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WO1997048676A1 - Triphenylalkyle servant d'agents antimicrobiens - Google Patents

Triphenylalkyle servant d'agents antimicrobiens Download PDF

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Publication number
WO1997048676A1
WO1997048676A1 PCT/US1996/010501 US9610501W WO9748676A1 WO 1997048676 A1 WO1997048676 A1 WO 1997048676A1 US 9610501 W US9610501 W US 9610501W WO 9748676 A1 WO9748676 A1 WO 9748676A1
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WIPO (PCT)
Prior art keywords
naphthylene
alkyl
compound according
hydroxy
phenyl
Prior art date
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PCT/US1996/010501
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English (en)
Inventor
James P. Demers
Sigmond Johnson
Michele Ann Weidner-Wells
Ramesh M. Kanojia
Stephanie A. Fraga
Dieter Klaubert
Original Assignee
Ortho Pharmaceutical Corporation
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Publication date
Application filed by Ortho Pharmaceutical Corporation filed Critical Ortho Pharmaceutical Corporation
Priority to AU61802/96A priority Critical patent/AU6180296A/en
Priority to PCT/US1996/010501 priority patent/WO1997048676A1/fr
Publication of WO1997048676A1 publication Critical patent/WO1997048676A1/fr

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    • 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
    • C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
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    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/44—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
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    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
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    • C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C323/31—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 nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/32—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 nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
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    • 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
    • C07C323/62—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 atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
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    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
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    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
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    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
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    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
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Definitions

  • the invention relates to triphenylalkyl antibacterial compounds, pharmaceutical compositions containing the compounds, and methods for their production and use. These compounds are effective in inhibiting the action of a bacterial histidine protein kinase and are thus useful as anti-infective agents against a variety of bacterial organisms, including organisms which are resistant to other known antibiotics.
  • Prokaryotes regulate the transcription of many of their genes in response to changes in the organisms' environment J. B. Stock, A. M. Stock, and J. M. Housing, Nature, 344, 395-400 (1990)).
  • Such regulation is essential if the organism is to adapt itself to survival in a changing environment, and pathogenic bacteria rely on such regulatory systems to enable them to survive within their host's body (J. F. Miller, J. J. Mekalanos, S. Falkow, Science, 243, 1059 (1989)).
  • Chemical compounds that interfere with the regulatory mechanisms would be expected to be useful anti-infective drugs, as they would prevent bacteria from making necessary adaptive changes in their patterns of gene expression.
  • Virulence, chemotaxis, toxin production, sporulation, and reproduction are examples of the bacterial processes that are under regulatory control, and which could be inhibited by such compounds.
  • the inhibition of one or more of these processes is expected to lead to reduced virulence, a slowing or halting of bacterial growth and reproduction, and even to bacterial cell death if vital functions are interrupted.
  • Salmonella species express certain proteins, under regulatory control and in response to the presence of intestinal epithelial cells, which enable them to adhere to and invade these cells. Bacteria unable to synthesize these proteins are avirulent: they cannot cause infection in mice (B. B. Finlay, F. Heffron, S. Falkow, Science, 243, 940-943 (1989)). A similar effect would be expected if the genes coding for these proteins were intact, but remained unexpressed.
  • HPK histidine protein kinase
  • this auto-phosphorylation is followed by transfer of the phosphate to an aspartyl residue of one or more acceptor proteins (the second components of the two-component switch), which are either regulators of gene expression (by binding to control regions on DNA, or to the RNA polymerase complex) or are themselves kinases for other acceptor molecules.
  • acceptor proteins the second components of the two-component switch
  • These secondary acceptors may again be regulatory proteins, or kinases toward yet another protein. This cascade of phosphate from protein to protein eventually results in the phosphorylation of one or more regulatory proteins, which then control gene expression.
  • Mammalian cells do not, or at least are not presently known to, utilize HPK-driven phosphorelay systems for gene regulation. Thus, compounds which selectively inhibit either the autophosphorylation of the HPK protein, or the phosphotransfer step(s), or both, would not be expected to have undesirable effects on the host organism, and are promising candidates for antiinfective drugs.
  • the emergence of drug- resistant pathogenic organisms that are resistant to one or more of the currently available drugs has created a need for novel antibiotics, that act by mechanisms unrelated to those of currently available agents, and inhibitors of HPK would fill this need.
  • HPK inhibitors a potential advantage over current antibiotics, in that mutations of a single HPK enzyme are unlikely to confer drug resistance to an organism.
  • workers in this field reported a method for detecting bacterial "virulence" genes that are selectively expressed when bacteria infect a host (M. J. Mahan, J. M. Slauch, and J. J. Mekalanos, Science, 259, 686-688 (1993)).
  • the potential use of this information in the design of new antibiotics was mentioned, but actual methods of reducing expression of these genes were not described.
  • the invention comprises compounds of the general structure 1 shown below:
  • Z , Z , and 2 are independently H, halogen, C1 -C6 alkyl, C1 -C6 alkoxy, hydroxy, amino, or nitro; m is an integer from 1-5;
  • X is CH20, CH2S, CH2NR, C(0)NR, CH20C(0)CH2, or CH 2 OC(0)CH 2 CH 2 ;
  • Ar is aryl optionally substituted with one to three substituents, selected from halogen, hydroxy, Cl -C6 alkyl and Cl -C6 alkoxy;
  • W is oxygen, sulfur, or a bond;
  • n is an integer from 0-5;
  • A is: (a) NRl R2;
  • R, R , R , and R are independently H, C ⁇ -C6 lower alkyl, or aryl-
  • Ci -C-6 alkyl is hydrogen or hydroxy
  • R5 is:
  • Another aspect of the invention comprises a method of treating bacterial infections in mammals by administering to a mammal suffering from such infection a therapeutically effective amount of a compound effective in inhibiting the action of a bacterial histidine protein kinase. More particularly, the invention involves a method of treating bacterial infections by inhibiting the autophosphorylation of bacterial histidine protein kinase A or inhibiting the transfer of phosphate from phosphorylated histidine kinases to the aspartyl residue of phosphate acceptor proteins involved in regulation of bacterial gene expression, particularly the operon protein SpoOF.
  • the compounds of the present invention inhibit the autophosphorylation of bacterial histidine kinases; they also inhibit the transfer of phosphate from phosphorylated histidine kinases to the aspartyl residues of the phosphate acceptor proteins involved in regulation of bacterial gene expression.
  • the compounds of the present invention have been found to inhibit the growth of bacteria by the standard method, measurement of minimum inhibitory concentrations (MIC values).
  • MIC values minimum inhibitory concentrations
  • the compounds are useful as bacteriostatic and bactericidal agents, and as anti-infective agents in the treatment of infectious diseases. They may also have utility in increasing the sensitivity of bacteria to conventional antibiotics.
  • Preferred embodiments of the invention are the compounds where X is CH20 or CH2S, Ar is phenylene, and where A carries a charge at physiological pH. More preferred are the embodiments where A is amino, guanidino, or comprises a quaternary nitrogen.
  • Preferred groups for X are CH20 and CH2S.
  • Preferred groups for Ar are 1 ,2-phenylene, 1 ,3-phenylene, 1 ,4- phenyiene, 1 ,6-naphthylene, 6,1 -naphthylene, 1 ,5-naphthylene, 2,5- naphthylene, 5,2-naphthylene, or 2,6-naphthylene.
  • X is selected from CH 2 0, and CH 2 S;
  • Ar is selected from 1 ,2-phenylene, 1 ,3-phenylene, or 1 ,4- phenylene; Ar may optionally be further substituted with one to three substituents selected from halogen, C-
  • A is selected from NR 1 R , guanidino, and N + R 1 R 2 R 3 B " wherein R 1 , R 2 , and R ⁇ are independently selected from H, Ci -
  • the compounds of the present invention are prepared in accordance with the methods described below and illustrated in the following Schemes.
  • the key step in the synthetic sequence, when X is CH2O or CH2S, is shown in Scheme 1 , and is usually a Mitsunobu reaction between the appropriately substituted triarylalkanol (2, L OH) and the appropriately substituted aryl compound 3, wherein B is is the moiety A, a protected A moiety or a precursor for A as described below and in Scheme 2.
  • An alternative to the Mitsunobu method is the reaction of 2, wherein L is halide, sulfonate, or another appropriate leaving group, with the aryl compound 3 in the presence of a suitable base, such as sodium hydride, sodium hydroxide, or potassium carbonate.
  • the Mitsunobu reaction may be one of several variants known in the art; the selection of the appropriate phosphine, azodicarbonyl reagent, and solvent will be at the discretion of the practitioner, based on published precedents and on empirical results with the particular combination of substrates to be coupled. Guidance can be found in the review article by D. L. Hughes, in Organic Reactions, 42, 335-656 (1992), and in the detailed examples below. In most cases triphenylphosphine (Ph3P) and diethylazodicarboxylate (DEAD), or alternatively tributylphosphine (BU3P) and (azodicarbonyl)dipiperidine (ADDP), will suffice. Alternatively, displacement of a halide or other leaving group by the appropriate phenoxide or thiophenoxide can be used to generate the CH 2 O or CH 2 S linkers.
  • the group A will in most cases have to be in a protected form B, or else (for instance when A is a heterocyle) B will be a precursor functional group convertible into the desired heterocycle or other group A.
  • B Once the linker X has been established, the group B is converted, if necessary, into the desired group A, as shown in Scheme 2.
  • Suitable protecting groups for guanidines and amines include, but are not limited to, trifluoroacetyl, t- butoxycarbonyl (Boc), and benzyloxycarbonyl.
  • Ar is 1 ,4- phenylene is shown in Scheme 2 for purposes of illustration only; the chemical processes presented in the scheme are in general applicable to all definitions of Ar.
  • Suitable protecting groups for carboxylic acids include, but are not limited to, lower alkyl esters or benzyl esters; suitable precursor groups include olefin, nitrile, or oxazolidine.
  • the nitrile may be hydrolyzed to a carboxylic acid, reduced to provide an amine, or converted to a tetrazole; where B « an olefin, it may be oxidized with ozone or other reagents to provide an aldehyde or acid.
  • the compounds may be converted into those of structure 1 where A is one of the heterocycles described.
  • A is a piperidine or piperazine, the terminal nitrogen is protected during the Mitsunobu reaction in the manner described above for amines.
  • the carboxylic acid partner of the coupling reaction is activated with one of a variety of reagents, such as carbonyldiimidazole (CDI), thionyl chloride, oxalyl chloride, or a carbodiimide reagent such as dicyclohexylcarbodiimide (DCC).
  • CDI carbonyldiimidazole
  • thionyl chloride thionyl chloride
  • oxalyl chloride oxalyl chloride
  • DCC dicyclohexylcarbodiimide
  • the coupling reactions may be chosen from, but are not limited to, the ones illustrated in the scheme and described further below. There are a wide variety of coupling methods known to one skilled in the art, and the majority of them would be applicable to the reactions in Schemes 3 and 4.
  • the starting materials for the Mitsunobu and acylation coupling reactions of Schemes 3 and 4 are, in general, known classes of compounds, and are prepared by routine methods, illustrated in Schemes 5 and 6.
  • the triarylalkanoic acid and triarymethane starting materials are in some cases commercially available, others can be prepared by various published methods (J. W. Wilt, J. A. Lundquist, J. Org. Chem., 29, 921 (1964); W. H. Starnes Jr., J. Org. Chem., S3, 2767 (1968).
  • the conversion of the acids to triarylalkanols by borane reduction is a known synthesis (M. Said et a/., Biochem. Biophys. Res.
  • triarylalkanol may also be prepared from the corresponding triarylmethanes as shown (C. G.
  • the various groups Z are compatible with one or more of these synthetic approaches.
  • the triarylalkanoic acid can be prepared and then nitrated, and the resulting isomers separated by chromatography.
  • the nitro groups can be reduced to amino, and then via diazotization to halogen, hydroxy, or alkoxy groups.
  • 4-mercaptobenzaldehyde may be coupled via the Mitsunobu reaction to the desired triarylalkanol, and the aldehyde then converted to the desired group (CH2) n -A or (CH2) n -B by the methods discussed below.
  • n is 0 and A is CHO
  • a suitable precursor group is nitro.
  • one would submit 4-nitrophenol to the Mitsunobu reaction of Scheme 1 , generating an intermediate where n 0 and B is a nitro group.
  • Reduction, diazotization and reaction with a xanthate the Leuckart thiophenol synthesis, see D. S. Tarbel, J. Amer. Chem. Soc, 74, 48 (1952)
  • alkylation with an alkylating agent such as Br(CH 2 ) n A or Br(CH 2 ) n B then provides access to the desired material.
  • stereochemically pure isomeric forms may be obtained by the application of art known principles. Diastereoisomers may be separated by physical separation methods such as fractional crystallization and chromatographic techniques, and enantiomers may be separated from each other by the selective crystallization of the diasteromeric salts with optically active acids or bases or by chiral chromatography. Pure stereoisomers may also be prepared synthetically from appropriate stereochemically pure starting materials, or by using stereospecific reactions.
  • Suitable pharmaceutical salts are those of inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, succinic acid, oxalic acid, malic acid and the like.
  • Suitable salts are also those of inorganic or organic bases, such as KOH, NaOH, Ca(OH)2, AI(OH)3, piperidine, morpholine, ethylamine, triethylamine and the like.
  • hydrated forms of the compounds which contain various amounts of water, for instance, the hydrate, hemihydrate and sesquihydrate forms.
  • Bacteria are capable of rapidly responding and adapting to such diverse stimuli as changes in nutrients, osmolarity, temperature, light, or host environment. These responses may be transient, such as those required for changes in motility or for entry into a host cell. Alternatively, the responses may require major shifts in gene expression and cell morphology, such as those required for sporulation, or for survival within a macrophage.
  • the mechanism by which bacteria are able to sense cues from the physical environment (or from within the cytoplasm) and process these signals into appropriate responses often involves the so-called "two-component" systems.
  • the treatment method of the present invention is based on the inhibition of this "two-component switch" system.
  • All bacteria use this mechanism to control various adaptive/virulence factors to facilitate establishment of a bacterial population in the environment (for example, a bacterial infection in a host).
  • the system invariably consists of a sensor which either activates a kinase or is a part of the kinase, and which upon stimulation, autophosphorylates.
  • This phosphorylated species is a highly active phosphodonor which immediately transfers its phosphate to a "regulatory" component, which in turn initiates the biological response such as transcription or further phosphotransfer in a cascade which eventually ends in regulation of bacterial gene expression.
  • each of the kinases and response regulators has a unique sequence (in fact, even functionally identical proteins have slightly different sequences in different species) they share a homologous biochemical mechanism and they share significant homology in the active site.
  • the present invention provides compounds which exhibit antibiotic activity by inhibiting the autophosphorylation of bacterial histidine kinases. They also inhibit the transfer of phosphate from phosphorylated histidine kinases to the aspartyl residues of the phosphate acceptor proteins involved in regulation of bacterial gene expression.
  • This invention further provides a method of treating bacterial infections, or enhancing the activity of other antibacterial agents, in warm-blooded animals, which comprises administering to the animals a compound of the invention alone or in admixture with a diluent or in the form of a medicament according to the invention.
  • the compounds When the compounds are employed for the above utility, they may be combined with one or more pharmaceutically acceptable carriers, e.g., solvents, diluents, and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing for example, from about 0.5% to 5% of suspending agent, syrups containing, for example, from about 10% to 50% of sugar, and elixirs containing, for example, from about 20% to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.5% to 5% suspending agent in an isotonic medium.
  • These pharmaceutical preparations may contain, for example, from about 0.5% up to about 90% of the active ingredient in combination with the carrier, more usually between 5% and 60% by weight.
  • compositions for topical application may take the form of liquids, creams or gels, containing a therapeutically effective concentration of a compound of the invention admixed with a dermatologically acceptable carrier.
  • any of the usual pharmaceutical media may be employed.
  • Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired.
  • Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
  • compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
  • active compounds may also be administered parenterally or intraperitoneally.
  • Solutions or suspensions of these active compounds as a free base or pharmacological acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropyl- cellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.1 mg/kg to about 400 mg/kg of animal body weight, preferably given in divided doses two to four times a day, or in sustained release form. For most large mammals the total daily dosage is from about 0.07 g to 7.0 g, preferably from about 100 mg to 1000 mg Dosage forms suitable for internal use comprise from about 100 mg to 500 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • compositions and medicaments are carried out by any method known in the art, for example, by mixing the active ingredients(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then forming the composition into the medicament (e.g. tablets).
  • a pharmaceutical composition e.g. a granulate
  • the compounds of the present invention have antibacterial activity as determined by the following tests. First, the compounds were tested for their activity in inhibiting the autophosphorylation of Kinase A and the transphosphorylation of SpoOF, two proteins involved in one of the above described signal transduction systems controlling gene expression in bacteria. Representative compounds were then tested for antibacterial activity against selected organisms by the standard MIC method. The results are set forth below.
  • Table 1 lists examples of compounds of the invention, along with their IC50 values in the HPK in vitro assay described below, and MIC value ranges for the selected microorganisms identified below. These examples are merely illustrative of the invention, and are not intended to limit the scope of the claims in any way.
  • the first locant of each Ar group is the carbon bearing the substituent -X-; the second locant refers to the carbon bearing the substituent -W-.
  • the SpoOF response regulator is the primary substrate for phosphorylation by the protein kinase, Kin A, involved in the sporulation process in bacteria. See D. Burbulys, K.A. Trach, J.A. Hoch, Cell, 64, 545-552 (1991 ). SpoOF and KinA were prepared from recombinant E. coli overexpressing the proteins (J. Cavanagh et al, Amino Acids, 6, 131 -140 (1994) and references therein).
  • 5X Loading Dye 0.5M TRIS-HCI-pH 6.8 (7.5 mL), 10% SDS (2 mL) 0.1% bromophenol blue (0.5 mL), 100% glycerol (3 mL) and 12.5 M 2- mercaptoethanol (0.3 mL)
  • the reaction mixture was prepared from 8X Salts (87 ⁇ L), 1M TRIS, pH 8 (118 ⁇ L), 50% glycerol (63 ⁇ L), SpoOF (14.1 ⁇ L) and KinA (7.0 ⁇ L).
  • Microcentrifuge tubes were charged with the reaction mixture (18.5 ⁇ L) and a 1.0 mM solution of the test compound in 5% DMSO (18.5 ⁇ L), and incubated for 1 5 min on ice. 100 mM ATP solution (3.0 ⁇ l, containing 625 ⁇ Ci [3 2 P]ATP) was added, and the mixture left for 10 minutes at room temperature.
  • the reaction was quenched with 5X loading dye (10 ⁇ L per tube) and the samples were loaded on a prepared 5% Stacking Gel, or stored on dry ice until ready for use.
  • the prepared wells were filled with SDS Running Buffer, samples were loaded into the wells, and 80 volts were applied to the gel until the dye front reached the bottom of the stacking gel. The voltage was then increased to 250 volts until electrophoresis was complete. Radioactive bands in the gel corresponding to phosphorylated KinA and SpoOF were imaged and quantitated with a phosphoimager.
  • IC50 was calculated by running the assay with a range of inhibitor concentrations from 1 to 500 ⁇ M- After electrophoresis of the reaction mixtures, percent inhibition was determined by measuring the concentration of radioactive phosphorus with a phosphoimager and calculating the values using a software program (BioRad Molecular Analyst).
  • test organisms are prepared by adjusting the turbidity of actively growing broth cultures so that the final concentration of test organism after it is added to the wells is approximately 5 x 10* CFUs/well).
  • the trays are incubated at 35 *c for 16-20 hours and then read.
  • the MIC is the lowest concentration of test compound that completely inhibits growth of the test organism.
  • the amount of growth in the wells containing the test compound is compared with the amount of growth in the growth-control wells (no test compound) used in each tray.
  • Tyramine (5.58 g, 40.7 mmol) was dissolved in 50 mL of THF at 5°C.
  • Di- t-butyl dicarbonate (8.90 g, 40.8 mmol) in 25 mL of THF was added dropwise. The reaction was allowed to warm to ambient temperature overnight, then diluted with water, extracted three times with ethyl acetate, and the organic extracts dried over MgS0 4 and concentrated in vacuo. The crude brown solid, 8.93 g (93%) was used as is.
  • 3-hydroxybenzylamine prepared as above (1.23 g) and N,N'- bis( tert-butoxycarbonyl)-S-methylisothiourea (2.90 g) were combined in 100 mL DMF, and silver acetate (2.9 g) was added in three portions over 30 min with mechanical stirring. The mixture became thick and a yellow color developed. After 1 hr, the mixture was diluted with 300 mL water, and the solids collected by filtration, re-suspended in dichloromethane, filtered to remove silver salts, and chromatographed on silica gel with 10% ethyl acetate in dichloromethane. Recrystallization provided the title compound as a white solid, mp 169- 172 ⁇ C (dec) (2.2 g, 61%).
  • Solvent was removed in vacuo at 1 OOX, and the residue was chromatographed on silica using a gradient of methanol in dichloromethane containing 0.5 % triethylamine. The desired product eluted with 10 % methanol, and was obtained as an oil (0.26 g, 29%).
  • the hydrochloride salt was prepared by passing gaseous HCl into an isopropanol soution. Recrystallization from isopropanol-ether gave 0.19 g tan powder, softening at 95-1 OOX and melting at 135-138X.
  • N-(t-butoxycarbonyl)-4- hydroxybenzylamine was converted into the hydrochloride salt of the title compound, mp 215-217X.
  • Example 6 2-f4-(3.3.3-tris(4-chlorophenvnpropoxv , >phenvnethvlamine. 3,3,3-Tr»s(4-chlorophenyl)propionic acid is reduced to the triarylpropanol with borane as described above. This material is converted by the method of example 3 into the title compound, obtained as the hydrochloride salt, mp 132-135X.
  • N-(t-butoxycarbonyl)-2-(3- hydroxyphenyOethylamine was converted to the title compound, and was then converted to the oxalate salt by combining with oxalic acid in ether. Recrystallization from ethyl acetate-ether provided the title compound as the 0.5 oxalate 0.5 hydrate, a white solid, mp 166-168X.
  • Example 9 N-(2-(4-(3.3.3-tris(4-chloroDhenynpropoxy)- phenyOethyQguanidi ⁇ e
  • 3,3,3-Tris(4- chlorophenyOpropanol is converted into the title compound, obtained as the bicarbonate salt, a white solid, mp 146-150X.
  • 6-(3,3,3-Triphenylpropoxy)-2-naphthonitrile prepared in example 20, was added to KOH (1 g) dissolved in ethanol (15 mL). The solution was heated at reflux under a nitrogen atmosphere for two days. After cooling, the ethanol was evaporated and the residue diluted with water. This was acidified with dilute HCl and extracted with dichloromethane. The organic layers were washed with water, dried (MgS04), filtered and evaporated, providing the title compound as a colorless solid, mp»243-
  • Example 19 4.5-Dihvdro-2-J2-r4-(3.3.3-triphenylprorjoxyV phenyllethyliQxazole.
  • ethanolamine was converted to
  • Example 21 4- ( 3.3.3-Triphenvlpropoxv>benzoic acid.
  • Example 24 3.3.3-Triphenvlpropvl 3-(4-hvdroxvphenvnpropionate.
  • 3-(4-hydroxyphenyl)propionic acid was converted to the title compound.
  • 1 H NMR ⁇ 7.15-7.30 (m, 15H), 7.05 (d, J 8.5 Hz, 2H), 6.75 (d, J-8.5 Hz, 2H), 4.64 (s, IH, exchangeable), 3.87 (t, J-7.9 Hz, 2H), 2.81-2.91 (m, 4H), 2.51 (t, J-7.8 Hz, 2H).
  • MS 437 (MH+) Anal, cated. for C 3 oH 2 8 ⁇ 3: C, 82.54; H, 6.46. Found: C, 82.09; H, 6.45.
  • Example 25 trans N-(2-Hvdroxvethvl)-4-(3.3.3-triphenvlpropoxyl- cinnamide.
  • methyl 4-(3,3,3- triphenylpropoxy)cinnamate was prepared. This ester (500 mg; 1.1 1 mmol) and ethanoiamine (1.5 mL) were heated in an oil bath at 10O'C for 3.5 h under a nitrogen atmosphere. After cooling, the reaction was poured into water (100 mL) and extracted with EtOAc (3 x 75 mL). The organic layers were washed with water (100 mL), dried (MgS0 4 ), filtered and evaporated to give the title compound as a hemihydrate, a
  • Example 27 5- ⁇ 2-f4-(3.3.3-TriphenylprQPQ ⁇ y)phenyl1ethyll-l H- tetrazole.
  • Example 28 N-Benzvl-N.N-dimethvl-r4-(3.3.3-triphenvlpropoxy>- phenvllmethvl ammonium chloride.
  • the material was dissolved in ethanol (0.5 mL), and the solution diluted with aqueous IN HCl (10 mL). The precipitate was collected and dried for 2 hr at 70° under high vacuum, to provide the title compound as a hydrate: shiny white flakes, losing water and/or chloromethane at 140X, and melting at 193-196X.
  • Example 32 5-r4-f3.3.3-Triphenvlpropoxv)phenvl1methvl-1 H-tetrazole.
  • Example 34 2-r3-(3,3,3-TriphenylpropQxy)phenynacetic acid.
  • Example 35 3-r3-(3.3.3-Triphenvlprorjoxvtohenvnpropionic acid.
  • methyl 3-(3- hydroxyphenyl)propionate was converted to the title compound, an amorphous solid, in 90% yield.
  • 1 H NMR (CDCI 3 ) ⁇ 7.09-7.35 (m, 16H), 6.74 (d, J-7.0 Hz, IH), 6.50-6.55 (m, 2H), 3.73 (t, J-7.6 Hz, 2H), 3.13 (t, J-7.6 Hz, 2H), 2.88 (t, J-7.6 Hz, 2H), 2.63 (t, J-7.6 Hz, 2H).
  • Example 36 2-(3.3.3-Triphenvlpropoxvtohenvlacetic acid.
  • methyl 2 -hydroxy phe nylacet ate was converted into the title compound.
  • 1 H NMR (CDCI3) ⁇ 7.11-7.32 (m, 17H), 6.84 (t, J-7.4 Hz, IH), 6.50 (d, J-8.1 Hz, 1H), 3.74 (t, J-7.6 Hz, 2H), 3.62 (s, 2H), 3.11 (t, J-7.6 Hz, 2H).
  • MS 423 (MH+). Anal, calcd. for C 29 H 26 O3*0.4H 2 O: C, 81.05; H, 6.29. Found: C, 81.08; H, 6.28.
  • Example 38 3-f2-f3.3.3-Triphenvlpropoxv ⁇ phenynpropionic acid.
  • methyl 3-(2- hydroxyphenyOpropionate was converted to the title compound.
  • White solid mp-118-120 ' C (i-PrOH).
  • 1 H NMR ⁇ 7.11-7.35 (m, 16H), 7.06 (t, J-7.8 Hz, IH), 6.82 (t, J-7.0 Hz, IH), 6.48 (d, J-8.0 Hz, IH), 3.75 (t, J-7.7 Hz, 2H), 3.15 (t, J-7.7 Hz, 2H), 2.95 (t, J-7.7 Hz, 2H), 2.68 (t, J-7.7 Hz, 2H).
  • Example 39 5-r4-(3.3.3-Triphenvlprorj ⁇ xv ⁇ phenyll-1H-tetrazole.
  • 4-hydroxybenzonitrile was converted into the title compound.
  • White solid, mp 232-233"C
  • the intermediate hydroxy ester was prepared by the method stated in example 37. To the hydroxy ester (225 mg; 0.497 mmol) in benzene (3 mL), was added thionyl choride (48 ⁇ I; 0.66 mmol) and pyridine (48 ⁇ ; 0.59 mmol) under a nitrogen atmosphere. After stirring overnight at room temperature, the benzene was evaporated. The residue was dissolved in EtOAc (75 mL) and washed with water (2 x 30 mL), dried (MgS0 4 ), filtered and evaporated. Chromatography on silica gel with 10% EtOAc/hexanes afforded chloroester as a viscous oil (210 mg; 90% yield).
  • Example 42 2-Hvdroxv-6-(3.3.3-triphenvlpropox ⁇ toenzoic acid.
  • methyl 2,6-dihydroxybenzoate was converted into the methyl ester of the title compound, isolated by chromatography on silica gel with a gradient of dichloromethane in hexane. This was saponified to give the title compound, isolated as a hydrate, a white solid, mp 167-168'C after recrystallization from ether-hexanes.
  • Example 44 3-f3.3.3-triphenvlpropoxvlphenoxvacette acid.
  • Example 47 4-r2-f3.3.3-triphenvlpropoxv>phenoxv1butvric acid.
  • ethyl 4-bromobutyrate was converted to the title compound, a white solid, mp 107-108 * C, in 83% yield.
  • IH NMR (CDCI3) ⁇ 7.16-7.34 (m, 15H), 6.78-6.86 (m, 3H), 6.57 (d, J-7.1 Hz, 1H), 4.06 (t, J-6.1 Hz ,2H), 3.76 (t, J-7.9 Hz, 2H), 3.18 (t, J-7.9 Hz, 2H), 2.63 (t, J-7.1 Hz, 2H), 2.05-2.17 (m, 2H).
  • MS 467 (MH+) 271 , 243.
  • Example 48 4-(3.3.3-triphenylpropoxv * )phenoxvacetic acid.
  • 4-(3,3,3-Triphenylpropoxy)benzaldehyde (2.16 g, 5.5 mmol), and mCPBA (2.85g, 8.25 mmol) in methylene chloride (60 mL) were heated at reflux under a nitrogen atmosphere for 4 h. After cooling, the volatiles were evaporated and the residue dissolved in ether (250 mL). This was washed with saturated NaHC.03 (2 x 150 mL), brine (150 mL), dried (MgS0 4 ), filtered and evaporated to afford the crude formate.
  • Fvample 49 4-r4-(3.3.3-triphenvlproPQXv)phenoxvlbutvric acid.

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Abstract

Composés antibactériens de triphénylalkyle définis par la formule générale (1), compositions pharmaceutiques contenant ces composés et méthodes pour les produire et les utiliser. Ces composés agissent en inhibant l'action d'une histidine protéine kinase bactérienne et sont donc utiles en tant qu'agents anti-infectieux contre des organismes bactériens variés, y compris contre des organismes résistants à d'autres antibiotiques connus.
PCT/US1996/010501 1996-06-18 1996-06-18 Triphenylalkyle servant d'agents antimicrobiens WO1997048676A1 (fr)

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AU61802/96A AU6180296A (en) 1996-06-18 1996-06-18 Triphenylalkyl antimicrobial agents
PCT/US1996/010501 WO1997048676A1 (fr) 1996-06-18 1996-06-18 Triphenylalkyle servant d'agents antimicrobiens

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US8809372B2 (en) 2011-09-30 2014-08-19 Asana Biosciences, Llc Pyridine derivatives
US9199975B2 (en) 2011-09-30 2015-12-01 Asana Biosciences, Llc Biaryl imidazole derivatives for regulating CYP17

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8809372B2 (en) 2011-09-30 2014-08-19 Asana Biosciences, Llc Pyridine derivatives
US9199975B2 (en) 2011-09-30 2015-12-01 Asana Biosciences, Llc Biaryl imidazole derivatives for regulating CYP17
US9266873B2 (en) 2011-09-30 2016-02-23 Asana Biosciences, Llc Pyridine derivatives
US9371316B2 (en) 2011-09-30 2016-06-21 Asana Biosciences, Llc Pyridine derivatives
US9533981B2 (en) 2011-09-30 2017-01-03 Asana Biosciences, Llc Pyridine derivatives

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