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WO2008119028A1 - Alcényldiarylméthanes présentant des dérivés d'acide carboxylique contenant de l'azote - Google Patents

Alcényldiarylméthanes présentant des dérivés d'acide carboxylique contenant de l'azote Download PDF

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WO2008119028A1
WO2008119028A1 PCT/US2008/058463 US2008058463W WO2008119028A1 WO 2008119028 A1 WO2008119028 A1 WO 2008119028A1 US 2008058463 W US2008058463 W US 2008058463W WO 2008119028 A1 WO2008119028 A1 WO 2008119028A1
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optionally substituted
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methyl
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Mark S. Cushman
Takeshi Sakamoto
Matthew D. Cullen
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/02—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/26—Esters of monothiocarboxylic acids having carbon atoms of esterified thiocarboxyl groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles

Definitions

  • the invention described herein relates to compositions useful for treating viral diseases.
  • the compounds described herein are useful for treating acquired immunodeficiency syndrome (AIDS), and/or human immunodeficiency virus (HTV) infection.
  • AIDS acquired immunodeficiency syndrome
  • HTV human immunodeficiency virus
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • NRTIs nucleoside reverse transcriptase inhibitors
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • PIs protease inhibitors
  • enfuvirtide fusion inhibitors
  • NNRTIs may have the advantage that they are minimally toxic. Even so, the risk of the development of NNRTI resistance remains as a potential issue.
  • HIV-I RT is one of the major targets of the antiretro viral drug therapies that are used in the treatment of AIDS. It has been reported that NNRTIs inhibit the enzyme by occupation of an induced allosteric binding site very close to the active site (see generally, De Clercq, E. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Past, Present, and Future. Chem. Biodiversity 2004, 1, 44-64; Esnouf et al. Mechanism of Inhibition of Reverse Transcriptase by Nonnucleoside Inhibitors. Nat. Struct. Biol. 1995, 2, 303-308). However, the emergence of resistant HIV viral strains is a limitation for all therapeutic classes.
  • alkenyldiarylmethanes are highly active, may be used in combination with other drugs, such as AZT, and importantly show activity against AZT- resistant strains of HIV-I (see, Cushman etal. Synthesis and Biological Evaluation of Certain Alkenyldiarylmethanes as Anti-HIV-1 Agents Which Act as Non-Nucleoside Reverse Transcriptase Inhibitors. /. Med. Chem. 1996, 39, 3217-3227; Cushmanet al. New
  • known compound Ia inhibited HIV-I RT with an IC 50 value of ⁇ 1.0 ⁇ M and displayed an EC 50 value of 1.0 ⁇ M for inhibition of HIV-I 111 B in MT-4 cells (see, Silestri et al. Design, Synthesis, Anti-HIV Activities, and Metabolic Stabilities of Alkenyldiarylmethane (ADAM) Non-nucleoside Reverse Transcriptase Inhibitors. J. Med. Chem. 2004, 47, 3149-3162; and Deng et al.
  • ADAM New Alkenyldiarylmethane
  • NRTIs Non-Nucleoside Reverse Transcriptase Inhibitors
  • the more recently synthesized compound 2 includes an oxazolone replacement for one of the methyl esters and an adjacent methyl ether present in Ia (see, Cushman et al.
  • ADAM Alkenyldiarylmethane
  • ADAM compounds may be hydrolyzed to biologically inactive acids by non-specific esterases present in blood plasma. Therefore, a need remains for the discovery of more stable analogs and derivatives of these ADAM esters.
  • Described herein are compounds useful for treating viral diseases, and methods for treating viral diseases.
  • described herein are processes for preparing the compounds useful for treating viral diseases.
  • the compounds described herein include one or more pharmacologically active replacements for the methyl esters present on the aryl rings and side chains of known ADAM compounds. Such replacements may also be bioisosteres.
  • alkenyldiarylmethanes of the general formula (I) are described
  • Ar 1 and Ar 2 are each independently selected from the group consisting of optionally substituted monocyclic aryl and optionally substituted bicyclic aryl; double bond (a) is a E-double bond or a Z-double bond; n is an integer in the range from 1 to about 5; and
  • Z is a nitrogen-containing carboxylic acid derivative, including a heteroaryl derivative.
  • the groups Ar 1 and Ar 2 are a nitrogen-containing carboxylic acid derivative, including a heteroaryl derivative.
  • Ar 2 are the same. In another aspect, the groups Ar 1 ands Ar 2 are different. In another aspect, the double bond in formula I has the E-geometry. In another aspect, the double bond in formula I has the Z-geometry. In another aspect, the group Z is an ester, such as an optionally substituted alkyl or optionally substituted aryl ester. In another aspect, when Z is a methyl ester, at least one of Ar 1 and Ar 2 are a monocyclic aryl substituted with an N-alkoxyimidoylhalo. In another aspect, the group Z is an optionally substituted heterocyclyl group, such as 3-methyl- 1,2,4- oxadiazol-5-yl, and the like. In another aspect, the groups Ar 1 and Ar 2 are different and the group Z is an N-alkoxyimidoyl halide. In another aspect, the integer n is 2 or 3.
  • alkenyldiarylmethanes of the general formula (II) are described
  • Het is optionally substituted heterocyclyl, such as an oxadizaole, tetrazole, and the like, and including compounds of the following formulae wherein R is optionally substituted alkyl.
  • alkenyldiarylmethanes where Z is a hydroxamic acid, or a derivative thereof are described, including compounds of the general formulae (III)
  • Ar 1 and Ar 2 are each independently selected from optionally substituted monocyclic and bicyclic aryls, and aryls fused with other rings; double bond a is an E-double bond or a Z-double bond; n is an integer in the range from 1 to about 5;
  • X is a halo or optionally substituted alkoxy group; and R is optionally substituted alkyl.
  • alkenyldiarylmethanes having the general formulae (V) are described
  • Ar 1 and Ar 2 are each independently selected from optionally substituted monocyclic and bicyclic aryls; double bond a is an E-double bond or a Z-double bond; and n is an integer in the range from 1 to about 5; and
  • Z' is a carboxylic acid, or an analog or derivative thereof; providing that at least one of Ar 1 or Ar 2 includes a hydroxamic acid or a derivative thereof.
  • compounds of formulae I-V described herein may be useful for treating viral diseases, such as acquired immunodeficiency syndrome (ADDS), human immunodeficiency virus (HIV) infection, and the like.
  • compounds of formulae I - IV described herein may be efficacious against viral strains, such as HIV viral strains, that have become resistant to other drugs, including other alkenyldiarylmethanes, azidothymidine (AZT), nevirapine, delavirdine, efavirenz, and the like.
  • compounds of formulae I-V described herein have improved metabolic stability, such as improved metabolic stability in plasma as determined by the half-life of the compounds in rat blood plasma.
  • compounds of formulae I-V described herein inhibit the cytopathic effect of HIV-I reverse transcriptase.
  • methods for treating viral diseases are described.
  • the viral disease is attributable to HIV.
  • the viral disease is responsive to enzyme inhibition, such as inhibition of HIV-I reverse transcriptase.
  • compounds of formulae I-V described herein may be combined with known or conventional compounds or therapies, such as drug combinations that include one or more of the compounds described herein and other alkenyldiarylmethanes, azidothymidine (AZT), nevirapine, delavirdine, efavirenz, and the like.
  • known or conventional compounds or therapies such as drug combinations that include one or more of the compounds described herein and other alkenyldiarylmethanes, azidothymidine (AZT), nevirapine, delavirdine, efavirenz, and the like.
  • processes for preparing the compounds of formulae I-V include the step of preparing an aromatic methyl ether, such as a methyl ether of a phenolic hydroxyl, where the step comprises contacting the corresponding aryl alcohol with dimethylsulfate, an inorganic base, and a phase- transfer catalyst, in a biphasic solvent.
  • the processes include the step of preparing a methyl ester, where the step comprises contacting the corresponding carboxylic acid with a methylating agent, in a biphasic solvent.
  • the processes include the step of incorporating an optionally substituted heterocycle, where the step comprises contacting the corresponding carboxylic acid with acetamide oxime, a tertiary amine, an acylation catalyst, and a coupling reagent, in a solvent comprising dimethylformamide (DMF).
  • the processes include the step of preparing an O-alkyl hydroxamic acid derivative, where the step comprises contacting the corresponding carboxylic acid with methoxyamine, an acylation catalyst, and a coupling reagent, in a solvent comprising DCM at room temperature.
  • the processes include the step of preparing an N-alkoxyimidoyl halide, where the step comprises contacting the corresponding O-methyl hydroxamic acid, triphenyl phosphine (PPh 3 ), and CCl 4 in a solvent comprising acetonitrile at reflux.
  • the processes include the step of preparing an N-alkoxyimidoyl halide, where the step comprises contacting the corresponding O-methyl hydroxamic acid, triphenyl phosphine (PPh 3 ), and CBr 4 in a solvent comprising acetonitrile at reflux.
  • alkenyldiarylmethane compounds having the general formula (I) are described
  • R Br show a short plasma half life of less than 10 minutes, and in some cases less than 1 minute.
  • compounds that include one or more replacement groups for such esters, including bioisosteres of ester groups are analogs and derivatives of esters, including heteroaryl derivatives of esters. It is appreciated that such replacement groups in the form of analogs and derivatives of esters, including heteroaryl derivatives of esters, may have longer half-lives in vivo. Such longer half- lives are illustrated by the longer plasma half-life as described herein.
  • compounds are described herein that show a plasma half life of at least about 10 minutes, or at least about 100 minutes.
  • compounds are described herein that show a plasma half life that is about 10 times or greater than the plasma half -life of the corresponding methyl ester. In other words, where one or more methyl esters have been replaced by analogs and derivatives of esters, including heteroaryl derivatives of esters, as described herein, those compounds show such increased half-lives.
  • the ester replacement is an ester analog, such as a cyclic carbamate, and the like.
  • the ester replacement is a hydroxamic acid or derivative thereof, such as a bromo, chloro, or fluoro N-methoxyiminyl group, and the like.
  • the ester replacement is a heteroaryl, such as a l,2,4-oxadiazol-5-yl, 1,3,4- oxadiazol-5-yl, or tetrazol-5yl group, and the like, each of which is optionally substituted.
  • the ester replacement is a ring fusion on Ar 1 and/or Ar 2 to form the corresponding oxazolone, isoxazolone, oxazole, alkoxyoxazole, or alkoxyisoxazole group, and the like.
  • the ester replacement is a thio derivative of an ester, including thioesters, thionoesters, and dithioesters.
  • the ester replacement is a cyano derivative.
  • the compounds described herein include more metabolically stable inhibitors.
  • the groups Ar 1 and Ar 2 are the same. In one variation, the groups Ar 1 ands Ar 2 are different.
  • the double bond in formula I has the E-geometry. In one variation, the double bond in formula I has the Z-geometry.
  • the group Z is an ester, such as an optionally substituted alkyl or optionally substituted aryl ester, and one or both of Ar 1 and Ar 2 include at least one hydroxamic acid or derivative thereof.
  • Ar 1 and/or Ar 2 is a monocyclic aryl substituted with the hydroxamic acid or derivative thereof.
  • Z is not an alkyl ester.
  • the group Z is an analog of a carboxylic acid or derivative thereof, such as an optionally substituted heterocyclyl group.
  • Illustrative optionally substituted heterocyclyl groups include oxazolidinonyl and oxazolidinon-2-yl, and the like.
  • the groups Ar 1 and Ar 2 are different and the group Z is an optionally substituted heterocyclyl group, or a hydroxamic acid or derivative thereof.
  • the integer n is 2 or 3.
  • the compounds described herein include Z that is a heteroaryl, such as a heteroaryl derivative of a carboxylic acid of the following formulae and the like.
  • the compounds described herein include Z that is a hydroxamic acid or derivative thereof, such as a hydroxamic acid compounds of the following formulae
  • Ar 1 and Ar 2 , n, and (a) are as defined herein; and X is a halo or optionally substituted alkoxy group; and R is optionally substituted alkyl.
  • Ar 1 and/or Ar 2 are bicyclic,such as a fused phenyl compound of the formulae where W is independently selected in each instance from N, O, and S, and where each of the above formulae is optionally substituted, vsuch as a substituent at a carbon, nitrogen, oxygen, or sulfur atom.
  • alkenyldiarylmethanes of the general formulae (IV) are described
  • Z is a nitrogen-containing carboxylic acid derivative
  • R a represents 1, 2, or 3 substituents each independently selected from the group consisting of halo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, hydroxy, nitro, carboxylate and derivatives thereof, thioesters, thionoesters, xanthates, cyano, carbamoyl, carboxamido, amino, alkylamino, dialkylamino, alkylalkylamino, sulfonamide, and alkylsulfonylamino;
  • R d represents 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of halo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, hydroxy, nitro, carboxylate and derivatives thereof, thioesters, thionoesters, xanthates, cyano, carbamoyl, carboxamido, amino, alkylamino, dialkylamino, alkylalkylamino, sulfonamide, alkylsulfonylamino, O-alkylhydroxamoyl, iV-alkoxyimidoylhalo; and one of bond b or bond c is a double bond, and the other of bond b or bond c is a single bond; and R b and R c are each an optionally substituted alkyl; providing that when bond b is a double bond, R b is absent; and when bond c is a double bond
  • R a represents 1 or 2 substituents, or only 1 substituent.
  • R d represents 1, 2, or 3 substituents.
  • R d represents cyano.
  • R d represents 3 substituents.
  • alkenyldiarylmethanes having the general formulae (V) are described
  • geometrically isomeric compounds are described, wherein Ar 1 and Ar 2 are different.
  • Ar 1 and Ar 2 are different.
  • separate isomers may be prepared, as is illustrated for (E)-5 and (Z)-5.
  • the term "optionally substituted monocyclic and bicyclic aryls" includes an aromatic mono or bicyclic ring of carbon atoms, such as phenyl, naphthyl, and the like, and to an aromatic mono or bicyclic ring of carbon atoms and at least one heteroatom selected from nitrogen, oxygen, and sulfur, such as pyridinyl, pyrimidinyl, indolyl, benzoxazolyl, benzisoxazolyl, benzoxazolinonyl, benzisoxazolinonyl, and the like, which may be optionally substituted with one or more independently selected substituents, such halo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, hydroxy, nitro, carboxylate and derivatives thereof, cyano, carbamoyl, carboxamido, amino, alkylamino, dialkylamino, alkylalkylamino,
  • substituted monocyclic and substituted bicyclic aryls include those compounds having at least one halo (e.g., fluoro) group, haloalkyl group, or halalkoxy group.
  • substituted monocyclic and substituted bicyclic aryls do not include a carboxylate or derivative thereof.
  • substituted monocyclic and substituted bicyclic aryls include those compounds having a cyano group.
  • alkyl includes a saturated monovalent chain of carbon atoms, which may be optionally branched. It is understood that in embodiments that include alkyl, illustrative variations of those embodiments include lower alkyl, such as C 1 -C 6 , Ci-C 4 alkyl, methyl, ethyl, propyl, 3-methylpentyl, and the like.
  • heterocyclyl includes a monovalent chain of carbon and heteroatoms, wherein the heteroatoms are selected from nitrogen, oxygen, and sulfur, a portion of which, including at least one heteroatom, form a ring.
  • dialkylamino includes alkylalkylamino where the amino is substituted with two different alkyl groups, and illustratively includes methylamino, dimethylamino, methylethylamino, and the like.
  • processes for preparing the compounds of formulae I-V include the step of preparing an aromatic methyl ether, such as a methyl ether of a phenolic hydroxyl, where the step comprises contacting the corresponding aryl alcohol with dimethylsulfate, an inorganic base such as potassium carbonate, sodium hydroxide, and the like, and a phase-transfer catalyst, such as a tetraalkylammoniura halide, in a biphasic solvent comprising dichloromethane (DCM) and water.
  • an aromatic methyl ether such as a methyl ether of a phenolic hydroxyl
  • an inorganic base such as potassium carbonate, sodium hydroxide, and the like
  • a phase-transfer catalyst such as a tetraalkylammoniura halide
  • the processes include the step of preparing a methyl ester, where the step comprises contacting the corresponding carboxylic acid with a methylating agent, such as (trimethylsilyl)diazomethane (TMSCHN 2 ), in a biphasic solvent comprising toluene and methanol.
  • a methylating agent such as (trimethylsilyl)diazomethane (TMSCHN 2 )
  • TMSCHN 2 trimethylsilyl)diazomethane
  • the processes include the step of incorporating an optionally substituted heterocycle, such as 3-methyl-l,2,4-oxadiazole, where the step comprises contacting the corresponding carboxylic acid with acetamide oxime, a tertiary amine, such as diisopropylethylamine (DIPEA), an acylation catalyst, such as N-hydroxybenzotriazole (HOBt), and a coupling reagent, such as TBTU, in a solvent comprising dimethylformamide (DMF).
  • DIPEA diisopropylethylamine
  • HOBt acylation catalyst
  • TBTU N-hydroxybenzotriazole
  • DMF dimethylformamide
  • the processes include the step of preparing an O-alkyl hydroxamic acid derivative, such as an O-methyl hydroxamic acid, where the step comprises contacting the corresponding carboxylic acid with methoxyamine, an acylation catalyst, such as N,N-dimethylaminopyridine (DMAP), and a coupling reagent, such as EDCI, in a solvent comprising DCM at room temperature.
  • an acylation catalyst such as N,N-dimethylaminopyridine (DMAP)
  • DMAP N,N-dimethylaminopyridine
  • EDCI coupling reagent
  • the processes include the step of preparing an N-alkoxyiminyl halide, such as an N-methoxyimidoyl chloride, where the step comprises contacting the corresponding 0-methyl hydroxamic acid, triphenyl phosphine (PPh 3 ), and CCl 4 in a solvent comprsing acetonitrile at reflux.
  • N-alkoxyiminyl halide such as an N-methoxyimidoyl chloride
  • the processes include the step of preparing an N-alkoxyimidoyl halide, such as an N-methoxyimidoyl bromide, where the step comprises contacting the corresponding O-methyl hydroxamic acid, triphenyl phosphine (PPh 3 ), and CBr 4 in a solvent comprsing acetonitrile at reflux.
  • N-alkoxyimidoyl halide such as an N-methoxyimidoyl bromide
  • the processes include the step of preparing a compound of the formula
  • n is an integer in the range from 1 to about 5;
  • Ar 1 is selected from optionally substituted monocyclic and bicyclic aryls;
  • R is an alkyl group, such as n-butyl, and Z is a carboxylic acid derivative or an analog thereof, where the step comprises slowly contacting a dilute solution of a metal catalyst, such as Pd(PPh 3 ) 4 , Pd(PPh 3 ⁇ Cl 2 , and the like, and a compound of the formula with a trialkyltin hydride.
  • the step proceeds with high regioselectivity and high geometric or stereoselectivity.
  • the processes include the step of preparing a compound of the formula
  • n is an integer in the range from 1 to about 5;
  • Ar 1 and Ar 2 are each independently selected from optionally substituted monocyclic and bicyclic aryls, and Z is a carboxylic acid derivative or an analog thereof, where the step comprises contacting a solution comprising toluene at reflux, a compound of the formula Ar 2 -L, where L is a leaving group such as a halo, trialkylstannnyl, boronyl, and the like, a metal catalyst, such as Pd(P(t-Bu) 3 ) 2 , and the like, CsF, and a compound of the formula
  • n is an integer in the range from 1 to about 5;
  • Ar 1 is selected from optionally substituted monocyclic and bicyclic aryls;
  • R is an alkyl group, such as n-butyl, and Z is a carboxylic acid derivative or an analog thereof.
  • illustrative embodiments of the compounds of formulae I-V may include those aspects wherein the double bond has the E-geometry and Z is a iV-alkoxyimidoyl halide.
  • illustrative embodiments of the compounds of formulae I - IV may include those aspects wherein the double bond has the Z-geometry, and Z is an optionally substituted heterocyclyl group.
  • illustrative embodiments of the methods described herein may include those aspects wherein the viral disease is AIDS, and the method also includes the step of adding another protease inhibitor, such as AZT. It is to be understood that the additional step may be separate in time from the step of adding a compound of formulae I-V; or may be contemporaneous or simultaneous. Further, it is to be understood that in the contemporaneous or simultaneous variation the compounds may be combined. In addition, illustrative embodiments of the processes described herein may include those aspects wherein the step of preparing a compound of the formula
  • Ar 1 , Ar 2 , n, R, and Z are as defined herein.
  • alkenyldiarylmethane compounds of formulae I-V are described.
  • compounds of formulae I-V may be prepared by the general synthesis shown in the following scheme, and illustrated for the preparation of compounds of formula I where n is 3 and Z is as defined herein, such as a carboxylic acid analog or derivative, or a heteroaryl group.
  • Ar-I (which may be used as Ar 1 -I or Ar 2 -I) include:
  • Thioester 81 was achieved through another aryl building block, ester 80. Saponification of 80 was effected through heating a mixture of the ester and potassium hydroxide in methanol at reflux to afford benzoic acid 88. Treatment of acid 88 with thionyl chloride to obtain the corresponding acyl chloride intermediate, followed by esterification with sodium thiomethoxide in benzene afforded thioester 81.
  • Synthesis of isoxazole 84 began with formation of oxime 90 from salicylic aldehyde 89 via condensation with hydroxylamine. Cyclization of oxime intermediate 90 was accomplished with triphenylphosphine and DIAD to afford isoxazole 84. Alkynes 97-100 were synthesized from their corresponding nitriles, 91 and 92, via tetrazole intermediates, as shown in the following scheme
  • alkenyldiarylmethane compounds of formulae I-V may be prepared by the general synthesis shown in the following scheme, and illustrated for compounds 4 and 5.
  • the Stille coupling of 20 with 21 was attempted using the reaction conditions previously described by Mee et al.
  • the significant feature of their conditions is that addition of a catalytic amount of cuprous iodide accelerates the reaction rate in a highly polar solvent, such as DMF.
  • a catalytic amount of cuprous iodide accelerates the reaction rate in a highly polar solvent, such as DMF.
  • no reaction was observed, probably due to the chelation of the 0-methylhydroxamic acid group of 20 and the neighboring methoxy group to Pd ⁇ -complexes.
  • the Omethylhydroxamic acid group could be deprotonated by cesium fluoride and act as a ligand for palladium.
  • alkenyldiarylmethane compounds of formulae I-V may be prepared by the general synthesis shown in the following scheme, and illustrated for compounds 6 and 7.
  • combination therapies are described, wherein the compounds described herein are combined with other known or conventional drugs or therapies.
  • a number of HIV-I strains containing AZT resistance mutations have shown increased sensitivity to alkenyldiarylmethane compounds, such as those compounds described herein, indicating a possible therapeutic role for those compounds in combination with AZT (see, Cushman et al. J. Med. Chem. 1998, 41, 2076-2089, the disclosure of which is incorporated herein by reference).
  • Alkenyldiarylmethane compounds have been found to inhibit the cytopathic effect of HIV-I in cell culture at low nanomolar concentrations, some with EC 50 values of about 0.02 ⁇ M to about 0.21 ⁇ M for inhibition of the cytopathic effect of HTV-I RF in CEM-SS cells, and IC 50 values of from about 0.074 ⁇ M to about 0.499 ⁇ M for HIV-I RT with rCdG as the template primer.
  • Preparative TLC separations utilized Analtech Uniplates with glass supported silica (20 x20 cm, 2000 micron thickness) and UV indicator (254 nm). Melting points are uncorrected. Unless otherwise stated, chemicals and solvents were of reagent grade and used as obtained from commercial sources without further purification. Anhydrous tetrahydrofuran was prepared by distillation from sodium ketyl. Lyophilized rat plasma (lot 065K7555) was obtained from Sigma Chemical Co., St. Louis, MO. Microanalyses were performed at the Purdue Microanalysis Laboratory. All yields refer to yields of isolated compounds. The hydrolytic stability assay utilized lyophilized rat plasma (LOTs 052K7609 and 065K7555) from Sigma Chemical Co., St.
  • the reaction mixture was allowed to stir at 60 0 C, under an argon atmosphere, for 1-24 h until the stannane starting material had been consumed.
  • the system was allowed to cool to room temperature and the reaction mixture was sonicated at room temperature for 30 sec, after being diluted with a mixture of ethyl acetate (5 mL), methanol (1 mL), and water (1 mL).
  • the reaction mixture was loaded onto a short column of silica (10-20 mL) and the products were eluted with ethyl acetate (50-75 mL).
  • the heterogeneous reaction mixture was allowed to stir at room temperature, under an argon atmosphere, for 3-24 h.
  • the reaction mixture was concentrated in vacuo, the remaining residue was absorbed onto silica.
  • the products were separated by column chromatography to obtain the desired alkyne product and, if necessary, additional purification methods were applied.
  • reaction mixture was stirred for 24 h at room temperature. After the reaction was complete, the mixture was diluted with ethyl acetate (40 mL). The organic solution was washed with 2% HCl (2 x 15 mL), 5% aq NaHCO 3 (2 x 15 mL), brine (2 x 15 mL), and dried over sodium sulfate.
  • Trimethylsilyl trifluoromethanesulfonate (0.59 mL, 3.27 mmol) was added to a solution of tert- butyl ester 25 (862 mg, 1.64 mmol) and triethylamine (0.46 mL, 3.27 mmol) in dioxane (25 mL) at room temperature under argon. The reaction mixture was stirred for 2 h at room temperature. After the reaction was complete, water (50 mL) was added to the mixture. The mixture was extracted with ethyl acetate (2 x 35 mL). The combined organic solvent was washed with brine (2 x 35 mL) and dried over sodium sulfate.
  • TBTU (2- (lH-benzotriazol-l-yl)-l,l,3,3,-tetramethyluronium hexafluorophosphate) (71 mg, 0.213 mmol) was added to a mixture of carboxylic acid 26 (100 mg, 0.213 mmol), acetamide oxime (16 mg, 0.213 mmol), ⁇ OBt (6 mg, 0.043 mmol), DIPEA (0.19 mL, 1.07 mmol) in DMF (4 mL). The mixture was stirred for 0.5 h at room temperature and for 3 h 110 0 C.
  • the reaction mixture was allowed to stir for 17 h.
  • the crude products were separated by column chromatography (100 mL silica gel, 2 in diameter) using an ethyl acetate-hexanes gradient (50-80%).
  • the product was isolated and purified again by column chromatography (80 mL silica gel, 2 in diameter) using an ethyl acetate-hexanes gradient (20-66%).
  • reaction mixture was allowed to stir for 16 h.
  • the crude products were absorbed onto silica (3 mL) and separated by column chromatography (100 mL silica, 2 in diameter) using an ethyl acetate-hexanes gradient (20-50%).
  • the reaction mixture was allowed to for 17 h.
  • the crude products were separated by column chromatography (125 mL silica, 2 in diameter) using an ethyl acetate-hexanes gradient (20-100%).
  • the desired product was further purified by preparative thin layer chromatography using 50% ethyl acetate-hexanes as the eluant (developed 4 times).
  • the reaction mixture was allowed to stir for 21 h.
  • the crude products were separated by column chromatography (110 mL silica gel, 2 in diameter) using an ethyl acetate-hexanes gradient (50-100%) and the desired product was further purified by preparative thin layer chromatography using 50% ethyl acetate- hexanes as the eluant (developed twice).
  • the desired product was further purified by preparative thin layer chromatography using ethyl acetate as the eluant (developed twice).
  • the product was isolated from the plate and purified again by preparative thin layer chromatography using 66% ethyl acetate-hexanes as the eluant (developed three times).
  • the pure product was isolated as a glassy, amber solid (80 mg, 52%): mp 43-47 0 C.
  • the crude products were purified by column chromatography (100 mL silica, 1.5 in diameter) using an ethyl acetate-hexanes gradient (50-100%) and the desired product was further purified by preparative thin layer chromatography using 2: 1 ethyl acetate-hexanes as the eluant.
  • the desired product was further purified by preparative thin layer chromatography using 70% ethyl acetate-toluene as the eluant.
  • the product was isolated as a white, microcrystalline solid after being exposed to hi vacuum conditions (92 mg, 51%): mp: 50-53 0 C.
  • the desired was further purified two more times by preparative thin layer chromatography for which 66% ethyl acetate-hexanes was used as the developing solution for the first plate and 80% ethyl acetate-toluene was used for the second.
  • the desired product was isolated as an opaque oil (6 mg, 4%).
  • the crude products were purified by column chromatography (60 mL silica, 1 in diameter) using an ethyl acetate-hexanes gradient (50-66%) and the desired product was further purified via preparative thin layer chromatography using 66% ethyl acetate-hexanes as the eluant (developed twice).
  • a white solid was obtained after concentrating the reaction mixture (occasionally the material is a yellow oil).
  • the solid was dissolved in benzene (3 mL) and sodium thiomethoxide (77 mg, 1.10 mmol) was added to the solution.
  • the heterogeneous mixture was allowed to stir at room temperature for 15 h and was then diluted with ethyl acetate (5 mL) and water (5 mL).
  • the phases were separated and the aqueous phase was extracted with ethyl acetate (3 x 15 mL).
  • Organic extracts were combined, dried over magnesium sulfate, filtered, and condensed in vacuo to afford an oil.
  • the aqueous phase was cooled in an ice bath and acidified to a pH of 1, via slow addition of concentrated hydrochloric acid, to produce a white precipitate.
  • the precipitate was extracted with ethyl acetate (3 x 20 mL) and the combined organic phases were washed with brine (1 x 30 mL), dried over magnesium sulfate, filtered, and condensed in vacuo to afford a white, fluffy, solid (248 mg, 85%): mp 163-165 0 C.
  • aqueous phase was extracted with ethyl acetate (4 x 20 mL) and the combined organic extracts were dried over magnesium sulfate, filtered, and condensed in vacuo to afford a yellow oil that, when triturated with hexanes, solidified to low melting point solid (1.259 g, 84%): mp 24-26 0 C.
  • the organic extracts were combined, washed with brine (1 x 40 mL), dried over magnesium sulfate, and condensed in vacuo to afford a yellow oil.
  • the crade products were purified by column chromatography (100 mL silica, 2 in diameter) using an ethyl acetate-hexanes gradient (33-50%).
  • RT Inhibition Assay The ability of target compounds to inhibit the enzymatic activity of recombinant HIV-I RT (p66/51 dimer) was evaluated as described in Cushman et al. J. Med. Chem. 1996, 39, 3217-3227; Rice et al. Discovery and in Vitro Development of AIDS Antiviral Drugs as Biopharmaceuticals, Adv. Pharmacol. (San Diego) 1995, 33, 389-438; and Buckheit et al., Comparitive Anti-HIV Evaluation of Diverse HIV-I -Specific Reverse Transcriptase Inhibitor-Resistant Virus Isolates Demonstrates the Existence of Distinct Phenotypic Subgroups, Antiviral Res.
  • HW-I reverse transcriptase inhibition was determined by the amount of 32 P labeled GTP incorporated into a nascent DNA strand, with a poly(rC)/oligo-(dG)(rCdG) homopolymer primer, in the presence of increasing concentrations of the target compounds. In Vitro Anti-Viral Assays.
  • the anti-viral activities of the compounds described herein were determined for the HIVstrains: HIV-I RF , HIV-I 11IB , and HIV-2 ROD - Evaluation of anti-viral activity against HIV-I RF was determined in infected CEM-SS cells while using the MTS cytoprotection assay, as described in Rice et al. (1995), the disclosure of which is incorporated herein by reference. Evaluation of anti-viral activity against the HIV-I 111B and HIV-2 ROD strains was performed in infected MT-4 cells using the MTT assay as described in Deng et al. J. Med. Chem. 2005, 48, 6140-6 P55; and Pauwels et al.
  • compounds 6 and 7 displayed anti-HIV- I RF activity in the submicromolar range. Also, the compounds 4-7 produced EC 50 values versus HIV-I 111B between 0.24-6.3 ⁇ M. Comparison between compounds 2 and 7 indicates that the N-methoxy imidoyl fluoride system retained the desired anti-HIV activity, although the potency of 7 was somewhat lower, both with regard to RT inhibition as well as prevention of the cytopathic effect of the virus. However, compounds 22 and 24, having N-methoxyamide groups, were inactive both in the enzymatic and cellular tests. Similar to other known NNRTIs, all of the compounds in this series were inactive against HIV-2.
  • a control compound was tested in both batches of rat plasma to insure that the hydrolysis rates of the two batches were approximately equivalent.
  • the aliquot supernatants were analyzed using a Waters binary HPLC system (Model 1525, 20 ⁇ L injection loop) and a Waters dual wavelength absorbance UV detector (Model 2487) set for 254 nM. Data were collected and processed using the Waters Breeze software (version 3.3) on a Dell Optiplex GX280 personal computer.
  • the mobile phase consisted of 8:2 (v/v) acetonitrile/water and the SYMMETRY HPLC column (4.6 mm x 150 mm) was packed with C 18 Silica from Waters. The column was maintained at room temperature during the analyses.
  • the reported half-lives for the compounds are averages calculated from a minimum of two replicates. Half-lives for the individual replicates were calculated from regression curves fitted to plots of the compound concentration versus time.
  • the metabolism data indicate that the ester replacements were effective in increasing the metabolic half-lives of the analogues relative to the methyl ester parent compounds. Many of the compounds, and especially the more potent inhibitors such as compound 66, exhibited half-lives of at least three hours, which should translate into a longer half-life in a human system with similar metabolic processes.
  • the side chain ester SAR indicates this region of compounds is more flexible to change, relative to the rest of the molecule; however, conservation of electrostatic potential and hydrogen bond acceptor sites appears to be desirable for achieving high potency. It is appreciated that replacing the remaining side chain ester with a hydrolytically stable heterocycle (such as an alkylated tetrazole or 1,3,4-oxadiazole) that possesses a similar electrostatic potential surface, volume, and number of hydrogen bond acceptor sites as an ester may be advantageous.
  • a hydrolytically stable heterocycle such as an alkylated tetrazole or 1,3,4-oxadiazole
  • EC 50 is the 50% inhibitory concentration for inhibition of the cytopathic effect of HIV-I RF in CEM-SS cells, HTV-I 11IB in MT-4 cells, or HIV-2 R0D in MT-4 cells.
  • c CC 5 o is the cytotoxic concentration required to induce cell death for 50% of the mock infected CEM-SS or MT-4 cells. ⁇ The metabolic half-life of the compound when it was incubated with rat plasma; determined from a minimum of two replicates. e Not Active. ⁇ Not Tested. (g) A mixture (1 : 1) of E- and Z-isomers.

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Abstract

La présente invention concerne des composés alcényldiarylméthanes. Ces composés constituent une catégorie d'inhibiteurs non-nucléosides de la transcriptase inverse du VIH-I, qui peuvent également être utilisés dans le cadre d'une thérapie combinatoire visant à traiter une infection par le VIH. Les composés décrits ici présentent une activité antivirale. Ces composés possèdent en outre une stabilité métabolique. La présente invention concerne également des procédés de préparation de composés alcényldiarylméthanes.
PCT/US2008/058463 2007-03-27 2008-03-27 Alcényldiarylméthanes présentant des dérivés d'acide carboxylique contenant de l'azote Ceased WO2008119028A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2007005531A2 (fr) * 2005-06-30 2007-01-11 Purdue Research Foundation Alcenyldiarylmethanes, analogues fondus et synthese

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Publication number Priority date Publication date Assignee Title
WO2007005531A2 (fr) * 2005-06-30 2007-01-11 Purdue Research Foundation Alcenyldiarylmethanes, analogues fondus et synthese

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
CASIMIRO-GARCIA A. ET AL.: "Synthesis and anti-HIV activity of cosalane analogues incorporating nitrogen in the linker chain", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 8, no. 1, 2000, pages 191 - 200, XP002428445, DOI: doi:10.1016/S0968-0896(99)00269-2 *
CULLEN M.D. ET AL.: "Synthesis and Biological Evaluation of Alkenyldiarylmethane HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors That Possess Increased Hydrolytic Stability", JOURNAL OF MEDICINAL CHEMISTRY, vol. 50, no. 20, 6 September 2007 (2007-09-06), pages 4854 - 4867 *
CUSHMAN M. ET AL.: "New Alkenyldiarylmethanes with Enhanced Potencies as Anti-HIV Agents Which Act as Non-Nucleoside Reverse Transcriptase Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 41, no. 12, 1998, pages 2076 - 2089, XP002924578, DOI: doi:10.1021/jm9800595 *
DENG B.L. ET AL.: "Replacement of the Metabolically Labile Methyl Esters in the Alkenyldiarylmethane Series of Non-Nucleoside Reverse Transcriptase Inhibitors with Isoxazolone, Isoxazole, Oxazolone, or Cyano Substituents", JOURNAL OF MEDICINAL CHEMISTRY, vol. 49, no. 17, 2006, pages 5316 - 5323 *
HORNER J.H. ET AL.: "Absolute Kinetics of Amidyl Radical Reactions", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 120, no. 31, 1998, pages 7738 - 7748 *
SAKAMOTO T. ET AL.: "Synthesis and anti-HIV Activity of New Metabolically Stable Alkenyldiarylmethane Non-Nucleoside Reverse Transcriptase Inhibitors Incorporating N-Methoxy Imidoyl Halide and 1,2,4-Oxadiazole Systems", JOURNAL OF MEDICINAL CHEMISTRY, vol. 50, no. 14, 19 June 2007 (2007-06-19), pages 3314 - 3321 *
XU G. ET AL.: "Solid-Phase Synthesis of the Alkenyldiarylmethane (ADAM) Series of Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors", JOURNAL OF ORGANIC CHEMISTRY, vol. 66, no. 18, 2001, pages 5958 - 5964, XP002428444, DOI: doi:10.1021/jo0100291 *
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