight percent.
  • Suitable carriers for topical application are creams, ointments and lotions having an alcohol base.
  • effective dosage ratios of ⁇ -lactams may range from about 1:100 to about 100:1.
  • the ⁇ -lactam antibiotics useful with the compound and composition of the invention include penicillins, cephalosporins and carbapenems known in the art.
  • the present invention is also directed to a method of treating bacterial infections in humans and animals, characterized by administering to a patient in need thereof, a therapeutically effective amount, to reduce bacterial infections, of the composition containing the thiol derivative compound.
  • the thiol derivative composition may be co-administered with a ⁇ -lactam antibiotic by separately administering the thiol derivative compound and the ⁇ -lactam antibiotic in close time succession, or by co-formulation, that is by preparing a single composition containing proportions of the thiol derivative compound and ⁇ -lactam antibiotic.
  • Suitable ⁇ -lactam antibiotics include carbapenems, penicillins, cephalosporins and other ⁇ -lactams known in the art. These compounds may also be administered in their salt and pro-drug forms.
  • Suitable carbapenems for co-administration with the thiol derivatives of the invention include imipenem, meropenem, biapenem, 3- [[2-(acetylamino)ethenyl]thio]-6-(l-methylethyl)-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, and those disclosed in U.S. Pat. No.
  • Suitable penicillins for co-administration include ampicillin, sulbenicillin, amoxycillin, propicillin, benzylpenicillin, mezlocillin, cyclacillin, phenoxymethylpenicillin, epicillin, ticarcillin, azidocillin, pirbenicillin, as well as others known in the art.
  • Suitable cephalosporins for co-administration include ceftriaxone, cephapirin, cephaloridine, cefazolin, cephradine, cephalexin, cephacetrile, cephaloglycin, cephalothin, cefatrizine, cefoperazone, ceftazidime, cefmetazole, cefotaxime as well as others known in the art.
  • DHP dehydropeptidase
  • a renal enzyme known as dehydropeptidase
  • DHP inhibitor use of a DHP inhibitor is contemplated to be part of the present invention.
  • Inhibitors of DHP and their use with carbapenems are disclosed in, e.g. European Patent Application Nos. 79102616.4, filed July 24, 1979 (Patent No. 0 007 614); and 82107174.3, filed August 9, 1982 (Publication No. 0 072 014), both incorporated herein by reference.
  • the method of the invention may include the co-administration suitable carbapenems, e.g. imipenem, and DHP inhibitors when desirable.
  • the thiol derivatives may, where DHP inhibition is desired or necessary, be combined or used with the appropriate DHP inhibitor as described in the aforesaid patents and published application.
  • the cited European Patent Applications define the procedure for determining DHP susceptibility of carbapenems and disclose suitable inhibitors, combination compositions and methods of treatment.
  • a preferred DHP inhibitor is 7-(L-2-amino-2-carboxy- ethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid or a useful salt thereof.
  • the method of the invention is further directed to the co- administration of a serine ⁇ -lactamase inhibitor such as clavulanic acid, sulbactam or tazobactam with the thiol derivative, salt or ester to treat bacterial infections.
  • a serine ⁇ -lactamase inhibitor such as clavulanic acid, sulbactam or tazobactam with the thiol derivative, salt or ester to treat bacterial infections.
  • the thiol derivative may be co-administered with various combinations of ⁇ - lactam antibiotics, serine ⁇ -lactamase inhibitors and DHP inhibitor, as will become readily apparent to those skilled in the art.
  • salt-forming ions of the carboxylic acid group of the compound of formula I may be prepared according to Berge, S. M., et al. J. Pharm. Sci. 66(1): 1-16 (1977), incorporated herein by reference thereto.
  • a preferred group of salt- forming cations are selected from aluminum, sodium, lithium, potassium, calcium, magnesium and ammonium. More preferably the cations are selected from Na + , Ca + 2 and K + .
  • a suitable amount of the carbon dioxide producing compound e.g. sodium bicarbonate or sodium carbonate, stabilized salts of the compounds may be prepared.
  • the pharmaceutically acceptable salts referred to above also include acid addition salts.
  • the thiol derivative compounds can be used in the form of salts derived from inorganic or organic acids. Included among such salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-pheny
  • esters of the carboxylic acid group of the compounds of formula I are such as would be readily apparent to a medicinal chemist, and include, for example, those described in detail in U.S. Pat. No. 4,309,438, incorporated herein by reference. Included within such pharmaceutically acceptable esters are those which are hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and others described in detail in U.S. Pat. No. 4,479,947, incorporated herein by reference. These are also referred to as "biolabile esters".
  • Biolabile esters are biologically hydrolizable, and may be suitable for oral administration, due to good absorption through the stomach or intenstinal mucosa, resistance to gastric acid degradation and other factors.
  • biolabile ester forming moieties include acetoxymethyl, 1-acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl, 1- isopropyloxycarbonyloxyeth l, 1-cyclohexyloxycarbonyloxyethyl, phthalidyl and (2-oxo-5-methyl-l,3-dioxolen-4-yl)methyl. These groups can be substituted in the alkyl or aryl portions thereof with acyl or halo groups.
  • the thiol derivative compound of the present invention may be synthesized in accordance with the schemes and reagents of Flow Sheets A through E, where R , R , R , R 5 and R x are as previously defined, as follows:
  • the substituted acetic acid starting material, Al is commercially available or can be prepared by a variety of methods known in the art.
  • Starting material Al wherein R is previously defined, is hydroxylated on the carbon adjacent to the carboxylate group, employing a chiral auxiliary group to achieve stereoselectivity in the reaction.
  • the hydroxyl group is then displaced with a thioacyl moiety by use of a Mitsunobu reaction.
  • the chiral auxiliary and the acyl group on the sulfur atom are then removed by hydrolysis.
  • the resulting thiolate is re-acylated with the desired activated acyl group to produce A6 or protonated to produce thiol A7.
  • a mixed anhydride is formed between the starting carboxylic acid Al and pivalic acid by treating Al with a tertiary amine base such as triethylamine and pivaloyl chloride in a suitable ethereal solvent such as tetrahydrofuran at reduced temperatures of from -78 to OC.
  • reaction is carried-out at a temperature of from about 0 to about 30C, for about 1 to about 12 hours.
  • the product, A4 is isolated and purified by conventional methods.
  • Compound A6 may be synthesized from A4 by a multi-step sequence of reactions without isolation of intermediates.
  • the first step is a hydrolysis reaction in which both the oxazolidinone chiral auxiliary and the acetyl group on the sulfur atom are removed.
  • Aqueous lithium hydroxide is employed for this reaction along with an organic co-solvent, e.g. tetrahydrofuran.
  • the resulting thiolate intermediate is re-acylated with an activated acylating reagent A5.
  • the carboxylic acid of A5 is activated as an N-hydroxysuccinimide ester.
  • those skilled in the art will realize that other means of acyl activation can be employed at A5.
  • Compounds of structure A7 are synthesized from A4 by hydrolysis, as described above, followed by protonation of the thiolate intermediate with an acid, e.g. aqueous hydrogen chloride, to produce compound A7.
  • an acid e.g. aqueous hydrogen chloride
  • 2- ⁇ protecting group such as allyloxycarbonyl (alloc) and then the chiral auxiliary group is removed by hydrolysis to provide compound Bl.
  • Compound Bl is attached to a solid support, making use of an acid cleavable linker group, producing B3. Removal of the alloc protecting group from the hydroxyl provides B4. Mitsunobu reaction of B4 with thioacid B5 yields thioester B6. Cleavage of the substrate from the resin under acidic conditions yields compound B7.
  • the solid support of Flow Sheet B is Rapp TentaGel® S-NH2 resin which exhibits good swelling properties in organic solvents and high accessibility of its reactive sites. Other known solid supports are also suitable.
  • attachment to the resin is made through a mild acid cleavable linker group.
  • the linker group chosen for this purpose is the 4- (4-hydroxy-methyl-3-methoxyphenoxy)-butyrate (HMPB) group.
  • HMPB 4- (4-hydroxy-methyl-3-methoxyphenoxy)-butyrate
  • Other known acid cleavable linker groups are also suitable. Attachment of Bl to the resin using this linker group can be accomplished by two alternative methods. In the first method, the HMPB linker group is initially derivatized as a 2,4-dichlorophenyl ester.
  • the HMPB linker group is first attached to the Rapp TentaGel S-NH2 resin using l-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride in DMF.
  • Compound Bl is then esterified onto this linker-resin combination (TentaGel-HMPB resin) using 1,3-diisopropylcarbodiimide and N,N- dimethylamino-pyridine in N,N-dimethylformamide as solvent to provide B3.
  • Removal of the alloc protecting group of B3 is accomplished by a palladium(O) catalyzed de-allylation reaction, using N-methyl- morpholine-acetic acid as the allyl acceptor and tetrakis(triphenyl- phosphine)palladium(O) as the palladium catalyst in N- methylpyrrolidinone as the solvent.
  • Mitsunobu reaction of B4 with a thioacid B5 yields thioester B6.
  • Thioacids B5 can be prepared by known methods, (e.g. Yamashiro, D.; Li, C. H. Int. J. Peptide Protein Res. 1988, 31, 322. Blake, J.; Yamashiro, D. Int. J. Peptide Protein Res. 1981, 18, 383).
  • the reaction of B4 with B5 is similar to the Mitsunobu reaction described in Flow Sheet A, except in this case B4 is bound to a solid support. In this reaction use of tris(4- chlorophenyl)-phosphine in place of triphenylphosphine is preferred.
  • an amine base such as N,N-diisopropylethylamine
  • the reaction is carried-out in tetrahydrofuran as solvent and employs diisopropyl azodicarboxylate as the dialkyl azodicarboxylate reagent. Since B4 is bound to a solid support, a large excess of reagents can be used in this reaction to make it more efficient. At the end of the reaction, the excess reagents can be removed by washing the resin with appropriate solvents, e.g. N,N-dimethylformamide, tetrahydrofuran, methanol and dichloromethane.
  • solvents e.g. N,N-dimethylformamide, tetrahydrofuran, methanol and dichloromethane.
  • Flow Sheet C describes a further extension of the synthesis shown in Flow Sheet B, starting with compound B4.
  • Mitsunobu reaction of B4 is carried-out using alloc-D-thioalanine dicyclohexylamine salt to provide thioester Cl.
  • This Mitsunobu reaction is analogous to that described in Flow Sheet B, except that addition of an amine base is usually not necessary since the thioacid used is already an amine salt.
  • compound Cl is reacted with anhydride C2 to produce C3 in a "trans-acylation" reaction. Similar reactions have been shown (e.g. Dessolin, M.; Guillerez, M.-G.; Thieriet, N.; Guibe, F.; Loffet, A.
  • Flow Sheet D describes another synthesis of compounds of the present invention, starting with B4. Mitsunobu reaction of B4 is
  • Compound D3 may be converted to compound D4 by cleavage of the thioacyl group. This is accomplished by reacting D3 with aqueous ammonium hydroxide in a suitable organic solvent, e.g. tetrahydrofuran in the presence of dithiothreitol, which inhibits the oxidation of thiol D4 to the corresponding disulfide. This reaction is preferably carried-out when the R3 group, previously defined, of D3 is methyl.
  • a suitable organic solvent e.g. tetrahydrofuran
  • Flow Sheet D also illustrates the inversion of the stereochemistry of the hydroxyl group of B4 to provide D5. This is accomplished by a Mitsunobu reaction of B4 with formic acid followed by cleavage of the resulting formate ester to yield D5.
  • This Mitsunobu reaction is similar to those described above, except that formic acid, a carboxylic acid, is employed instead of a thioacid.
  • triphenylphosphine is used as the triarylphosphine reagent, and no amine base is added to the reaction.
  • Cleavage of the formate ester to produce D5 is accomplished by reacting the product of the Mitsunobu reaction with N,N-diisopropyl-ethylamine and hydroxylamine hydrochloride employing a suitable solvent mixture, e.g. tetrahydrofuran and N,N- dimethylformamide.
  • a suitable solvent mixture e.g. tetrahydrofuran and N,N- dimethylformamide.
  • Flow Sheet D operates as described above for B4, to provide compounds D7 and D8.
  • Flow Sheet E describes a further synthesis of compounds of the present invention.
  • B4 Mitsunobu reaction with thioacetic acid yields El.
  • Cleavage of the acetyl group from the sulfur atom of El followed by reacylation with carboxylic acid E3 produces E4.
  • Cleavage from the solid support provides compound E5.
  • the Mitsunobu reaction of B4 to produce El is carried-out in the same manner as described in Flow Sheet B for the reaction of B4 with B5 and in Flow Sheet D for the reaction of B4 with Dl.
  • Cleavage of the acetyl group of El is accomplished by reacting El with N,N- diisopropylethylamine and hydroxylamine hydrochloride employing a suitable solvent mixture such as tetrahydrofuran and N,N- dimethylformamide.
  • the resulting thiol compound E2 is reacylated with the carboxylic acid E3 employing l-hydroxy-7-azabenzotriazole, 1,3- diisopropylcarbodiimide and N,N-diisopropylethylamine as activating
  • a solution of D-alanine (4.03 g, 45.2 mmol) in 100 mL of THF and 80 mL of water is cooled to 0°C and the pH is adjusted to 9.5 by addition of 2.5 N aqueous NaOH.
  • Neat allyl chloroformate (5.8 mL, 54 mmol) is added dropwise during about 15 min, and the pH is maintained at from about 7 to about 9 by portionwise addition of 2.5 N aqueous
  • the alloc-D-alanine product of Step A (5.85 g, 33.8 mmol) is dissolved in 70 mL of MeCN and N-hydroxysuccinimide (4.67 g, 40.6 mmol) is added thereto. The resulting solution is cooled to 0°C and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.78 g, 40.6 mmol) is added. Upon stirring for 4 hours, the reaction mixture is diluted with EtOAc and washed with water, sat. aqueous NaHCO3, sat. aqueous NH4CI and brine.
  • the resin-solution was mixed for 17 hours, at which point a Kaiser test on a small sample of the resin-solution yielded negative results.
  • the resin-solution was drained and washed with DMF (3x4 mL). These washes were saved for later recovery of the excess starting material, Compound 8.
  • To the drained-resin was added a solution of acetic anhydride (0.136 mL, 1.44 mmol) and pyridine (0.140 mL, 1.73 mmol) in 4 mL of DMF, and the drained-resin was mixed for 1 hour and again drained.
  • Resin 9 (0.20 mmol/g, 1.182 g, 0.2365 mmol) was swelled with dry N-methylpyrrolidinone (NMP) and then washed with NMP (3x5 mL) and drained.
  • NMP dry N-methylpyrrolidinone
  • acetic acid 0.140 mL, 2.45 mmol
  • N- methylmorpholine 0.65 mL, 2.41 mmol
  • Resin 10 (0.20 mmol/g, 0.551 g, 0.110 mmol) was swelled with 5 mL of dry THF under nitrogen in a solid phase reaction cartridge and then washed 4x3 mL with dry THF.
  • tris(4- chlorophenyDphosphine (0.202g, 0.552 mmol) was dissolved in 2 mL of THF, cooled, via cooling bath, to 0°C and diisopropyl azodicarboxylate (0.109 mL, 0.552 mmol) was added dropwise during 5 minutes. The cooling bath was removed and the yellow solution was stirred for 15 minutes.
  • Resin 11 (0.20 mmol/g, 0.024 g, 0.0048 mmol) was swelled with 0.5 mL of dry CH2CI2 under nitrogen and then washed 3x0.5 mL with dry CH2CI2.
  • Resin 10 was added 0.1 mL of a 0.5M solution of acetic anhydride in CH2CI2 (10 eq). This was followed after 1 minute by addition of 0.1 mL of a CH2CI2 solution containing 0.25 eq of Pd(PPh3)4, 0.5 eq of PPI13 and 5 eq of PhSiH3. The reaction was allowed to proceed at room temperature for 1 hour, mixing periodically, and some gas evolution was observed.
  • Resin 10 (0.20 mmol/g, 0.075 g, 0.015 mmol) was swelled with 1 mL of dry THF under nitrogen in a solid phase reaction cartridge and then washed 4x1 mL with dry THF and drained.
  • tris(4-chlorophenyl)phosphine (0.219g, 0.60 mmol) was dissolved in 3 mL of THF, cooled to 0°C, via cooling bath, and diisopropyl azodicarboxylate (0.118 mL, 0.60 mmol) was added dropwise during 5 minutes. The cooling bath was removed and the yellow solution was stirred for 15 minutes.
  • Resin 14 (0.075 g, 0.015 mmol) was swelled with 1.0 mL of dry CH2CI2 under nitrogen and then washed 3x0.5 mL with dry CH2CI2. The product was cleaved from the resin with 5% TFA/CH2CI2 (5x0.5 mL, 2 min each) and the combined solutions were evaporated to give the Compound 15 as an oil.
  • Resin 10 (0.20 mmol/g, 0.096 g, 0.019 mmol) was swelled with 1 mL of dry THF under nitrogen in a solid phase reaction cartridge and then washed 4x1 mL with dry THF and drained.
  • a THF solution (0.8 mL) containing 8 equivalents of formic acid and 8 equivalents of PPI13 was added to the resin followed by dropwise additon of diisopropyl azodicarboxylate (0.031 mL, 0.16 mmol, 8 equiv.) to provide a reaction mixture, which was mixed for 3.5 hours at room temperature.
  • the solution was drained and the resin was washed with THF (4x), DMF (4x), THF (4x), MeOH (4x) and CH2CI2 (6x).
  • the resin was dried briefly under a stream of nitrogen and then in ⁇ acuo.
  • Resin 10 was re-swelled with 1 mL of dry THF under nitrogen and then washed 4x1 mL with dry THF and drained.
  • a 1:1 THF- DMF solution (0.8 mL) containing 8 equivalents of N,N- diisopropylethylamine and 8 equiv. of hydroxylamine hydrochloride was added thereto and the preparation was mixed for 20 hours at room temperature.
  • the solution was drained and the resin was washed with DMF (4x), THF (4x), MeOH (4x) and CH2CI2 (6x). The resin was dried briefly under a stream of nitrogen and then in ⁇ acuo to give Resin 17.
  • Resin 17 (0.20 mmol/g, 0.024 g, 0.0048 mmol) was swelled with 0.5 mL of dry THF under nitrogen in a solid phase reaction cartridge and then washed 4x0.5 mL with dry THF and drained.
  • tris(4- chlorophenyl)phosphine (0.0.037g, 0.10 mmol) was dissolved in 0.5 mL of THF, cooled to 0°C, via cooling bath, and diisopropyl azodicarboxylate (0.0 20 mL, 0.10 mmol) was added dropwise. The cooling bath was removed and the yellow solution was stirred for 15 minutes.
  • Resin 20B (0.20 mmol g) was prepared starting from the propionic acid derivative 20A following the procedures described in Examples 1, 2, 6-10 and 14. A portion of Resin 20B (0.023 g, 0.0048 mmol) was swelled with 0.5 mL of dry THF under nitrogen in a solid phase reaction cartridge and then washed 4x0.5 mL with dry THF and drained. A 1:1 THF-DMF solution (0.35 mL) containing 14 equivalents of N,N-diisopropylethylamine and 14 equivalents of hydroxylamine hydrochloride was added and the reactants was mixed for 2 hours at room temperature.
  • N,N-diisopropylethylamine (0.019 mL. 0.11 mmol) was added to the solution.
  • a 0.40 mL portion of the solution (-9 equivalents) was added to the above drained resin and the reactants were mixed for 16 hours at room temperature.
  • the solution was drained and the resin was washed with DMF (4x), THF (4x), MeOH (4x) and CH2CI2 (6x).
  • the product was cleaved from the resin with 5% TFA/CH2CI2 (5x0.5 mL, 2 minutes each) and the combined solutions were evaporated to give an oil.
  • ⁇ IMP-1 metallo- ⁇ -lactamase lacking the N-terminal 18 hydrophobic amino acids which encode the putative periplasmic signal sequence was PCR amplified from plasmid DNA prepared from a carbapenem-resistant strain of Pseudomonas aeruginosa (CL5673). The PCR product was cloned into pET30a+ (Novegen) and expressed in E.coli BL2KDE3) after induction with 0.5 mM IPTG for 20 hours at room temperature in minimal media supplemented with casamino acids and 348 ⁇ M ZnSO 4 . Soluble IMP-1 was purified from cell extracts by SP-Sepharose (Pharmacia) ion exchange and Superdex 75 (Pharmacia) size-exclusion chromatography.
  • IC 50 of thiol derivatives was determined following a 15 minute incubation at 37°C with IMP-1 (0.75nM in 50mM MOPS, pH 7). Using initial velocity as a measure of activity, inhibition was monitored spectrophotometrically at 490nm in a Molecular Devices SPECTRAmaxTM 250 96-well plate reader employing nitrocefin as the reporter substrate at approximately K m concentration (60 ⁇ M).
  • a laboratory strain o ⁇ E.coli engineered to express IMP-1 was used to evaluate the ability of thiol derivatives to reverse metallo- ⁇ - lactamase-mediated carbapenem resistance in bacteria.
  • Native IMP-1 which included the N-terminal periplasmic signal sequence, was PCR amplified from CNA isolated from a carbapenem resistant P. aeruginosa clinical isolate, CL56673, and cloned into the pET30a vector. The basal (uninduced) level of IMP-1 expressed when pET30a-IMP-l was introduced into E.
  • coli BL2KDE3 resulted in 4-, 64- or 500-fold reduced sensitivity to impenem, meropenem or (lS,5R,6S)-l-methyl-2- ⁇ 7-[4- (aminocarbonylmethyl)-l,4-diazoniabicyclo(2.2.2)octan-l-yl]methyl- fluoren-9-on-3-yl ⁇ -6-(lR-hydroxyethyl)-carbapen-2-em-3-carboxylate chloride (a carbapenem synthesized at Merck Research Laboratories) respectively.
  • the minimum inhibitory concentration (MIC) of (lS,5R,6S)-l-methyl-2- ⁇ 7-[4-(aminocarbonylmethyl)-l,4- diazoniabicyclo(2.2.2)octan-l-yl]methyl-fluoren-9-on-3-yl ⁇ -6-(lR- hydroxyethyl)-carbapen-2-em-3-carboxylate chloride was typically increased from 0.06-0.12 ⁇ g/ml to 16-32 ⁇ g/ml by the expression of IMP-1.
  • an overnight culture of E was typically increased from 0.06-0.12 ⁇ g/ml to 16-32 ⁇ g/ml.
  • coli BL2(DE3)/pET30a-IMP-l grown 35°C in LB broth (Difco) or Mueller Hinton broth (BBL) supplemented with kanamycin (50 ⁇ M/ml), was diluted to a final concentration of ⁇ 10 5 cells/ml in Mueller Hinton broth (BBL) containing a subinhibitory concentration (0.25x MIC) of the carbapenem, (lS,5R,6S)-l-methyl-2- ⁇ 7-[4-(aminocarbonylmethyl)-l,4- diazoniabicyclo(2.2.2)octan-l-yl]methyl-fluoren-9-on-3-yl ⁇ -6-(lR- hydroxyethyl)-carbapen-2-em-3-carboxylate chloride.
  • IMP-1 inhibitor Various concentrations of IMP-1 inhibitor were added to the bacterial growth medium and their capacity to effect a four-fold or greater increase in sensitivity to the carbapenem was monitored. The readout for antibacterial activity showed no visible growth after 20 hours incubation at 35°C.
  • thiol derivatives against purified IMP-1 metallo- ⁇ -lactamase was tested and found to be active in an IC 50 range from about 0.0004 to about 750 ⁇ M.

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Abstract

Cette invention se rapporte à des composés dérivés de thiol, à des sels acceptables sur le plan pharmaceutique et à des esters biolabiles de ceux-ci, qui servent à inhiber les métallo-β-lactamases, des enzymes bactériennes qui confèrent une résistance aux antibiotiques β-lactames cliniquement pertinents, ces composés se caractérisant par la formule générale (I), où: R1 est choisi parmi alkyle droit, ramifié, insaturé ou alicyclique, éventuellement substitué par 1 à 3 groupes R¿x?; et (CH2)nAr, où Ar représente un aryle choisi dans le groupe constitué par phényle, furanyle, thiényle, pyridyle, naphtyle, biphényle, dibenzofuranyle, dibenzothiényle, fluorényle et fluorénonyle, où n est égal à 0, 1, 2 ou 3, et où Ar est éventuellement substitué par 1 à 3 groupes Rx; R?2¿ est choisi parmi hydrogène; et un groupe de formule (II), où: R3 est choisi parmi hydrogène; alkyle droit, ramifié, insaturé ou alicyclique, éventuellement substitué par 1 à 3 groupes R¿x?; (CH2)nAr, où Ar représente un aryle choisi parmi phényle, furanyle, thiényle, pyridyle, naphtyle, biphényle, dibenzofuranyle, dibenzothiényle, fluorényle et fluorénonyle, où Ar est éventuellement substitué par 1 à 3 groupes Rx et où n est égal à 0, 1, 2 ou 3; et un groupe de formule (III), où: R?4¿ est choisi parmi hydrogène; et alkyle droit ou ramifié; R5 est choisi parmi hydrogène; alkyle droit, ramifié, insaturé ou alicyclique, éventuellement substitué par 1 à 3 groupes R¿x?, où le groupe allkyle est éventuellement interrompu par X, X étant choisi parmi O, S, NH et N(COCH3); allyloxy et 9-fluorénylméthyloxy; et (CH2)nAr, où Ar est choisi parmi phényle, furanyle, thiényle, pyridyle, napthtyle, biphényle, dibenzofuranyle, dibenzothiényle, fluorényle et fluorénonyle, où n est égal à 0, 1, 2 ou 3; et où Ar est éventuellement substitué par 1 à 3 groupes Rx; et Rx est choisi parmi OR, CN, C(O)NH2, C(O)NHR, C(O)N(R)2, OC(O)NH2, OC(O)R, CHO, SO2NH2, SOR, CF3, C(O)r, COOR, F, Cl, Br, I, OCH2Ph, NHR, N(R)2, NHCOR, NHCO2t-Bu, NHCO2allyle, NH2, et R, R représentant hydrogène, alkyle C1 à C15, ou aryle. Cette invention se rapporte en outre à une composition pharmaceutique contenant ce composé, ainsi qu'à un procédé de traitement des infections bactériennes chez les animaux ou chez l'homme, cette composition pouvant être administrée en association avec un antibiotique β-lactame.
EP00941349A 1999-06-15 2000-06-12 Derives de thiol servant d'inhibiteurs des metallo-beta-lactamases Withdrawn EP1192128A4 (fr)

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JP4122049B2 (ja) 2005-09-22 2008-07-23 明治製菓株式会社 メタロ−β−ラクタマーゼ阻害剤
JP2008019233A (ja) * 2006-06-14 2008-01-31 Hitachi Chem Co Ltd 側鎖に硫黄原子を有するグラフトポリマー及びその製造方法
GB201310542D0 (en) 2013-06-13 2013-07-31 Antabio Sas Compounds
GB201317619D0 (en) 2013-10-04 2013-11-20 Uni I Oslo Compounds
GB201613946D0 (en) 2016-08-15 2016-09-28 Univ Oslo Compounds
EP3795149A4 (fr) * 2018-05-14 2022-01-05 National University Corporation Tokai National Higher Education and Research System Inhibiteur de beta-lactamase

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GB9323165D0 (en) * 1993-11-10 1994-01-05 Chiros Ltd Compounds

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DATABASE CROSSFIRE BEILSTEIN [Online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; Database accession no. 135888 XP002239862 & MONATSH. CHEM., vol. 49, 1928, page 125 *
DATABASE CROSSFIRE BEILSTEIN [Online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; Database accession no. 1721734 XP002239863 & J BIOL CHEM, vol. 75, 1927, page 344 *
DATABASE CROSSFIRE BEILSTEIN [Online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; Database accession no. 1721756 XP002239864 & J ORG CHEM , vol. 25, 1960, pages 164-1168, *
DATABASE CROSSFIRE BEILSTEIN [Online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; Database accession no. 1760765 XP002239865 & CHEM ZENTRALBL GE, vol. 102, no. I, 1931, page 3577 *
DATABASE CROSSFIRE BEILSTEIN [Online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; Database accession no. 1761137, 1768628 XP002239861 & US 2 657 136 A 27 October 1953 (1953-10-27) *
DATABASE CROSSFIRE BEILSTEIN [Online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; Database accession no. 1875071 XP002239866 & HELV CHIM ACTA, vol. 40, 1957, page 2148,2154 *
DATABASE CROSSFIRE BEILSTEIN [Online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; Database accession no. 2441533 XP002239867 & ACTA CHEM SCAND, vol. 19, 1965, pages 1490-1491, *
DATABASE CROSSFIRE BEILSTEIN [Online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; Database accession no. 5553205 XP002239869 & J ORG CHEM, vol. 51, no. 19, 1986, *
DATABASE CROSSFIRE BEILSTEIN [Online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; Database accession no. 7689555 XP002239868 & BIOORG MED CHEM LETT, vol. 6, no. 19, 1996, pages 2317-2322, *
GOTO M ET AL: "INHIBITION OF THE METALLO-BETA-LACTAMASE PRODUCED FROM SERRATIA MARCESCENS BY THIOL COMPOUNDS" BIOLOGICAL & PHARMACEUTICAL BULLETIN (OF JAPAN), PHARMACEUTICAL SOCIETY OF JAPAN, JP, vol. 20, no. 11, 1997, pages 1136-1140, XP001147705 ISSN: 0918-6158 *
GREENLEE, MARK L. ET AL: "Synthesis and SAR of thioester and thiol inhibitors of IMP-1 metallo-.beta.- lactamase" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS , vol. 9, no. 17, 6 September 1999 (1999-09-06), pages 2549-2554, XP002239910 *
HAMMOND, G. G. ET AL: "Inhibition of IMP-1 metallo-.beta.- lactamase and sensitization of IMP-1-producing bacteria by thioester derivatives" FEMS MICROBIOLOGY LETTERS , vol. 179, no. 2, 15 October 1999 (1999-10-15), pages 289-296, XP002239859 *
See also references of WO0076962A1 *

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