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WO2005113580A1 - Composes et compositions anti-coronavirus, utilisations pharmaceutiques associees et materiaux pour la synthese de ces composes et compositions - Google Patents

Composes et compositions anti-coronavirus, utilisations pharmaceutiques associees et materiaux pour la synthese de ces composes et compositions Download PDF

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Publication number
WO2005113580A1
WO2005113580A1 PCT/IB2005/001289 IB2005001289W WO2005113580A1 WO 2005113580 A1 WO2005113580 A1 WO 2005113580A1 IB 2005001289 W IB2005001289 W IB 2005001289W WO 2005113580 A1 WO2005113580 A1 WO 2005113580A1
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Prior art keywords
oxopyrrolidin
oxo
amino
methyl
methoxy
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PCT/IB2005/001289
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English (en)
Inventor
Robert Louis Hoffman
Robert Steven Kania
James Andrew Nieman
Simon Paul Planken
George Joseph Smith, Iii
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Pfizer Inc.
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Publication of WO2005113580A1 publication Critical patent/WO2005113580A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N

Definitions

  • the invention relates to compounds and methods of inhibiting Severe Acute Respiratory Syndrome viral replication activity comprising contacting a SARS-related coronavirus 3C-like proteinase with a therapeutically effective amount of a SARS 3C-like protease inhibitor.
  • the invention further relates to pharmaceutical compositions containing the SARS 3C like proteinase inhibitor in a mammal by administering effective amounts of such coronavirus 3C like proteinase inhibitor.
  • a worldwide outbreak of .Severe Acute Respiratory Syndrome-related coronavirus (“SARS”) has been associated with exposures originating from a single ill health care worker from Guangdongzhou, China. Recently, the causative agent has been identified as a novel coronavirus.
  • coronavirus replication and transcription function is encoded by the so-called "replicase” gene (Thiel, Herald et al. 2001), which consists of two overlapping polyproteins that are extensively processed by viral proteases. The C-proximal region is processed at eleven conserved interdomain junctions by the coronavirus main or "3C-like" protease (Ziebuhr, Snijder et al. 2000).
  • 3C-like protease derives from certain similarities between the coronavirus enzyme and the well-known picornavirus 3C proteases (Gorbalenya, Koonin et al. 1989). These include substrate preferences, use of cysteine as an active site nucleophile in catalysis, and similarities in their putative overall polypeptide folds. Very recently Hilgenfeld and colleagues published a high- resolution X-ray structure of the porcine transmissible gastroenteritis coronavirus main protease (Anand, Palm et al. 2002). Atomic coordinates are available through the Protein Data Bank under accession code 1 LVO.
  • the present invention relates to compounds of formula I:
  • n is an integer selected from 0 and 1 ;
  • Y is selected from the group consisting of H, -CH 3 , and -CH 2 CH 3 ;
  • R 1 is Ci to C 7 alkyl, C 3 to C 10 cycloalkyl, and benzyl wherein said alkyl, benzyl and cycloalkyl is unsubstituted or independently substituted with 1 to 3 R 7 substituents;
  • R 2 is selected from
  • R 3 is independently selected from H and C ⁇ to C 3 alkyl
  • each R 4 and R 4 is independently H, Ci to C 3 alkyl or C 3 to C 6 cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with oxo, 1 to 3 halogens or 1 to 3 hydroxyls;
  • R 5 is H or selected from R 7 substituents
  • R 6 is C 6 to C 10 aryl, benzyl, C 3 to C 10 cycloalkyl, 4 to 10 member heterocycle or C-i to C 7 alkyl wherein the foregoing R 6 substituents are unsubstituted or independently substituted with 1 to 3 R 7 substituents;
  • each R 7 is independently selected from halogen, oxo, C-i to C 4 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, C 3 to C 6 cycloalkyl, -OR 4 , -NR C(0)R 4 , -NR 4 R 4' , SR 4 , -SOR 4 , -S0 2 R 4 , -C(0)R 4 , -C0 2 R 4 , - C(O)NR 4 R 4' , -S0 2 NR 4 R 4' , -NR 4 S0 2 NR R 4' , 4 to 10 member heterocycle and -OC(O)R 4 , wherein the foregoing alkyl, alkenyl, alkynyl, cycloalkyl and heterocycle groups are each optionally substituted with halogen, hydroxy, C-i to C 6 alkoxy, and oxo;
  • Z is selected from the group consisting of and n is 0 to 3;
  • A is 4 to 10 member heterocycle, C 3 to C 10 cycloalkyl, C 6 to C 0 aryl and Ci to C 7 alkyl , wherein said heterocycle, cycloalkyl, alkyl and aryl are unsubstituted or independently substituted with 1 to 3 R 7 substituents;
  • X is selected from -OH, -OR 6 , CI, Br, I, and -OC(O)R 6 .
  • the compounds of the invention also include compounds with the following structure:
  • n is an integer selected from 0 and 1 ;
  • Y is selected from the group consisting of H, -CH 3 , and -CH 2 CH 3 ;
  • R 1 is Ci to C 7 alkyl, C 3 to C 10 cycloalkyl, and benzyl wherein said alkyl, benzyl and cycloalkyl is unsubstituted or independently substituted with 1 to 3 R 7 substituents;
  • R is selected from
  • R is selected from H and C- ⁇ to C 3 alkyl
  • each R and R 4' is independently H or Ci to C 3 alkyl
  • R 5 is H or selected from R 7 substituents;
  • R 6 is C 6 to C 10 aryl, benzyl, C 4 to C 10 cycloalkyl, 4 to 10 member heterocycle or C ⁇ to C 7 alkyl wherein the foregoing R 6 substituents are unsubstituted or independently substituted with 1 to 3 R 7 substituents;
  • each R 7 is independently selected from halogen, oxo, C-i to C 4 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, -OR 4 , -NC(0)R 4 , -NR R 4' , SR 4 , -SOR 4 , -S0 2 R 4 , -C(0)R 4 , -C0 2 R 4 , -C(0)NR 4 R 4' , -S0 2 NR 4 R 4' , - NR 4 S0 2 NR R 4' , 4 to 10 member heterocycle and -OC(0)R 4 , wherein the foregoing R 7 groups are each optionally substituted with halogen, hydroxy, C-i to C 6 alkoxy, and C 3 to C 6 cycloalkyl wherein said cycloalkyl is unsubstituted or independently substituted with 1 to 3 of substituents independently selected from halogen, hydroxy and Ci to C 6 alkoxy;
  • Z is selected from the group consisting of n is 0 to 3;
  • A is 4 to 10 member heterocycle, C 4 to C 10 cycloalkyl, C 6 to C 10 aryl and C ⁇ to C 7 alkyl , wherein said heterocycle, cycloalkyl, alkyl and aryl are unsubstituted or independently substituted with 1 to 3 R 7 substituents;
  • X is selected from -OH, -OR 6 , CI, Br, I, and -OC(0)R 6 .
  • the present invention provides methods of inhibiting the activity of a coronavirus 3C protease (also known as proteinase), comprising contacting the coronavirus 3C protease with an effective amount of a SARS 3C protease inhibitor compound or agent.
  • the present invention provides a novel method of interfering with or preventing SARS viral replication activity comprising contacting a SARS protease with a therapeutically effective amount of a rhinovirus protease inhibitor.
  • the SARS coronavirus 3C-like protease inhibitor is administered orally or intravenously.
  • the present invention also provides a method of treating a condition that is mediated by coronavirus 3C-like protease activity in a patient by administering to said patient a pharmaceutically effective amount of a SARS protease inhibitor.
  • the present invention also provides a method of targeting SARS inhibition as a means of treating indications caused by SARS-related viral infections.
  • the present invention also provides a method of targeting viral or cellular targets identified by using rhinovirus inhibitors against SARS coronavirus 3C-like protease for treating indications caused by SARS-related viral infections.
  • the present invention also provides a method of identifying cellular or viral pathways interfering with the functioning of the members of which could be used for treating indications caused by SARS infections by administering a SARS protease inhibitor.
  • the present invention also provides a method of using SARS protease inhibitors as tools for understanding mechanism of action of other SARS inhibitors.
  • the present invention also provides a method of using SARS 3C like protease inhibitors for carrying out gene profiling experiments for monitoring the up or down regulation of genes for the purposed of identifying inhibitors for treating indications caused by SARS infections.
  • the present invention further provides a pharmaceutical composition for the treatment of SARS in a mammal containing an amount of a SARS 3C like protease inhibitor that is effective in treating SARS and a pharmaceutically acceptable carrier.
  • halo means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
  • alkyl as used herein, unless otherwise indicated, includes saturated and unsaturated monovalent hydrocarbon radicals having straight or branched moieties.
  • alkenyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above and including E and Z isomers of said alkenyl moiety.
  • alkynyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above.
  • alkoxy as used herein, unless otherwise indicated/includes O-alkyl groups wherein alkyl is as defined above.
  • cycloalkyl refers to a non-aromatic, saturated or partially saturated, monocyclic or fused, spiro or unfused bicyclic or tricyclic hydrocarbon referred to herein containing a total of from 3 to 10 carbon atoms, preferably 5-8 ring carbon atoms.
  • cycloalkyls include monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Illustrative examples of cycloalkyl are derived from, but not limited to, the following:
  • aryl includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
  • 4 to 10 membered heterocyclic includes aromatic and non-aromatic heterocyclic gfbups containing one to four heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4 to 10 atoms in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms.
  • Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system.
  • the heterocyclic groups include benzo-fused ring systems.
  • An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine).
  • An example of a 5 membered heterocyclic group is thiazolyl and an example of a 10 membered heterocyclic group is quinolinyl.
  • non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,6- tetrahydropyridinyl, 2-pyrroIinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1 ,3- dioxolanyl, pyrazol
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached).
  • the 4 to 10 membered heterocyclic may be optionally substituted on any ring carbon, sulfur, or nitrogen atom(s) by one to two oxo, per ring.
  • heterocyclic group wherein 2 ring carbon atoms are substituted with oxo moieties is 1 ,1-dioxo-thiomorpholinyl.
  • Other illustrative examples of 4 to 10 membered heterocyclic are derived from, but not limited to, the following:
  • pharmaceutically acceptable salt(s) includes salts of acidic or basic groups which may be present in the compounds of formula L
  • the compounds of formula I that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula I are those that form non-toxic acid addition salts, La., salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsultate, mu
  • Certain compounds of formula I may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of formula I, and mixtures thereof, are considered to be within the scope of the invention.
  • the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof.
  • the compounds of formula I may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
  • Certain functional groups contained within the compounds of the present invention can be substituted for bioisosteric groups, that is, groups which have similar spatial or electronic requirements to the parent group, but exhibit differing or improved physicochemical or other properties.
  • Suitable examples are well known to those of skill in the art, and include, but are not limited to moieties described in Patini et al., Chem. Rev, 1996, 96, 3147-3176 and references cited therein.
  • the subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium, i.e., 2 H can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • This invention also encompasses pharmaceutical compositions containing and methods of treating SARS infections through administering prodrugs of compounds of the formula I.
  • Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of formula I.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, omithine and methionine sulfone. Additional types of prodrugs are also encompassed.
  • free carboxyl groups can be derivatized as amides or alkyl esters.
  • Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • dosing a SARS coronavirus infected patient with the SARS coronavirus 3CL protease inhibitor of the invention and an interferon, such as interferon alpha, or a pegylated interferon, such as PEG-lntron or Pegasus may provide a greater clinical benefit than dosing either the interferon, pegylated interferon or the SARS coronavirus inhibitor alone.
  • interferon such as interferon alpha
  • a pegylated interferon such as PEG-lntron or Pegasus
  • Examples of greater clinical benefits could include a larger reduction in symptoms, a faster time to alleviation of symptoms, reduced lung pathology, a larger reduction in the amount of SARS coronavirus in the patient (viral load), and decreased mortality.
  • the SARS coronavirus infects cells which express p-glycoprotein.
  • SARS coronavirus 3CL protease inhibitors of the invention are p-glycoprotein substrates.
  • Compounds which inhibit the SARS coronavirus which are also p-glycoprotein substrates may be dosed with p- glycoprotein inhibitor.
  • p-glycoprotein inhibitors are verapamil, vinblastine, ketoconazole, nelfinavir, ritonavir or cyclosporine.
  • the p-glycoprotein inhibitors act by inhibiting the efflux of the SARS coronavirus inhibitors of the invention out of the cell. The inhibition of the p-glycoprotein based efflux will prevent reduction of intracellular concentrations of the SARS coronavirus inhibitor due to p- glycoprotein efflux.
  • Inhibition of the p-glycoprotein efflux will result in larger intracellular concentrations of the SARS coronavirus inhibitors.
  • Dosing a SARS coronavirus infected patient with the SARS coronavirus 3CL protease inhibitors of the invention and a p-glycoprotein inhibitor may lower the amount of SARS coronavirus 3CL protease inhibitor required to achieve an efficacious dose by increasing the intracellular concentration of the SARS coronavirus 3CL protease inhibitor.
  • the agents that may be used to increase the exposure of a mammal to a compound of the present invention are those that can as inhibitors of at least one isoform of the cytochrome P450 (CYP450)enzymes.
  • the isoforms of CYP450 that may be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4.
  • the compounds of the invention include compounds that are CYP3A4 substrates and are metabolized by CYP3A4.
  • a SARS coronavirus inhibitor which is a CYP3A4 substrate such as a SARS coronavirus 3CL protease inhibitor
  • a CYP3A4 inhibitor such as ritonavir, nelfinavir or delavirdine
  • SARS-inhibiting agent means any SARS related coronavirus 3C like protease inhibitor compound represented by formula l or a pharmaceutically acceptable salt, hydrate, prodrug, active metabolite or solvate thereof.
  • interfering with or preventing" SARS-related coronavirus (“SARS") viral replication in a cell means to reduce SARS replication or production of SARS components necessary for progeny virus in a cell as compared to a cell not being transiently or stably transduced with the ribozyme or a vector encoding the ribozyme.
  • Simple and convenient assays to determine if SARS viral replication has been reduced include an ELISA assay for the presence, absence, or reduced presence of anti-SARS antibodies in the blood of the subject (Nasoff et al., PNAS 88:5462-5466, 1991), RT-PCR (Yu et al., in Viral Hepatitis and Liver Disease 574-477, Nishioka, Suzuki and Mishiro (Eds.); Springer- Verlag Tokyo, 1994). Such methods are well known to those of ordinary skill in the art.
  • total RNA from transduced and infected "control" cells can be isolated and subjected to analysis by dot blot or northern blot and probed with SARS specific DNA to determine if SARS replication is reduced.
  • reduction of SARS protein expression can also be used as an indicator of inhibition of SARS replication. A greater than fifty percent reduction in SARS replication as compared to control cells typically quantitates a prevention of SARS replication.
  • an inhibitor compound used in the method of the invention is a base
  • a desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like), or with an organic acid (such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid (such as glucuronic acid or galacturonic acid), alpha-hydroxy acid (such as citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid or cinnamic acid), sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid), and the like.
  • an inorganic acid such
  • an inhibitor compound used in the method of the invention is an acid
  • a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base (such as an amine (primary, secondary, or tertiary)), an alkali metal hydroxide, or alkaline earth metal hydroxide.
  • suitable salts include organic salts derived from amino acids (such as glycine and arginine), ammonia, primary amines, secondary amines, tertiary amines, and cyclic amines (such as piperidine, morpholine, and piperazine), as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • amino acids such as glycine and arginine
  • ammonia such as primary amines, secondary amines, tertiary amines, and cyclic amines (such as piperidine, morpholine, and piperazine)
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • hydroxamate compound, prodrugs, salts, or solvates used in the method of the invention, may exist in different polymorph or crystal forms, all of which are intended to be within the scope of the present invention and specified formulas.
  • hydroxamate compound, salts, prodrugs and solvates used in the method of the invention may exist as tautomers, all of which are intended to be within the broad scope of the present invention.
  • Solubilizing agents may also be used with the compounds of the invention to increase the compounds solubility in water or physiologically acceptable solutions.
  • solubilizing agents include cyclodextrans, propylene glycol, diethylacetamide, polyethylene glycol, Tween, ethanol and micelle forming agents.
  • Oreffered solubilizing agents are cyclodextrans, particularly beta cyclodextrans and in particular hydroxypropyl betacyclodextran and sulfobutylether betacyclodextran.
  • the inhibitor compounds, salts, prodrugs and solvates used in the method of the invention may have chiral centers. When chiral centers are present, the hydroxamate compound, salts, prodrugs and solvates may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers.
  • an optically pure compound is one that is enantiomerically pure.
  • the term "optically pure” is intended to mean a compound comprising at least a sufficient activity.
  • an optically pure amount of a single enantiomer to yield a compound having the desired pharmacological pure compound of the invention comprises at least 90% of a single isomer (80% enantiomeric excess), more preferably at least 95% (90% e.e.), even more preferably at least 97.5% (95% e.e.), and most preferably at least 99% (98% e.e.).
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • “treating” or “treatment” means at least the mitigation of a disease condition in a human, that is alleviated by the inhibition of the activity of one or more coronaviral 3C-like proteases, including, but not limited to the 3C-like protease of the causative agent for SARS.
  • representative disease conditions include fever, dry cough, dyspnea, headache, hypoxemia, lymphopenia, elevated am inotransf erase levels as well as viral titer.
  • Methods of treatment for mitigation of a disease condition include the use of one or more of the compounds in the invention in any conventionally acceptable manner.
  • the compound or compounds of the present invention are administered to a mammal, such as a human, in need thereof.
  • the mammal in need thereof is infected with a coronavirus such as the causative agent of SARS.
  • the present invention also includes prophylactic methods, comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate thereof to a mammal, such as a human, at risk for infection by a coronavirus.
  • an effective amount of one or more compounds of the invention, or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate thereof is administered to a human at risk for infection by the causative agent for SARS.
  • the prophylactic methods of the invention include the use of one or more of the compounds in the invention in any conventionally acceptable manner. The following are examples of specific embodiments of the invention:
  • I 7 Chart 1 depicts the general preparation of compounds I , wherein the definitions of R 2 , Z, Y, X, A and B are given in the summary of the invention and PG is a suitable protecting group.
  • Compound 1 is selectively de-protected employing standard conditions known in the art (see Protective Groups in Organic Synthesis, Greene & Wuts, Wiley-lnterscience, New York, 3 rd edition, 1999) to provide the corresponding amino acid 2 wherein PG is a suitable protecting group.
  • Compound 2 is converted to a mixed anhydride followed by treatment with diazomethane to generate the diazo ketone 3 (see Rich, D., et al., Journal of Medicinal Chemistry, 35, 1992, 3803-3812).
  • Compound 3 is subjected to an excess of a mineral acid (such as hydrochloric acid or hydrobromic acid) to provide halomethylketone 4.
  • Halomethylketone 4 is reacted with an N-protected amino acid (such as a BOC- protected amino acid) employing standard peptide coupling conditions and/or methods known in the art (for example HATU in the presence of a suitable base such as NMM or TEA) to provide 5.
  • Compound 5 is subjected to standard nitrogen de-protecting conditions (such as HCL in a solvent such as dioxane) followed by reaction with a carboxylic acid utilizing standard peptide coupling conditions and/or methods known in the art to provide 6.
  • Compound 6 is reacted with a carboxylic acid in the presence of a suitable base (such as CsF or KF) and solvent (for example DMF) to produce 1 (see Krantz, A., et al., Biochemistry, 30, 1991 , 4678-4687).
  • a suitable base such as CsF or KF
  • solvent for example DMF
  • Compound 6 is reacted with benzoylformic acid and an appropriate base (for example cesium fluoride or potassium fluoride) in a suitable solvent (such as DMF) to provide 7 (for general procedure see Marquis, R., et al., Bioorganic & Medicinal Chemistry, 7, 1999, 581-588).
  • Compound 7 is reacted with methanol and catalytic amounts of an appropriate base (such as potassium carbonate) or alternatively with an aqueous base (for example 1 M sodium bicarbonate) in a suitable solvent such as THF to provide hydroxymethylketone I where R 1 is hydrogen (see Mendonca, R., etal., Bioorganic & Medicinal Chemistry Letters, 12, 2002, 2887-2891 or Ellman, J., et al., Bioorganic & Medicinal Chemistry, 11, 2003, 21-29).
  • an appropriate base such as potassium carbonate
  • an aqueous base for example 1 M sodium bicarbonate
  • Compound I is reacted with an alkylhalide in the presence of a suitable agent (such as silver(l) oxide) and an appropriate solvent (for example DCM, or 1 ,2-DCE) to afford alkoxymethylketones I.
  • a suitable agent such as silver(l) oxide
  • an appropriate solvent for example DCM, or 1 ,2-DCE
  • the activity of the compounds of the present invention as inhibitors of coronavirus 3C-like protease activity may be measured by any of the suitable methods known to those skilled in the art, including in vivo and in vitro assays.
  • suitable assays for activity measurements include the antiviral cell culture assays described herein as well as the antiprotease assays described herein, such as the assays described in the Example section.
  • Administration of the inhibitor compounds and their pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates may be performed according to any of the accepted modes of administration available to those skilled in the art.
  • a SARS-inhibiting agent may be administered as a pharmaceutical composition in any suitable pharmaceutical form.
  • suitable pharmaceutical forms include solid, semisolid, liquid, or lyopholized formulations, such as tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols.
  • the SARS-inhibiting agent may be prepared as a solution using any of a variety of methodologies.
  • the SARS-inhibiting agent can be dissolved with acid (e.g., 1 M HCI) and diluted with a sufficient volume of a solution of 5% dextrose in water (D5W) to yield the desired final concentration of SARS-inhibiting agent (e.g., about 15 mM).
  • a solution of D5W containing about 15 mM HCI can be used to provide a solution of the SARS-inhibiting agent at the appropriate concentration.
  • the SARS-inhibiting agent can be prepared as a suspension using, for example, a 1% solution of carboxymethylcellulose (CMC). Acceptable methods of preparing suitable pharmaceutical forms of the pharmaceutical compositions are known or may be routinely determined by those skilled in the art.
  • compositions of the invention may also include suitable excipients, diluents, vehicles, and carriers, as well as other pharmaceutically active agents, depending upon the intended use. Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles, or excipients may be employed in the pharmaceutical compositions.
  • Illustrative solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, pectin, acacia, magnesium stearate, and stearic acid.
  • Illustrative liquid carriers include syrup, peanut oil, olive oil, saline solution, and water.
  • the carrier or diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g., solution), or a nonaqueous or aqueous liquid suspension.
  • a dose of the pharmaceutical composition may contain at least a therapeutically effective amount of an SARS-inhibiting agent and preferably is made up of one or more pharmaceutical dosage units.
  • the selected dose may be administered to a mammal, for example, a human patient, in need of treatment mediated by inhibition of SARS-related coronavirus activity, by any known or suitable method of administering the dose, including topically, for example, as an ointment or cream; orally; rectally, for example, as a suppository; parenterally by injection; intravenously; or continuously by intravaginal, intranasal, intrabronchial, intraaural, or intraocular infusion.
  • the phrases "therapeutically effective amount” and "effective amount” are intended to mean the amount of an inventive agent that, when administered to a mammal in need of treatment, is sufficient to effect treatment for injury or disease conditions alleviated by the inhibition of SARS viral replication.
  • the amount of a given SARS-inihibiting agent used in the method of the invention that will be therapeutically effective will vary depending upon factors such as the particular SARS- inihibiting agent, the disease condition and the severity thereof, the identity and characteristics of the mammal in need thereof, which amount may be routinely determined by artisans. It will be appreciated that the actual dosages of the SARS-inhibiting agents used in the pharmaceutical compositions of this invention will be selected according to the properties of the particular agent being used, the particular composition formulated, the mode of administration and the particular site, and the host and condition being treated. Optimal dosages for a given set of conditions can be ascertained by those skilled in the art using conventional dosage-determination tests.
  • a dose that may be employed is from about 0.01 to about 1000 mg/kg body weight, preferably from about 0.1 to about 500 mg/kg body weight, and even more preferably from about 1 to about 500 mg/kg body weight, with courses of treatment repeated at appropriate intervals.
  • a dose of up to 5 grams per day may be employed.
  • a particular compound of decreases cytochrome P450 enzyme activity can be determined by methods known to those of ordinary skill in the art and the methods described herein.
  • Protein functions required for coronavirus replication and transcription are encoded by the so-called "replicase” gene. Two overlapping polyproteins are translated from this gene and extensively processed by viral proteases. The C-proximal region is processed at eleven conserved interdomain junctions by the coronavirus main or "3C-like" protease.
  • the name "3C-like" protease derives from certain similarities between the coronavirus enzyme and the well-known picornavirus 3C proteases.
  • Substrate specificity is largely determined by the P2, P1 and P1 ' positions. Coronavirus main protease cleavage site specificities are highly conserved with a requirement for glutamine at P1 and a small amino acid at P1' (Journal of General Virology 83, pp. 595-599 (2002)). Recently, Hilgenfeld and colleagues published a high-resolution x-ray structure of the porcine transmissible gastroenteritis coronavirus main protease (The EMBO Journal, Vol. 21 , pp. 3213-3224 (2002)). Atomic coordinates are available through the Protein Data Bank under accession code 1LVO.
  • ⁇ H NMR Proton magnetic resonance
  • the samples are run on a Hewlett Packard- 1100 systemA gradient solvent method is used running 100 percent ammonium acetate / acetic acid buffer (0.2 M) to 100 percent acetonitrile over 10 minutes. The system then proceeds on a wash cycle with 100 percent acetonitrile for 1.5 minutes and then 100 percent buffer solution for 3 minutes. The flow rate over this period is a constant 3 ml / minute.
  • Et means ethyl
  • Ac means acetyl
  • Me means methyl
  • ETOAC or "ETOAc” means ethyl acetate
  • THF means tetrahydrofuran
  • Bu means butyl Et 2 0 refers to diethyl ether
  • DMF refers to ⁇ /, ⁇ /-dimethylformamide
  • DMSO refers to dimethylsulfoxide.
  • MTBE refers to te/f-butyl methyl ether.
  • DCM ethylene glycol dimethyl ether
  • 1 ,2 DCE ethylene glycol dimethyl ether
  • Ph phenyl
  • Tr triphenylmethyl
  • Cbz benzyloxycarbonyl
  • Boc terf-butoxycarbonyl
  • TFA trifluoroacetic acid
  • DIEA ⁇ /, ⁇ -diisopropylethylamine
  • TMEDA ⁇ /, ⁇ /, ⁇ /', ⁇ /'-tetramethylethylenediamine
  • AcOH acetic acid
  • Ac 20 acetic anhydride
  • NMM 4-methylmorpholine
  • HOBt (1-hydroxybenzotriazole hydrate
  • HATU 0-(7-azabenzotriazol-1 -yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /'-tetramethyluronium hexa
  • amino ester A-1 (described by Tian, Q., et al., Tetrahedron Letters, 42, 2001 , 6807-6809) is converted under standard conditions known in the art (such as aqueous LiOH and methanol) to the corresponding amino acid A-2.
  • Compound A-2 is converted to a mixed anhydride followed by treatment with diazomethane to generate the diazo ketone A-3 (Rich, D., etal., Journal of Medicinal Chemistry, 35, 1992, 3803-3812).
  • Compound A-3 is subjected to excess hydrochloric acid to provide chloromethylketone A-5 with concomitant removal of the ferf-butoxycarbonyl (Boc) nitrogen protecting group.
  • A-3 is reacted with stoichiometric quantities of hydrobromic acid to generate the nitrogen Boc-protected bromomethylketone A-4.
  • Chart B describes an alternative preparation of A-5.
  • Amino ester A-1 is reacted with a species produced by the action of a suitable base (for example n-Bu ⁇ or LDA) and chloroiodomethane to generate B-1 (see Chen, P., et al., Tetrahedron Letters, 38, 1997, 3175-78).
  • Compound B-1 is subjected to standard N-Boc de-protection procedures (such as HCL in a solvent such as dioxane) to afford A-5 (see Protective Groups in Organic Synthesis, Greene & Wuts, Wiley-lnterscience, New York, 3 rd edition, 1999).
  • Chart C describes an alternative preparation of A-5.
  • Amino ester A-1 is reacted with a species produced by the action of a suitable base (for example n-Bu ⁇ or LDA) and chloroiodomethane to generate B-1 (see Chen, P., et al., Tetrahedron Letters
  • chloromethylketone A-5 is reacted with an N-protected amino acid employing standard peptide coupling conditions and/or methods known in the art (for example HATU in the presence of a suitable base such as NMM or TEA) to provide C-1.
  • Compound C-1 is subjected to standard nitrogen de-protecting conditions (such as HCL in a solvent such as dioxane) followed by reaction with a carboxylic acid utilizing standard peptide coupling conditions and/or methods known in the art to provide C-2.
  • Compound C-2 is reacted with benzoylformic acid and an appropriate base (for example cesium fluoride or potassium fluoride) in a suitable solvent (such as DMF) to generate C- 3 (for general procedure see Marquis, R., et al., Bioorganic & Medicinal Chemistry, 7, 1999, 581-588).
  • an appropriate base for example cesium fluoride or potassium fluoride
  • a suitable solvent such as DMF
  • Compound C-3 is reacted with methanol and catalytic amounts of an appropriate base (such as potassium carbonate) or alternatively with an aqueous base (for example 1 M sodium bicarbonate) in a suitable solvent such as THF to provide hydroxymethylketone C-4 (see Mendonca, R., ef al., Bioorganic & Medicinal Chemistry Letters, 12, 2002, 2887-2891 or Ellman, J., et al., Bioorganic & Medicinal Chemistry, 11, 2003, 21-29).
  • Compound C-4 is reacted with an alkylhalide in the presence of a suitable agent (such as silver(l) oxide) and an appropriate solvent (for example DCM, or 1,2- DCE) to afford alkoxymethylketones C-5.
  • Chart D a suitable agent
  • an appropriate solvent for example DCM, or 1,2- DCE
  • Compound D-3 is treated with an excess of an organometallic species generated from benzyloxymethyl chloride (see Mendonca, R.V., et al., Bioorganic & Medicinal Chemistry Letters, 11, 2002, 2887-91 for Grignard procedure or Buchanan, J.L., et al., Tetrahedron Letters, 40, 1999, 3985-3988 for organostanane procedure) to provide (benzyloxy)methyl ketone D-4.
  • organometallic species generated from benzyloxymethyl chloride
  • Compound D-4 is subjected to standard nitrogen de- protecting conditions followed by reaction with a N-protected amino acid employing standard peptide coupling conditions and/or methods known in the art (for example HATU in the presence of a suitable base such as NMM or TEA) to provide D-5.
  • Compound D-5 is subjected to standard nitrogen de- protecting conditions (such as HCI in a solvent such as dioxane) followed by reaction with a carboxylic acid utilizing standard peptide coupling conditions and/or methods known in the art to provide D-6.
  • Chart E depicts the preparation of (acyloxy)methylketones E-1.
  • Compound C-2 is reacted with a carboxylic acid in the presence of a suitable base (such as CsF or KF) and solvent (for example DMF) to produce E-1 (see Krantz, A., et al., Biochemistry, 30, 1991, 4678-4687).
  • a suitable base such as CsF or KF
  • solvent for example DMF
  • Chart F An alternative method for the preparation of (acyloxy)methylketones E-1 is depicted in Chart F.
  • A-4 is reacted with a carboxylic acid in the presence of a suitable base (such as CsF or KF) and solvent (for example DMF) to produce F-1 (see Krantz, A., et al., Biochemistry, 30, 1991 , 4678-4687).
  • Compound F-1 is subjected to standard nitrogen de-protecting conditions (such as HCI in a solvent such as dioxane) followed by reaction with a N-protected amino acid employing standard peptide coupling conditions and/or methods known in the art (for example HATU in the presence of a suitable base such as NMM or TEA) to provide F-2.
  • Compound F-2 is subjected to standard nitrogen de- protecting conditions followed by reaction with a carboxylic acid utilizing standard peptide coupling conditions and/or methods known in the art to provide E-1.
  • Chart G An alternative method for the preparation of (
  • chloromethylketone C-2 is converted to the corresponding azidomethylketone G-1 employing sodium azide in a suitable solvent (see Ellman, J.A., et al., Bioorganic & Medicinal Chemistry Letters, 12, 2002, 2993-2996).
  • Compound G-1 is reacted with a suitable palladium catalyst in the presence of hydrogen and hydrochloric acid to provide aminomethylketone G-2 (see DeGraw, J.I., et al, Journal of Medicinal Chemistry, 33, 1990, 212-215).
  • Compound G-2 is reacted with various acid halides, carboxylic acids, sulfonylchlorides, or isocyanates under standard methods and conditions known in the art to afford G-3.
  • azide G-1 is reduced in the presence of a suitable reagent (such as acetic acid anhydride) to directly afford G-3 (see US 4,325,877).
  • Chart H Another preparation of aminomethylketones is illustrated in Chart H.
  • Compound C-2 is reacted with secondary amines in a suitable solvent (such as THF or DMF) to afford tertiary amines H-1 (see Norbeck, D.W., et al., Journal of Medicinal Chemistry, 33, 1990, 1285-1288).
  • Compound C-2 is also reacted with primary amines to provide H-2.
  • Compound H-2 is reacted with various acid halides, carboxylic acids, sulfonylchlorides, or isocyanates under standard conditions and methods known in the art (for example see Digenis, G.A., etal., Journal of Medicinal Chemistry, 29, 1986, 1468-1476) to provide H-3.
  • Compound 1-3 is subjected to standard N-Boc de-protection procedures to afford 1-4 (see Protective Groups in Organic Synthesis, Greene & Wuts, Wiley-lnterscience, New York, 3 rd edition, 1999).
  • Compound I-4 is reacted with a N-protected amino acid utilizing standard peptide coupling conditions and/or methods known in the art to provide I-5.
  • Compound I-5 is subjected to standard nitrogen de-protecting conditions (such as HCI in a solvent such as dioxane) followed by reaction with a carboxylic acid utilizing standard peptide coupling conditions and/or methods known in the art (for example HATU in the presence of a suitable base such as NMM or TEA) to provide I-6.
  • Compound I- 6 is reacted with benzoylformic acid and an appropriate base (for exarnple cesium fluoride or potassium fluoride) in a suitable solvent (such as DMF) to generate I-7 (for general procedure see Marquis, R., et al., Bioorganic & Medicinal Chemistry, 7, 1999, 581-588).
  • a suitable solvent such as DMF
  • Compound I-7 is reacted with methanol and catalytic amounts of an appropriate base (such as potassium carbonate) or alternatively with an aqueous base (for example 1 M sodium bicarbonate) in a suitable solvent such as THF to provide hydroxymethylketone I-8 (see Mendonca, R., et al., Bioorganic & Medicinal Chemistry Letters, 12, 2002, 2887-2891 or Ellman, J., etal., Bioorganic & Medicinal Chemistry, 11, 2003, 21-29.
  • an appropriate base such as potassium carbonate
  • an aqueous base for example 1 M sodium bicarbonate
  • Chart J depicts the preparation of (acyloxy)m ethyl ketones J-1.
  • Compound I-6 is reacted with a carboxylic acid in the presence of a suitable base (such as CsF or KF) and solvent (for example DMF) to produce J-1 (see Krantz, A., et al., Biochemistry, 30, 1991, 4678-4687).
  • a suitable base such as CsF or KF
  • solvent for example DMF
  • Example 1 N- 1 S)-1 -ffffl S)-3-chloro-2-oxo-1 -(rf3S)-2-oxopyrrolidin-3- yllmethyl>propy0aminolcarbonyll-3-methylbutyl)-4-methoxy-1H-indole-2-carboxamide
  • the resulting solution was stirred at 0 °C for 1 hour before neutralizing with cone, hydrochloric acid (keeping internal temp below 10 °C), then removing the methanol in vacuo.
  • the residue was diluted with ethyl acetate (400 mL), acidified to pH 3 with cone, hydrochloric acid, then the mixture transferred to a sep funnel, and the organics removed.
  • the aqueous was extracted with ethyl acetate (2 x 400 mL), and the combined organics washed with brine, dried over MgS0 , filtered and concentrated to yield the title compound as a white foam, 95%.
  • reaction was stirred for an additional hour and quenched with a mixture of AcOH (33 mL) and THF (200 mL) with rate of addition regulated to maintain the internal temperature below -65 °C. After complete addition, the dark suspension was stirred for 10 minutes then warmed to ambient temperature. The reaction was diluted with ethyl acetate (500 mL) and the organics were washed with water (250 mL), satd. NaHCO 3 (250 mL), brine (250 mL), dried over MgS0 4 , filtered and the solvents removed in vacuo to yield the crude product as a dark oil which was purified by flash chromatography eluting with ethyl acetate.
  • the colorless filtrate was transferred to a non-ground joint flask, cooled to 0 °C, and slowly treated with a solution of diazomethane (-35 mL, -16.6 mmol) in diethyl ehter.
  • the diazomethane was generated employing a Diazald kit according to the procedure described in the Aldrich Technical Bulletin AL-180.
  • the resulting yellow clear solution was gradually warmed to RT over 16 hr. At this time, N 2 was bubbled thru the reaction to remove excess diazomethane followed by in vacuo concentration.
  • the resulting residue was diluted with ethyl acetate (100 mL), washed once with sat.
  • Example 3 4-methoxy- ⁇ H(1 S)-1 -f f((1 S)-3-methoxy-2-oxo-1 -ir(3S)-2-oxopyrrolidin-3- vnmethyllpropyl)aminolcarbonyll-3-methylbutyl)-1 r-indole-2-carboxamide
  • Example 7 ⁇ H(1 S)-1-fl ⁇ (1 S)-3-chloro-2-oxo-1- ⁇ r(3S)-2-oxopyrrolidin-3- vnmethyl ⁇ propyl)aminolcarbonyl)pentyl)-4-methoxy-1 f -indole-2-carboxamide
  • Example 8 N- ⁇ ( ⁇ S)-1 -f ⁇ (( ⁇ S)-3-hvdroxy-2-oxo-1 -f r(3S)-2-oxopyrrolidin-3- yllmethyl
  • Example 9 iV-ffl S)-1 -ffffl S)-3-chloro-2-oxo-1 -(r(3S)-2-oxopyrrolidin-3- vnmethyl ⁇ propyl)aminolcarbonyll-4-methylpentyl)-4-methoxy-1f/-indole-2-carboxamide
  • Example 10 N-((1 S)-1 -1 r «1 S)-3-hvdroxy-2-oxo-1 -f rf3S)-2-oxopyrrolidin-3- vnmethyl ⁇ propyl)aminolcarbonyll-4-methylpentyl)-4-methoxy-1r/-indole-2-carboxamide
  • Example 11 4-methoxy-Jv-((1 S)-1 -f K(1 S)-3-methoxy-2-oxo-1 -(r(3S)-2-oxopyrrolidin-3- vnmethyl>propyl)amino1carbonyl ⁇ -4-methylpentyl)-1r -indole-2-carboxamide
  • Example 12 N-((1 S)-1 -ffffl S)-3-chloro-2-oxo-1 -f r(3S)-2-oxopyrrolidin-3- yllmethyl
  • Example 13 N-(( 1 S)-1 -i ⁇ ((1 S)-3-hvdroxy-2-oxo-1 -f rf3S)-2-oxopyrrolidin-3- yllmethyllpropy0aminolcarbonyll-3,3-dimethylbutyl)-4-methoxy-1rV-indole-2-carboxamide
  • Example 14 4-methoxy- ⁇ H(1 S)-1 -f ⁇ ( (1 S)-3-methoxy-2-oxo-1 - ⁇ r(3S)-2-oxopyrrolidin-3- yllmethyl
  • Example 15 N-(( ⁇ S)-1 -i (C ⁇ S)-3-chloro-2-oxo-1 -i rf3S)-2-oxopyrrolidin-3- vnmethyl ⁇ propyl)amino1carbonyl)-3.3-dimethylbutyl)-1r/-indole-2-carboxamide
  • Example 16 N-(( ⁇ S)-1 - fffl S)-3-hvdroxy-2-oxo-1 -f r 3S)-2-oxopyrrolidin-3- vnmethyl ⁇ propyl)aminolcarbonyll-3,3-dimethylbutyl)-1H-indole-2-carboxamide
  • Example 17 N-((1 S)-1 -ir (1 S)-3-methoxy-2-oxo-1 -f r(3S)-2-oxopyrrolidin-3- yllmethyl ⁇ propyl)aminolcarbonyll-3.3-dimethylbutyl)-1rY-indole-2-carboxamide
  • Example 18 N-((1 S)-1 -ffffl S)-3-ethoxy-2-oxo-1 -f r(3S)-2-oxopyrrolidin-3- yllmethyl ⁇ propyl)aminolcarbonyll-3,3-dimethylbutyl)-1r-indole-2-carboxamide
  • Example 19 N ⁇ -(( ⁇ S)-3-chloro-2-oxo-1-fr 3S)-2-oxopyrrolidin-3-vnmethyl ⁇ propyl)-4-methyl-/v a - r(2ffl-tetrahvdrofuran-2-ylcarbonv ⁇ -L-leucinamide
  • Example 20 ⁇ / 1 -((1 S)-3-hvdroxy-2-oxo-1-fr 3S)-2-oxopyrrolidin-3-yllmethyl ⁇ propyl)-4-methyl- ⁇ ft-r(2fl)-tetrahvdrofuran-2-ylcarbonyll-L-leucinamide
  • This material was purified by a series of two radial chromatographies (1 st - 2mm plate, 90:10 dichloromethane-methanol to 90:20, sample loaded in 90:10)(2 ⁇ d -1 mm plates, 90:10 dichloromethane-methanol to 95:5, sample loaded in dichloromethane) to provide 0.402 g (46%) of the title compound as a light yellow foam.
  • Example 21 JV 1 -((1 S)-3-methoxy-2-oxo-1 -f r(3S)-2-oxopyrrolidin-3-v ⁇ methyl ⁇ propyl)-4-methyl- ⁇ f-r(2fl)-tetrahvdrofuran-2-ylcarbonyll-L-leucinamide
  • Example 23 ⁇ H(1 S)-3-hvdroxy-2-oxo-1 -f r(3S)-2-oxopyrrolidin-3-yllmethyllpropyl)-/V-r(4- methoxy-1Wndol-2-yl)carbonyll-L-phenylalaninamide
  • Example 24 ⁇ M1 S)-1 -(IY(1 S)-3-chloro-2-oxo-1 -f r(3S)-2-oxopyrrolidin-3- vnmethyl)propyl)aminolcarbonyl ⁇ -3-methylbutyl)- ⁇ -methyl-1 r ⁇ indole-2-carboxamide
  • Example 25 N-((1 S)-1 -f K(1 S)-3-hydroxy-2-oxo-1 -(r(3S)-2-oxopyrrolidin-3- yllmethyl ⁇ propyl)aminolcarbonyl ⁇ -3-methylbutyl)- ⁇ /-methyl-1 H-indole-2-carboxamide
  • ⁇ /.O-dimethylhydroxylamine hydrochloric acid salt (68 g, 698 mmol) was added followed by N-methyl morpholine (230 mL, 2.09 mol), HOBt.hydrate (106 g, 698 mmol) and EDCI (147g, 768 mmol) and the mixture stirred at 0 °C under nitrogen for 6 hours before quenching with water (500 mL).
  • the bi-phasic mixture was transferred to a sep-funnel and the organics isolated, washed with 1 M hydrochloric acid (2 x 500 mL), water (400 mL) satd.
  • the crude hydrochloride salt was taken into DMF (3 mL) and the solution cooled to 0 °C before adding ⁇ /-BOC-cyclohexylalanine-OH (139mg, 0.53 mmol), collidine (156 ⁇ L, 1.22 mmol) and HATU (194 mg, 0.53 mmol) in order, and the resulting suspension stirred at 0 °C for 5 hours.
  • the reaction was quenched by the addition of water (30 mL) and the mixture extracted with diethyl ether (3 x 75 mL).
  • Example 26 ⁇ Hfl S)-2-IT(1 S)-3-(benzyloxy)-2-oxo-1 -f r(3S)-2-oxopyrrolidin-3- vnmethyl propy ⁇ aminol-1-(cvclohexylmethyl)-2-oxoethvn-4-methoxy-1 tf-indole-2-carboxamide
  • the crude hydrochloride salt was taken into DMF (3 mL) and the solution cooled to 0 °C before adding 4-methoxy-indole-2-carboxylic acid (73 mg, 0.38 mmol), collidine (125 ⁇ L, 0.95 mmol) and HATU (144 mg, 0.38 mmol) in order, and the resulting suspension stirred at 0 °C for 6 hours.
  • the reaction was quenched by the addition of water (20 mL) and the mixture extracted with diethyl ether (3 x 50 mL).
  • Example 27 ⁇ H(1 S)-1 -(cvclohexylmethyl)-2-r((1 S)-3-hvdroxy-2-oxo-1 -f r(3S)-2-oxopyrrolidin-3- vnmethyl
  • Example 28 N-l (1 S)-1 -ffff 1 S)-3-( benzyloxy)-2-oxo-1 -f r(3S)-2-oxopyrrolidin-3- yllmethyllpropyl)aminolcarbonyl
  • Example 29 ⁇ K(1 S)-1 -f Kfl S)-3-hvdroxy-2-oxo-1 -f rf3S)-2-oxopyrrolidin-3- vnmethyl>propy ⁇ amino1carbonyll-3-methylbutyl)-4-methoxy- V-methyl-1H-indole-2- carboxamide
  • Example 30 N-l ( 1 S ⁇ -1 -f K(1 S)-3-(benzyloxy)-2-oxo-1 -f r(3S)-2-oxopyrrolidin-3- yllmethyl)propyl)aminolcarbonyl
  • Boc-N-methyl-Leu-OH (2.53 g, 10.33 mmol), HATU (3.9 g, 10.33 mmol) and NMM (2.4 mL, 21.59 mmol) were added, and the resulting mixture stirred at 0 °C for 90 minutes before quenching with ice / satd. NaHC0 3 (100 mL each).
  • the mixture was extracted with ethyl acetate (3 x 150 mL) and the combined organics washed with water (3 x 50 mL), 1 M hydrochloric acid (50 mL), NaHC0 3 (50 mL) and brine (50 mL), dried over MgS0 4 , filtered and concentrated to provide a crude brown oil.
  • Example 31 4-Methoxy-1 H-indole-2-carboxylic acid ⁇ 1-[3-chloro-1-(2-dimethylcarbamoyl- ethyl)-2-oxo-propylcarbamoyll-3-methyl-butyl ⁇ -amide
  • Example 32 Jv a -acetyl- ⁇ I
  • the crude hydrochloride salt was taken into DMF (15 mL) and cooled to 0 °C before adding acetyl chloride (339 ⁇ l, 4.77 mmol) followed by triethylamine (1.33 mL, 9.54 mmol).
  • the resulting yellow suspension was stirred at 0 °C for 1 hour before quenching with water (30 mL).
  • the mixture was saturated with NaCl and extracted with ethyl acetate (5 x 75 mL), and the combined organics dried over MgS0 4 , filtered and concentrated to provide a pale brown oil.
  • Example 33 / 2 -acetyl-JV 1 -r(1 S)-4-(dimethylamino)-1 -qlvcoloyl-4-oxobutv ⁇ -Jv g -methyl-L- leucinamide
  • the reaction was cooled to ambient temperature, diluted with ethyl acetate (200 mL), and washed with water (3 x 50 mL), brine (50 mL), dried over MgS0 4 , filtered and the solvents removed in vacuo.
  • the residue was taken into methanol (120 mL), K 2 C0 3 (38 mg, 0.27 mmol) added, and the suspension stirred at ambient temperature for 1 hour.
  • the reaction was neutralized by the addition of 1 M hydrochloric acid (273 ⁇ l, 0.27 mmol) and the solvents removed in vacuo.
  • Example 34 4-Methoxy-1H-indole-2-carboxylic acid ⁇ 1-H-(2-dimethylcarbamoyl-ethyl)-3- hvdroxy-2-oxo-propylcarbamoyll-3-methyl-butyl ⁇ -amide
  • Example 35 3S)-3-r( ⁇ -acetyl- ⁇ /-methyl-L-leucv0aminol-6-(dimethylamino)-2.6-dioxohexyl 2.6- dichlorobenzoate
  • the reaction was cooled to ambient temperature, diluted with ethyl acetate (100 mL), and washed with water (3 x 30 mL), brine (50 mL), dried over MgS0 4 , filtered and the solvents removed in vacuo.
  • the crude product was purified by flash chromatography eluting with dichloromethane / methanol to afford the title compound (252 mg, 75%) as a white foam.
  • Example 36 (3S)-3-(f ⁇ H(4-methoxy-1 H-indol-2-yl)carbonyll-L-leucyl ⁇ amino)-2-oxo-4-r(3S)-2- oxopyrrolidin-3-yllbutyl acetate
  • Example 55 A/-((1 S)-1 -fff (1 S)-3-azido-2-oxo-1 -f rf3S)-2-oxopyrrolidin-3- yllmethyl>propyl)aminolcarbonyll-3-methylbutyl)-4-methoxy-1H-indole-2-carboxamide
  • Example 56 ⁇ /-((1 S)-1 -Wd S)-3-(acetylamino)-2-oxo-1 - ⁇ r(3S)-2-oxopyrrolidin-3- vnmethyl ⁇ propyl)aminolcarbonyl)-3-methylbutyl)-4-methoxy-1 r -indole-2-carboxamide
  • Example 57 4-methoxy- ⁇ f-((1 S)-3-methyl-1 -ff((1 S)-3-f(methylsulf onvnamino1-2-oxo-1 -ir(3S)-2- oxopyrrolidin-3-vnmethyl
  • Example 58 ⁇ H(1 S)-1 -f U( ⁇ S)-3-r(2-cvanobenzoyl)aminol-2-oxo-1 - ⁇ r(3S)-2-oxopyrrolidin-3- vnmethyl ⁇ propyl)aminolcarbonyll-3-methylbutyl)-4-methoxy-1f -indole-2-carboxamide
  • Example 59 4-methoxy- ⁇ ffl1 S)-3-methyl-1 -f r((1 S)-3-morpholin-4-yl-2-oxo-1 -f IT3S)-2- oxopyrrolidin-3-yllmethyllpropyl)aminolcarbonyllbutyl)-1r/-indole-2-carboxamide
  • Example 60 4-methoxy-M-((1 S)-3-methyl-1 - ⁇ IT(1 S)-3-(4-methylpiperazin-1 -yl)-2-oxo-1 - ⁇ M3S)-2- oxopyrrolidin-3-yllmethyl ⁇ propyl)aminolcarbonyl ⁇ butv0-1 -/-indole-2-carboxamide
  • Example 61 Ml 1 S)-1 -M( ⁇ S)-3-(dimethylamino)-2-oxo-1 -irf3S)-2-oxopyrrolidin-3- vnmethyllpropyl)aminolcarbonyl
  • Neutral Red Endpoint The ability of compounds to protect cells against infection by the SARS coronavirus is measured by a cell viability assay similar to that described in Borenfreund, E., and Puerner, J. 1985. Toxicity determined in vitro by morphological alterations and neutral red absorption Toxicology Letters. 24:119-124, utilizing neutral red stainipg as an endpoint. Briefly, medium containing appropriate concentrations of compound or medium only is added to Vero cells. Cells are infected with SARS-associated virus or mock-infected with medium only. One to seven days later, the medium is removed and medium containing neutral red is added to the test plates.
  • EC50 fifty percent effective concentration
  • the 50% cytotoxicity concentration (CC50) is calculated as the concentration of compound that decreases the percentage of neutral red produced in uninfected, compound-treated cells to 50% of that produced in uninfected, compound-free cells.
  • the therapeutic index is calculated by dividing the cytotoxicity (CC50) by the antiviral activity (EC50).
  • Glo endpoint The ability of compounds to protect cells against infection by the SARS coronavirus can also be measured by a cell viability assay utilizing luciferase to measure intracellular ATP as an endpoint. Briefly, medium containing appropriate concentrations of compound or medium only is added to Vero cells. Cells are infected with SARS-associated virus or mock-infected with medium only. One to seven days later, the medium is removed and the amount of intracellular ATP is measured as per Promega Technical Bulletin No. 288: CellTiter-Glo® Luminescent Cell Viability Assay (Promega, Madison, Wl).
  • the CellTiter-Glo® reagent is added to the test plates and following incubation at 37°C for 1.25 hours, the amount of signal is quantified using a luminometer at 490nm. Data is expressed as the percent of luminescent signal from wells of compound-treated cells compared to the luminescent signal from wells of uninfected, compound-free cells.
  • the fifty percent effective concentration (EC50) is calculated as the concentration of compound that increases the percent of the luminescent signal from infected, compound-treated cells to 50% of the luminescent signal from uninfected, compound-free cells.
  • the 50% cytotoxicity concentration (CC50) is calculated as the concentration of compound that decreases the percentage of the luminescent signal from uninfected, compound-treated cells to 50% of the luminescent signal from uninfected, compound-free cells.
  • the therapeutic index is calculated by dividing the cytotoxicity (CC50) by the antiviral activity (EC50).
  • Cytotoxicity The ability of compounds to cause cytotoxicity in cells is measured by a cell viability assay similar to that described in Weislow, O.S., Kiser, R., Fine, D.L., Bader, J., Shoemaker, R.H., and Boyd, M.R.1989. New Soluble-Formazan Assay for HIV-1 Cytopathic Effects: Application to High-Flux Screening of Synthetic and Natural Products for AIDS-Anti viral Activity. Journal of the National Cancer Institute 81 (08): 577-586), utilizing formazan as an endpoint. Briefly, Vero cells are resuspended in medium containing appropriate concentrations of compound or medium only.
  • XTT and PMS are added to the test plates and following incubation at 37°C for two hours the amount of formazan produced is quantified spectrophotometrically at 540nm. Data is expressed as the percent of formazan produced in compound-treated cells compared to formazan produced in wells of compound-free cells.
  • the 50% cytotoxicity concentration (CC50) is calculated as the concentration of compound that decreases the percentage of formazan produced in uninfected, compound-treated cells to 50% of that produced in uninfected, compound-free cells.
  • the 50% cytotoxicity concentration (CC50) is calculated as the concentration of compound that decreases the percentage of formazan produced in uninfected, compound-treated cells to 50% of that produced in uninfected, compound-free cells.
  • the therapeutic index is calculated by dividing the cytotoxicity (CC50) by the antiviral activity (EC50).
  • Coronavirus 3C Protease FRET Assay and Analysis Proteolytic activity of Coronavirus 3C protease is measured using a continuous fluorescence resonance energy transfer assay.
  • the SARS 3CL pro FRET assay measures the protease catalyzed cleavage of TAMRA- SITSAVLQSGFRKMK-(DABCYL)-OH to TAMRA - SITSAVLQ and SGFRKMK- (DABCYL)-OH .
  • the fluorescence of the cleaved TAMRA (ex. 558 nm / em. 581 nm) peptide was measured using a TECAN SAFIRE fluorescence plate reader over the course of 10 min.
  • Typical reaction solutions contained 20 mM HEPES (pH 7.0), 1 mM EDTA, 4.0 uM FRET substrate, 4% DMSO and 0.005% Tween-20. Assays were initiated with the addition of 25 nM SARS 3CL pro (nucleotide sequence 9985-10902 of the Urbani strain of SARS coronavirus complete genome sequence (NCBI accession number AY278741)). Percent inhibition was determined in duplicate at 0.001 mM level of inhibitor.
  • FU offset + (limit)(1- e "(kobs,t ) where offset equals the fluorescence signal of the uncleaved peptide substrate, and limit equals the fluorescence of fully cleaved peptide substrate.
  • the kobs is the first order rate constant for this reaction, and in the absence of any inhibitor represents the utilization of substrate.
  • the calculated kobs represents the rate of inactivation of coronavirus 3C protease.
  • the slope (kobs/ 1) of a plot of kobs vs. [I] is a measure of the avidity of the inhibitor for an enzyme.
  • kobs/l is calculated from observations at only one or two [I] rather than as a slope.
  • the following table describe the mean antiviral EC50 and the inhibition of the C3 like protease in the FRET assay.

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Abstract

L'invention concerne des procédés d'inhibition de l'activité de réplication virale du coronavirus associé au SRAS. Ces procédés consistent à mettre en contact une protéase du coronavirus associé au SRAS avec une quantité thérapeutiquement efficace d'un inhibiteur de protéase de type 3C du SRAS de formule (I). L'invention concerne également des compositions contenant ledit composé.
PCT/IB2005/001289 2004-05-21 2005-05-09 Composes et compositions anti-coronavirus, utilisations pharmaceutiques associees et materiaux pour la synthese de ces composes et compositions WO2005113580A1 (fr)

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