[go: up one dir, main page]

WO1997048675A1 - Agents antimicrobiens cyclohexenyl et cyclohexyl 2-disubstitues - Google Patents

Agents antimicrobiens cyclohexenyl et cyclohexyl 2-disubstitues Download PDF

Info

Publication number
WO1997048675A1
WO1997048675A1 PCT/US1996/010357 US9610357W WO9748675A1 WO 1997048675 A1 WO1997048675 A1 WO 1997048675A1 US 9610357 W US9610357 W US 9610357W WO 9748675 A1 WO9748675 A1 WO 9748675A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
formula
moiety
amino
Prior art date
Application number
PCT/US1996/010357
Other languages
English (en)
Inventor
Robert H. Chen
Maud Urbanski
Min Xiang
John F. Barrett
Original Assignee
Ortho Pharmaceutical Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ortho Pharmaceutical Corporation filed Critical Ortho Pharmaceutical Corporation
Priority to AU62801/96A priority Critical patent/AU6280196A/en
Priority to PCT/US1996/010357 priority patent/WO1997048675A1/fr
Publication of WO1997048675A1 publication Critical patent/WO1997048675A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/49—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having at least two amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • 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
    • C07C217/60—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • 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
    • C07C217/62—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 at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—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
    • C07C279/08—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 singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • This invention relates to certain new cyclohexenyl and cyclohexyl compounds, to processes for their production, and to their use as antimicrobial agents.
  • 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 processs 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.
  • All bacteria have two-component regulatory systems that have essentially the same type of "switch” composed of a sensor protein (a histidine protein kinase), paired with a regulatory protein (an aspartate-rich carboxylate pocket). These switches have the net effect of transmitting information from the environment to the cell nucleus, where the information is responded to by the switching on or off of transcription of relevant genes.
  • the first step of this phosphorelay scheme relies on numerous histidine protein kinase (HPK) enzymes. Each of these HPK enzymes is a sens ⁇ or molecule, and responds to stimulation by a specific environmental signal by transferring phosphate from ATP to a histidine residue of the HPK protein.
  • 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.
  • these proteins have been shown to control most adaptive responses of bacteria in response to stress, and are directly responsible for the ability of the bacteria to survive in the human host by expressing virulence factors encoded downstream from these regulatory "switches” (and therefore under the control of the "switches”). Inhibition of these regulatory "switches” would prevent the bacteria from growing or surviving in the host.
  • the compounds of the present invention are active in inhibiting histidine protein kinase, one of the components of this regulatory "switch", and are thus effective in inhibiting bacterial growth.
  • the invention relates to compounds of the formula I:
  • Ri is independently selected from branched or unbranched (Ci - C6)alkyl, (Ci -C ⁇ ) hydroxyalkyi, and a moiety of the formula:
  • R ⁇ wherein: p is an integer from 0-6; and R3 , R4 and R5 are independently selected from hydrogen, halo, (C-
  • n is an integer from 1-6;
  • q is an integer from 0-2;
  • X is selected from NH, 0 and S;
  • R2 is selected from phenyl and a heterocyclic moiety wherein the heterocyclic moiety is a monocyclic heterocyclic group having 5 or 6 ring atoms and 1-4 nitrogen, oxygen, or sulfur atoms and is saturated or unsaturated, and wherein the phenyl or heterocyclic moiety is substituted with amino, moieties of the formula: carboxy, carboxy(C ⁇ -C6)alkyl, alkyl(C ⁇ -C6)carboxy, or a moiety of the formula:
  • RQ is selected from hydrogen and (C-
  • Ry is selected from hydrogen, (C1 -C6 ) alkyl, (C3-C6) cycloalkyl, (C1 -C6) hydroxyalkyi, (C ⁇ -C6)acyl, a moiety of the formula:
  • m is an integer from 1-4; and Re is selected from amino, amino(C ⁇ -C6)alkyl, amino((C ⁇ -C6)alkyl)2, an aryl group and a heterocyclic group wherein the aryl group is a monocyclic or bicyclic aromatic hydrocarbon group having from 6 to 10 carbon atoms and the heterocyclic group is a monocyclic or bicyclic group of 4-10 ring atoms wherein the heteroatom or heteratoms are selected from 1-4 oxygen, nitrogen or sulfur atoms and each ring of the heterocycle is composed of 4-6 atoms and is saturated or unsaturated; and the pharmaceutically acceptable salts thereof.
  • Ri is selected from branched or unbranched (Ci - Ce) alkyl, (Ci C ⁇ ) hydroxyalkyi, and a moiety of the formula:
  • p is an integer from 0-6;
  • R3, R4 and R5 are independently selected from hydrogen, halo, (Ci - C4) alkyl, and (Ci - C4) alkoxy;
  • n is an integer from 1-3;
  • X is NH, O or S:
  • R2 is selected from phenyl, pyrimidine, and pyrazole and R2 is substituted with amino, moieties of the formula:
  • substituents selected from oxo, halo, trifluoromethyl, hydroxy, -(Ci -C ⁇ ) alkyl and (Ci -C ⁇ ) alkoxy,
  • Re is selected from hydrogen and (C ⁇ -C6)alkyl; and Ry is selected from hydrogen, (Ci - CQ) alkyl, (C4-C6) cycloalkyl, (C1 -C6) hydroxyalkyi, a moiety of the formula :
  • n is an integer from 1-4;
  • R8 is selected from amino, amino(C-
  • R1 is benzyl optionally substituted with one to three substituents independently selected from halo, (C-
  • n is the integer 2;
  • X is O or NH2
  • R2 is phenyl substituted with amino or a moiety selected from the formula:
  • Re is selected from hydrogen and (C ⁇ -C6)alkyl and Ry is selected from hydrogen, (C ⁇ -C6)alkyl, (C4-C6)cycloalkyl, (C-J-C6) hydroxyalkyi and a moiety selected from those of the formula: wherein m is an integer from 1 -2 and Rs is selected from amino, amino(C-
  • dimers of the compounds of Formula I formed by the condensation of two molecules having an aminoalkyl substituent on the R2 moiety as illustrated by the compounds having the structure:
  • the 2-disubstituted cyclohexenyl and cyclohexyl compounds of the present invention are inhibitors of histidine protein kinase enzyme and as such have utility as antibacterial agents in treating bacterial infections in warm-blooded animals.
  • the compounds of the present invention may generally be prepared by reacting a substituted cyclohexenyl compound of formula III with a substituted hydroxy, amino or thiol containing compound of formula IV as follows:
  • W represents an appropriate reactive leaving group such as, for example, halo; such as chloro, bromo or iodo or a sulfonyloxy group, such as methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, 4-methylbenzenesulfonyloxy and the like leaving groups.
  • X' is hydroxy, a primary or secondary amine. or a thiol group, depending on the nature of the moiety X in the final compound.
  • R2' may be any of the moieties of R2 or, as shown in the following Scheme 2, particularly in the case where R2 is a substituted phenyl or substituted heterocyclic moiety, R2 may be an intermediate such as a (hydroxyalkyi) phenyl moiety. 9 ⁇ which may be further reacted with, for example, a secondary amine, to yield the final compounds having further substituents, like an (alkylamino) compound H, on the phenyl or heterocyclic moiety of R2.
  • the reaction can be conveniently carried out by mixing the reactants in an inert solvent such as hexane, diethyl ether, toluene, tetrahydrofuran and the like under appropriate temperatures from room temperature or below up to the boiling point of the solvent used.
  • an inert solvent such as hexane, diethyl ether, toluene, tetrahydrofuran and the like under appropriate temperatures from room temperature or below up to the boiling point of the solvent used.
  • the products are isolated by filtration or by evaporation of the solvent and they may be purified by recrystallization, absorption chromatography or distillation under reduced pressure.
  • the substituted cyclohexenyl starting material of Formula II may be prepared in accordance with Scheme I in which the 3-ethoxy-2- cyclohexanone compound of formula 1 is reacted with the Grignard reagent or an alkyllithium compound derived from the alkyl, protected hydroxyalkyi or phenyl moiety Ri , to yield the substituted 2-cyclohexanone compound 2.
  • the reaction may conveniently be conducted in an appopriate solvent , such as, for example ether or tetrahydrofuran. Elevated temperatures may be appropriate to enhance the reaction rate.
  • This compound is then reduced with a reducing agent such as a sodium borohydride, lithium aluminum hydride or the like in suitable solvents such as alcohols , THF or ether to yield the hydroxy cyclohexenyl compound 2-
  • a reducing agent such as sodium borohydride, lithium aluminum hydride or the like in suitable solvents such as alcohols , THF or ether
  • suitable solvents such as alcohols , THF or ether
  • the hydroxy cyclohexenyl intermediate 2 is then converted to the alkylhydroxy cyclohexenyl compound fi by reacting 3. with either (a) sodium hydride/ phenylvinylsulfoxide or (b) triethyl orthoester followed by reduction of the resulting intermediate 2a with a reducing agent such as sodium borohydride or lithium aluminum hydride or the like, to yield the hydroxyalkylcyclohexenyl intermediate £.
  • the ether linked compounds where X is oxygen are conveniently prepared by reacting the substituted hydroxyalkyi cyclohexenyl intermediate fi with a reagent capable of converting the alcohol function into a reactive leaving group W, for example halo or methanesulfonyl chloride and the like.
  • a reagent capable of converting the alcohol function into a reactive leaving group W for example halo or methanesulfonyl chloride and the like.
  • the resulting compound Z is then reacted with the appropriate phenol 8_; such as 4-hydroxy phenethyl alcohol to yield the cyclohexenyloxy compound 9_.
  • the reaction is generally carried out in the presence of a base, such as, potassium carbonate, potassium hydroxide, sodium hydroxide, and the like at temperatures of room temperature to reflux.
  • the methanesulfonyl compound Z may be reacted with the (hydroxyalkyi) phenol compound SL to yield the cyclohexenyl phenoxy compound 21.
  • This compound may be further reacted with methanesulfonyl chloride in the presence of triethylamine to form the methanesulfonat ⁇ intermediate 1Q, which can be reacted with ammonia or a primary or secondary amine to obtain the amino compound H.
  • the amino compound H can be obtained directly by reacting the cyclohexenyl methanesulfonyl intermediate Z with an alkylaminophenol compound 14 or l ⁇ under basic conditions, such as in the presence of potassium carbonate, potassium hydroxide or sodium hydroxide.
  • the guanidino compound 12 may be prepared by reacting the amino derivative 12 with 3,5-dimethylpyrazole-1 -carboxamidine nitrate in N.N-dimethyl formamide at room temperature to 100°C.
  • the intermediate j_9_ is converted to the methanesulfonyl compound 20. by hydrolysis with an aqueous base such as sodium hydroxide at temperatures of room temperature to 80°C followed by decarboxylation at about 180°C.
  • the mono acid is reduced with lithium aluminum hydride or the like and then reacted with methanesulfonyl chloride in triethyl amine.
  • JJ3. or 2Q are converted to the final compounds by the procedures of Scheme 2.
  • Those compounds wherein X is sulfur can be prepared in accordance with Scheme 4 by reacting the cyclohexenyl methanesulfonyl intermediate Z with the appropriate thiol reagent. So, for example, the thiol compound 2Z can be prepared from reaction of the thiol derivative 20. with the cyclohexenyl intermediate 1_. Scheme 4
  • the saturated cyclohexyl compounds of Formula I may be prepared in accordance with Scheme 5 by hydrogenation of the cyclohexenyl compound using conventional catalytic hydrogenation techniques, such as, for example, with hydrogen under pressure using 10% palladium on carbon in a suitable solvent such as triflouroacetic acid.
  • the compounds of the invention may have one or more asymmetrical carbon atoms in their structure. It is intended that the present invention include within its scope the stereochemically isomeric forms of the compounds as well as their racemates. Pure sterochemically 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. Pure stereoisomers may also be prepared synthetically from the corresponding pure isomers 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 furthermore those of inorganic or organic bases, such as KOH, NaOH, Ca(OH)2, AI(OH)3, piperidine, morpholine, ethylamine, triethylamine and the like.
  • the hydrated forms of the compounds which contain various amounts of water, for instance, the hydrate, hemihydrate and sesquihydrate forms.
  • the compounds of the present invention have antibacterial activity as determined by the following tests. First, the compounds are tested for their activity in inhibiting the autophosphorylation of Kinase A and the transphosphorylation of SPoOF, two proteins involved in the signal transduction system controlling regulatory gene expression in bacteria. Representative compounds are then tested for antibacterial activity against selected pathogenic organisms by the MIC method. The results are set forth below.
  • the SpoOF response regulator is the primary substrate for phosporylation 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 ).
  • 5X Loading Dye 0.5M TRIS-HCl-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 b- mercaptoethanol (0.3 mL) 1 -1.3 mg/mL KinA:15 mM TRIS-HCI, pH 8.0, 6 mM KCI; 4 mM b- mercaptoethanol; 40% glycerol (-20 °C)
  • the reaction mixture was prepared from 8X Salts (87 mL), 1 M TRIS, pH 8 (87 mL), 50% glycerot (63 mL), 2% gelatin (31 mL), SPoOF (14.1 mL) and KinA (7.0 mL).
  • Microcentrifuge tubes were filled with the reaction mixture (18.5 mL) as well as 1mM solution of the test compound in DMSO (18.5 mL) and incubated for 15 min on ice. Add 100 mM [32p]ATP/ATP solution (625 mCi, 3.0 mL) and leave for 10 minutes at room temperature.
  • an IC 50 is calculated by running predetermined inhibitor concentrations (500, 250, 125, 62.5, 31.3, 15.7 and 7.9 mM). The % inhibition is determined by measuring the concentration of radioactive phosphorus with a phosphoimager and calculating the values using a software program (Biorad Molecular Analyst). Results
  • the in vitro antimicrobial spectrum of the compounds of the present invention were determined by the microdilution broth method following the test method from the National Committee for Laboratory Standards (NCCLS). The method is described in the NCCLS Document M7-A2, Vol. 10, No.8 "Methods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically - Second Edition".
  • 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 4 colony forming units per well delivered by the Steers replicating device.
  • the trays are incubated at 35°C for 16-20 hours and then read.
  • the minimal inhibitory concentration (MIC) is the lowest concentration of antimicrobial 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 used in each tray.
  • 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.
  • 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 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 400mg/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 0.07g to 7.0g, preferably from about 100mg to 1000mg Dosage forms suitable for internal use comprise from about 100mg to 500mg 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
  • This invention further provides a method of treating bacterial infections 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.
  • Methanesulfonyl chloride (2.3 mL, 0.029 mol) was added to a solution of alcohol 1 E (6.3 g, 0.029 mol) and triethylamine (8.7 mL, 0.062 mol) in
  • Methanesulfonyl chloride (1.1 mL, 0.014 mol) was added dropwise to a solution of 1G (4.0 g, 0.012 mol). Et3N in CH2CI2 (100 mL) at 0 °C under N 2 . The reaction mixture was stirred for 30 min, an additional portion of methanesulfonyl chloride (0.5 mL, 0.007 mol) was added and the resulting mixture was stirred for another 2 h. Water was added and the resulting mixture was extracted with several portions of CH2CI2. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the mesylate derivative 1 H, as an oil (5.68 g).
  • Methanesulfonyl chloride (7 mL, 9.2 mmol) was added dropwise to a stirred solution of alcohol 4D (2.12 g, 9.2 mmol), triethylamine (3 mL) and CH2CI2 (200 mL) at 0 °C under N2. The reaction mixture was stirred for 2 h and partitioned between H2O and CH2CI2. The resulting organic layer was dried (MgSO4) and concentrated in vacuo to give the mesylate 4D as an oil (4.39
  • Methanesulfonyl chloride (0.5 g, 3.78 mmol) was added dropwise to a solution of 4E (1.2 g, 3.43 mmol) in CH2CI2 (50 mL) at 0 °C under N 2 . The reaction mixture was stirred for 2h. Water was added and the resulting mixture was extracted with several portions of CH2CI2- The combined organic extracts were dried (Na2SU4) and concentrated in vacuo to give the mesylate derivative 4F, as an oil (1.28 g).
  • Derivative 6A (200.5 mg, ??), compound 5, and triethylamine (1 mL) in DMF (15 mL) was heated at 60 °C for 16 h and concentrated in vacuo. The residue was washed with several portions of ether and stirred in H2O for 8 h. The resulting solid was isolated and dried in vacuo to give the title compound as a solid: mp 128-130 °C; IR (KBr, cm-1): 3380, 3190, 2938, 1669, 1626; Anal. Calc'd for C23H28CIN3O ⁇ NO3
  • Methanesulfonyl chloride (0.15 mL, 1.94 mmol) was added to a stirred solution of triethylamine (0.5mL, 3.6 mmol), 11 B (0.7 g, 1.97 mmol) in CH2CI2 (30 mL) at 0 °C. After 15 min the reaction mixture was poured into H2O and extracted with several portions of CH2CI2. The combined extracts were dried (MgS04), concentrated in vacuo and purified by column chromatography using ether.hexanes (30:70) as an eluent to give the mesylate 11C.
  • 15B Sodium hydride (270 mg, 11.25 mmol) was added in portions to a stirred solution of 15A (1.0 g, 7.04 mmol) in THF (150 mL) at room temperature under N2. After 30 min of stirring, phenyl vinyl sulfoxide (2.64 g, 17.6 mmol) was added and the resulting mixture was stirred for 16 h. The reaction was quenched with H2O, extracted with successive portions of ether as well as ethyl acetate and the combined organic extracts were concentrated in vacuo to give 15B as an oil (5.6 g).
  • Methanesulfonyl chloride 70 mg, 0.56 mmol was added dropwise to a stirred solution of 15F (183 mg, 0.55 mmol) and triethylamine (2 mL) in CH2CI2 (100 mL) at 0 °C under N2. This mixture was stirred for 15 h and partitioned between H2O and CH2CI2. The resulting organic layer was separated, dried (Na2S04) and concentrated in vacuo to give the mesylate 15 G as an oil (180 mg).
  • 16B A mixture of 16B (800 mg, 3.10 mmol) acetic acid (2 mL) and RO2 (20 mg) in EtOH (25 mL) was placed on a hydrogenation apparatus and treated with H 2 at 55 psi for 6 h. The resulting mixture was filtered through celite and the filter cake was washed with CH 2 CI2. The combined organic extracts were concentrated in vacuo to give the saturated derivative 16B as an oil (510 mg).
  • Compound 16 Alcohol 16D was treated in the same manner, following the same reaction sequence as intermediate 1 E of Example 1 to give Compound 16 as a solid:mp 120-123 °C; IR (KBr, cm-1): 2939, 1298, 1238; Anal. Calc'd for C23H 3 oN 2 ⁇ 3'C2H2 ⁇ 4O.5H2 ⁇ ; Calculated: C, 62.36; H, 6.91 ; N, 5.82 Found: C, 62.12; H, 6.95; N, 6.21

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés antibactériens cyclohexényle définis par la formule (I) dans laquelle R1 est choisi parmi un (C1-C6) alkyle, (C1-C6) hydroxyalkyle, et un fragment défini par la formule (a), dans laquelle p est un nombre entier entre 0 et 6 et R3, R4 et R5 sont sélectionnés indépendamment dans un groupe comprenant l'hydrogène, l'halo, (C1-C4)alkyle, (C1-C4)alkoxy, hydroxy, hydroxyalkyle, amino, (C1-C4)alkylamino et nitro; N est un nombre entier entre 0 et 2, X est sélectionné parmi NH, O et S; R2 est sélectionné dans un phényle et une fraction hétérocyclique, cette fraction hétérocyclique possédant 5 ou 6 atomes formant le cycle et 1 à 4 atomes d'azote, d'oxygène ou de soufre et étant saturée ou insaturée, et le phényle ou la fraction hétérocyclique étant substitué par des fractions amino définies par la formule (b), carboxy, carboxy(C1-C6)alkyle, (C1-C6)alkylcarboxy ou une fraction définie par la formule (c) et, éventuellement, 1 à 3 substituants séléctionnés dans un groupe comprenant oxo, halo, trifluorométhyle, hydroxy, -(C1-C6) alkyle et (C1-C6)alkoxy; et compositions pharmaceutiques contenant ces composés et méthodes de production et d'utilisation de ces composés.
PCT/US1996/010357 1996-06-18 1996-06-18 Agents antimicrobiens cyclohexenyl et cyclohexyl 2-disubstitues WO1997048675A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU62801/96A AU6280196A (en) 1996-06-18 1996-06-18 2-disubstituted cyclohexenyl and cyclohexyl antimicrobial agents
PCT/US1996/010357 WO1997048675A1 (fr) 1996-06-18 1996-06-18 Agents antimicrobiens cyclohexenyl et cyclohexyl 2-disubstitues

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1996/010357 WO1997048675A1 (fr) 1996-06-18 1996-06-18 Agents antimicrobiens cyclohexenyl et cyclohexyl 2-disubstitues

Publications (1)

Publication Number Publication Date
WO1997048675A1 true WO1997048675A1 (fr) 1997-12-24

Family

ID=22255332

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/010357 WO1997048675A1 (fr) 1996-06-18 1996-06-18 Agents antimicrobiens cyclohexenyl et cyclohexyl 2-disubstitues

Country Status (2)

Country Link
AU (1) AU6280196A (fr)
WO (1) WO1997048675A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999052861A1 (fr) * 1998-04-09 1999-10-21 Institut für Diagnostikforschung GmbH an der Freien Universität Berlin NOUVEAUX DERIVES DE BENZYLGUANIDINE POUR LA THERAPIE ET LE DIAGNOSTIC IN VIVO ET $i(IN VITRO)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991015495A1 (fr) * 1990-04-02 1991-10-17 Pfizer Inc. Composes d'acide benzylphosphonique utilises comme inhibiteurs de la tyrosine kinase
JPH08134044A (ja) * 1994-11-09 1996-05-28 Nippon Shoji Kk 新規ピリミジン化合物、中間体及びそれらの製造法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991015495A1 (fr) * 1990-04-02 1991-10-17 Pfizer Inc. Composes d'acide benzylphosphonique utilises comme inhibiteurs de la tyrosine kinase
JPH08134044A (ja) * 1994-11-09 1996-05-28 Nippon Shoji Kk 新規ピリミジン化合物、中間体及びそれらの製造法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 9631, Derwent World Patents Index; Class B03, AN 96-306532, XP002024098 *
HUANG, JIANMIN ET AL: "Genistein inhibits protein histidine kinase", J. BIOL. CHEM. (1992), 267(22), 15511-15, XP002024096 *
S. ROYCHOUDHURY ET AL.: "Inhibitors of two-component signal transduction systems: Inhibition of alginate gene activation in pseudomonas aeruginosa", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, vol. 90, 1993, WASHINGTON US, pages 965 - 69, XP002024095 *
SOHDA, TAKASHI ET AL: "Studies on antidiabetic agents. III. 5-Arylthiazolidine-2,4-diones as potent aldose reductase inhibitors", CHEM. PHARM. BULL. (1982), 30(10), 3601-16, XP002024094 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999052861A1 (fr) * 1998-04-09 1999-10-21 Institut für Diagnostikforschung GmbH an der Freien Universität Berlin NOUVEAUX DERIVES DE BENZYLGUANIDINE POUR LA THERAPIE ET LE DIAGNOSTIC IN VIVO ET $i(IN VITRO)

Also Published As

Publication number Publication date
AU6280196A (en) 1998-01-07

Similar Documents

Publication Publication Date Title
US5707990A (en) 2-substituted amino and thio alkyl benzoxazine antimicrobial agents
US20210107912A1 (en) Inhibitors of cyclin-dependent kinase 7 (cdk7)
US5773469A (en) Diaryl antimicrobial agents
US5849770A (en) Tri-substituted phenyl derivatives useful as PDE IV inhibitors
RU2191179C2 (ru) Бензоксазиновые или пиридооксазиновые соединения, способы их получения, промежуточные соединения, фармацевтические композиции, обладающие антибактериальной активностью, способы лечения бактериальных инфекций
EP1194144B1 (fr) Composes antibacteriens
US5798373A (en) Tri-substituted phenyl derivatives useful as PDE IV inhibitors
US8354443B2 (en) Cyclopropane indolinone derivatives
US5942532A (en) 2-substituted phenyl-benzimidazole antibacterial agents
US10662187B2 (en) Bruton's tyrosine kinase inhibitors
EP4132907B1 (fr) Dérivés de (1h-indol-5-yl)acrylamide en tant qu'inhibiteurs de protéines tead et de la cascade de signalisation hippo-yap1/taz pour le traitment du cancer
US20110212080A1 (en) Urea derivatives as antibacterial agents
US6348482B1 (en) Catechols as antimicrobial agents
KR20150112953A (ko) 테트라하이드로- 및 디하이드로-이소퀴놀린 prmt5 억제제 및 이의 용도
US6914058B2 (en) Antibacterial compounds: process for their preparation and pharmaceutical compositions containing them
WO2004020414A1 (fr) Inibiteurs de l'oxytocine
US5753715A (en) 2-disubstituted cyclohexenyl and cyclohexyl antimicrobial agents
AU2004260759A1 (en) Protein kinase inhibitors
CA2405532A1 (fr) Antibacteriens a base de pyridoarylphenyle oxazolidinone, compositions et procedes associes
US5874436A (en) Triphenylalkyl antimicrobial agents
CS3692A3 (en) Heterocyclic hydroxylamines, process of their preparation, their use andpharmaceutical preparations comprising said compounds
JP2023535482A (ja) アクリルアミド置換インダン化合物およびその治療的使用
WO1997048675A1 (fr) Agents antimicrobiens cyclohexenyl et cyclohexyl 2-disubstitues
US7332485B2 (en) Peptide deformylase inhibitors
WO2000018772A1 (fr) Imidazolidinones condensees utilisees comme inhibiteurs de l'arnt-synthetase

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IS JP KE KG KP KR KZ LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 98502854

Format of ref document f/p: F

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase