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WO2012048013A2 - Dérivés phosphorodiamidate de composés nucléosidiques à base de guanosine destinés à traiter des infections virales - Google Patents

Dérivés phosphorodiamidate de composés nucléosidiques à base de guanosine destinés à traiter des infections virales Download PDF

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Publication number
WO2012048013A2
WO2012048013A2 PCT/US2011/054945 US2011054945W WO2012048013A2 WO 2012048013 A2 WO2012048013 A2 WO 2012048013A2 US 2011054945 W US2011054945 W US 2011054945W WO 2012048013 A2 WO2012048013 A2 WO 2012048013A2
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Prior art keywords
methoxy
amino
methyltetrahydrofuran
purin
bis
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WO2012048013A3 (fr
Inventor
Christopher Mcguigan
Mohamed ALJARAH
Karolina MADELA
Claire Bourdin
Sarah Jones
Stanley Chamberlain
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University College Cardiff Consultants Ltd
Cardiff University
Inhibitex Inc
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University College Cardiff Consultants Ltd
Cardiff University
Inhibitex Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • This application relates to novel nucleoside phosphorodiamidates and their use as agents for treating viral diseases.
  • Such compounds are inhibitors of RNA- dependant RNA viral replication and specifically, inhibitors of HCV NS5B polymerase.
  • As inhibitors of HCV replication such compounds are useful for treatment of hepatitis C infection in mammals.
  • HCV is a member of the Flaviviridae family of RNA viruses that affect animals and humans.
  • the genome is a single 9.6-kilobase strand of RNA, and consists of one open reading frame that encodes for a polyprotein of approximately 3000 amino acids flanked by untranslated regions at both 5' and 3' ends (5'- and 3'-UTR).
  • the polyprotein serves as the precursor to at least 10 separate viral proteins critical for replication and assembly of progeny viral particles.
  • HCV infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world population. There are an estimated 4.5 million infected people in the United States alone, according to the U.S. Center for Disease control. According to the World Health Organization, there are more than 200 million infected individuals worldwide, with at least 3 to 4 million people being infected each year. Once infected, about 20% of people clear the virus, but the remainder can harbor HCV for the rest of their lives. [0008] Ten to twenty percent of chronically infected individuals eventually develop liver- destroying cirrhosis or cancer. The viral disease is transmitted parenterally by contaminated blood and blood products, contaminated needles, or sexually and vertically from infected mothers or carrier mothers to their offspring
  • interferon alpha interferon alpha
  • ribavirin interferon alpha
  • adverse side effects such as fatigue, fever, chills, headache, myalgias, arthralgias, mild alopecia, psychiatric effects and associated disorders, autoimmune phenomena and associated disorders and thyroid dysfunction.
  • Ribavirin an inhibitor of inosine 5 '-monophosphate dehydrogenase (IMPDH)
  • Ribavirin causes significant hemolysis in 10-20% of patients treated at currently recommended doses, and the drug is both teratogenic and embryotoxic. Even with recent improvements, a substantial fraction of patients do not respond with a sustained reduction in viral load and there is a clear need for more effective antiviral therapy of HCV infection.
  • a number of other approaches are being pursued to combat the virus. They include, for example, application of antisense oligonucleotides or ribozymes for inhibiting HCV replication. Furthermore, low-molecular weight compounds that directly inhibit HCV proteins and interfere with viral replication are considered as attractive strategies to control HCV infection.
  • the NS3/4A protease/helicase and the NS5B RNA-dependent RNA polymerase are considered the most promising viral targets for new drugs.
  • WO 2003010140 relates to specific inhibitors of RNA dependent RNA polymerases, particularly viral polymerases within the Flaviviridae family, more particularly to HCV polymerase.
  • WO 200204425 incorporated by reference herein, relates to specific inhibitors of RNA dependent RNA polymerases, particularly viral polymerases within the Flaviviridae family, and more particularly the NS5B polymerase of HCV.
  • WO 200147883, incorporated by reference herein relates to specific fused-ring compounds or the like or pharmaceutically acceptable salts thereof. Such compounds and salts exhibit an anti-HCV (hepatitis C virus) activity by virtue of their inhibitory activity against HCV polymerase, thus being useful as therapeutic or preventive agents for hepatitis C.
  • HCV hepatitis C virus
  • Flaviviridae virus family and in view of the limited treatment options, there is a strong need for new effective drugs for treating infections caused by these viruses.
  • This invention is directed to novel compounds that are useful in the treatment of viral infections in mammals mediated, at least in part, by a virus in the Flaviviridae family of viruses.
  • the present invention provides for novel compounds of formula (I) having the structure:
  • R 2 , R 3 , and R 4 are each independently
  • R 7' and R 8° are each independently
  • R 9 is independently
  • Ci-Cgalkyl optionally substituted by C 3 -C 6 cycloalkyl
  • R 1 and R 2 when taken together with the N atom to which they are attached, may form
  • R 3 and R 4 when taken together with the N atom to which they are attached, may form
  • R 6 is selected from H, Ci-Cgalkyl optionally substituted by Ce-Qoaryl, and
  • R 10 and R 11 are independently selected from H, C Csalkyl optionally substituted by C6-C 10 aryl, and C -C 8 cycloalkyl;
  • the present invention includes other forms of all of the disclosed compounds including solvates, hydrates and polymorphs.
  • Such compounds are inhibitors of RNA-dependant RNA viral replication and inhibitors of HCV NS5B polymerase and thus may be utilized in methods wherein such inhibition is desired.
  • the present invention extends to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of formula I and a pharmaceutically acceptable carrier, excipient or diluent.
  • the pharmaceutically acceptable carrier, excipient or diluent may be pure sterile water, phosphate buffered saline or an aqueous glucose, solution.
  • an instant method comprises administering to a mammal that has been diagnosed with said viral infection a pharmaceutical composition comprising compounds of formula I..
  • an instant method comprises administering to a human or animal patient in need thereof an effective amount of a pharmaceutical composition comprising compounds of formula I.
  • the virus is hepatitis C virus (or HCV).
  • the present methods further extend to combination treatment comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus.
  • agents active against hepatitis C virus may include interferon- alpha or pegylated interferon-alpha alone or in combination with ribavirin or levovirin.
  • the present invention relates to chemical compounds, their preparation and their use in the treatment of viral infections particularly in mammals. Particularly, although not exclusively, the present invention relates to chemical compounds useful as anti-hepatitis C virus (HCV) agents.
  • HCV anti-hepatitis C virus
  • the present invention describes certain nucleoside phosphorodiamidates, their synthesis, and their use as inhibitors of RNA-dependent RNA viral polymerase, particularly their use as inhibitors of hepatitis C virus (HCV) NS5-B polymerase, as inhibitors of HCV replication, and for the treatment of hepatitis C infection.
  • the compounds can also be precursors for such inhibitors.
  • the present invention relates to novel compounds of formula (I) having the structure:
  • R 2 , R 3 , and R 4 are each independently
  • R 7' and R 8° are each independently
  • Ci-Cgalkyl Ci-C 3 alkylaryl
  • R 9 is independently
  • R 1 and R 2 when taken together with the N atom to which they are attached, may form
  • R 3 and R 4 when taken together with the N atom to which they are attached, may form
  • R 5 is selected from CI, X'R 6 and NR 10 R U ,
  • X' is O or S
  • R 6 is selected from H, CrCsalkyl optionally substituted by C6-C 10 aryl, and
  • R 10 and R 11 are independently selected from H, CrCgalkyl optionally substituted by C6-C 10 aryl, and Cs-Cgcycloalkyl;
  • the present invention includes other forms of all of the disclosed compounds including solvates, hydrates and polymorphs.
  • the above compounds are provided along with their phosphorus diastereomers.
  • phosphorous diastereomers may be possible in cases where Rl and R2 are not identical to R3 and R4.
  • (2S,2'S)-bis(3,3-dimethylbutyl) 2,2'-((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H- purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2- yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate
  • compounds in accordance with the present invention include:
  • alkyl refers to a straight or branched saturated
  • cyclic or acyclic hydrocarbon radical having the number of carbon atoms as indicated (or where not indicated, an acyclic alkyl group preferably has 1-20, more preferably 1-6, more preferably 1-4 carbon atoms and a cyclic alkyl group preferably has 3-20, preferably 3-10, more preferably 3-7 carbon atoms), optionally substituted with one, two, three or more substituents independently selected from the group set out above.
  • suitable alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, isopropyl, 2-butyl, cyclopropyl, cyclohexyl, cyclopentyl and dodecyl.
  • C3-C 8 cycloalkyl refers to cyclic alkyl group comprising from about 3 to about 8 C atoms.
  • Cs-Cscycloalkyl-alkyl refers to an acyclic alkyl group substituted by a cyclic alkyl group comprising from about 3 to about 8 C atoms.
  • suitable alkenyl groups include vinyl, propenyl, butenyl, pentenyl and hexenyl.
  • alkynyl refers to a straight or branched unsaturated monovalent acyclic or cyclic hydrocarbon radical having one or more triple C/C bonds and having the number of carbon atoms as indicated (or where not indicated, an acyclic alkynyl group preferably has 2-20, more preferably 2-6, more preferably 2-4 carbon atoms and a cyclic alkynyl group preferably has 7-20, more preferably 8-20 carbon atoms), optionally substituted with one, two, three or more substituents independently selected from the group set out above.
  • alkoxy refers to the group alkyl- 0-, where alkyl is as defined above and where the alkyl moiety may optionally be substituted by one, two, three or more substituents as set out above for alkyl.
  • suitable alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy, n- butoxy, ie/t-butoxy, sec-butoxy, w-pentoxy, w-hexoxy and 1,2-dimethylbutoxy.
  • cycloalkyloxy refers to the group cyclicalkyl - 0-, where cyclicalkyl is as defined above and where the cyclicalkyl moiety may be optionally substituted by one, two, three or more substituents as set out above for alkyl.
  • alkylthio refers the group alkyl-S-, where alkyl is as defined above and where the alkyl moiety may optionally be substituted by one, two, three or more substituents as set out above for alkyl.
  • suitable alkylthio groups include methylthio, ethylthio, n- propylthio, isopropylthio, w-butylthio, iert-butylthio, sec-butylthio, w-pentylthio, w-hexoxy and 1,2-dimethylbutylthio.
  • aryloxy refers to the group aryl-O-, where aryl is as defined below and where the aryl moiety may optionally be substituted by one, two, three or more substituents as set out above with respect to the group Ar.
  • alkoxyalkyl refers to an alkyl group having an alkoxy substituent. Binding is through the alkyl group.
  • the alkyl moiety and the alkoxy moiety are as defined herein with respect to the definitions of alkyl and alkoxy, respectively.
  • the alkoxy and alkyl moieties may each be substituted by one, two, three or more substituents as set out above with regard to the definition of alkyl.
  • alkylthioalkyl refers to an alkyl group having an
  • alkylthio substituent Binding is through the alkyl group.
  • the alkyl moiety and the alkylthio moiety are as defined herein with respect to the definitions of alkyl and alkylthio, respectively.
  • the alkylthio and alkyl moieties may each be substituted by one, two, three or more substituents as set out above with regard to the definition of alkyl.
  • alkoxyaryl refers to an aryl group having an alkoxy substituent. Binding is through the aryl group.
  • the alkoxy moiety and the aryl moiety are as defined herein with respect to the definitions of alkoxy and aryl, respectively.
  • the alkoxy and aryl moieties may each be substituted by one, two, three or more substituents, as defined herein with regard to the definitions of alkoxy and aryl, respectively.
  • cycloalkylaryl refers to an aryl group having a cyclic alkyl substituent. Binding is through the aryl group.
  • the cycloalkyl moiety and the aryl moiety are as defined herein with respect to the definitions of cycloalkyl and aryl, respectively.
  • aryl(C 1 -C 6 )alkyl- refers to a CrC 6 alkyl group substituted at any carbon by an aryl group. Binding is through the alkyl group.
  • the aryl moiety and the alkyl moiety are as defined herein with respect to the definitions of aryl and alkyl.
  • the aryl group may be substituted.
  • suitable aryl(C 1 -C 6 )alkyl- groups include benzyl, 1- phenylethyl, 3-phenylpropyl, 4-chlorobenzyl, 4-fluorobenzyl, 2,4-difluorobenzyl, and the like.
  • the alkyl moiety is as defined hereinabove.
  • a cycloalkyl moiety and the aryl moiety may each be optionally substituted by one, two, three or more substituents as set out herein with regard to the definitions of alkyl and aryl, respectively.
  • aryl refers to a monovalent unsaturated aromatic
  • aryl group may optionally be substituted by one, two, three or more substituents as set out above with respect to optional substituents that may be present on the group Ar.
  • Preferred aryl groups are: an aromatic monocyclic ring containing 6 carbon atoms; an aromatic bicyclic or fused ring system containing 7, 8, 9 or 10 carbon atoms; or an aromatic tricyclic ring system containing 10, 11, 12, 13 or 14 carbon atoms.
  • Non-limiting examples of aryl include phenyl and naphthyl.
  • heterocycloalkyl refers to a saturated or partially
  • unsaturated heterocyclic ring system having one, two, three, four, five or six rings, preferably one, two or three rings, which may be fused or bicyclic, and having contained within the ring or rings at least one member selected from the group consisting of N, O and S.
  • C5-C 2 o" or “C5-C used before heterocycloalkyl means, respectively, a five to twenty or a five to ten-membered ring system at least one of which members is selected from the group consisting of N, O and S.
  • Preferred heterocycloalkyl systems are: a monocyclic ring system having five members of which at least one member is a N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atoms; a monocyclic ring having six members of which one, two or three members are a N or O atom; a bicyclic ring system having nine members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms; or a bicyclic ring system having ten members of which one, two or three members are a N atom.
  • suitable heterocycloalkyl groups include tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothiopyranyl, thiomorpholinyl, and piperidinyl
  • indanyl refers to the fused bicyclic radical of structure, point of attachment of the radical to the rest of the molecule is on any available non-aromatic carbon atom.
  • heteroatom substituents are selected from oxygen, nitrogen, sulphur and halogen (F, CI, Br and I).
  • halogen F, CI, Br and I
  • the ring(s) is substituted with one or more heteroatoms, preferably there are 1, 2, 3 or 4 heteroatom substituents selected from the group consisting of oxygen, nitrogen and/or halogen.
  • Preferred substituent groups are independently selected from hydroxy, acyl, acyloxy, nitro, amino, S0 3 H, SH, SR', wherein R' is independently selected from the same groups as R; carboxyl, cyano, (C 1 -C 6 )alkylamino, (C 1 -C 6 )dialkylamino, thiol, chloro, bromo, fluoro and iodo.
  • the compounds of this invention contain one or more chiral centers.
  • stereoisomers i.e., as individual enantiomers or diastereomers, or as stereoisomer- enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • the compounds of this invention may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms or phosphorous atoms may be present in the (R) or (S) configuration or (R,S) configuration. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • Substituents on a ring may also be present in either cis or trans form, and a substituent on a double bond may be present in either Z or E form. It is intended that all such configurations (including enantiomers and diastereomers) are included within the scope of the present invention.
  • Preferred compounds are those with the absolute configuration of the compound of this invention which produces the more desirable biological activity.
  • Separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention.
  • Such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention.
  • Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art.
  • racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like, also well-known in the art and exemplified the experimental examples below.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • “pharmaceutically acceptable salts” refers to compounds having a substituent capable of having more than one group form a salt but less than the maximum amount of such groups actually form a salt.
  • a diphospho group can form a plurality of salts and, if only partially ionized, the resulting group is sometimes referred to herein as a partial salt.
  • polymers arrived at by defining substituents with further substituents to themselves e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc.
  • the maximum number of such substituents is three.
  • each of the above definitions is constrained by a limitation that, for example, substituted aryl groups are limited to -substituted aryl- (substituted aryl)-substituted aryl.
  • the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups or a hydroxyl group pendent to a carbon atom of an ethenylic or acetylenic unsaturation). Such impermissible substitution patterns are well known to the skilled artisan.
  • the present compounds include other known forms of the compounds including solvates, hydrates and polymorphs.
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce or Sigma (St. Louis, Mo., USA).
  • Reaction Scheme 1 illustrates a general method of preparation of symmetrical phosphorodiamidates.
  • Application PCT/US 10/20632 is dissolved in a neutral aprotic solvent such as THF or triethyl phosphate or similar solvent and cooled to below ambient temperature, preferably to 0-5°C.
  • Phosphorus oxychloride phosphoryl chloride
  • the reaction is stirred for 1-48 h at temperatures from -20 °C to 20 °C and optimally for 24 h at 5 °C forming compound (III).
  • the solution is diluted with an aprotic solvent, preferably DCM, and a primary or secondary amine, such as the HC1 or tosylate salt of an amino acid ester, is added at reduced temperatures -78 °C to 5 °C and preferably at 0 °C.
  • a primary or secondary amine such as the HC1 or tosylate salt of an amino acid ester
  • a non-nucleophilic base such as a tertiary amine such as triethylamine, or preferably diisopropylethylamine.
  • the solution is stirred for 1 h to 10 days at reduced temperatures and preferably at 5 °C for 5 days, forming phosphorodiamidate (I).
  • the nucleoside (II) can be dissolved in a neutral aprotic solvent such as THF or triethyl phosphate or similar solvent, but preferably THF, and a non- nucleophilic base such as a tertiary amine or diisopropylethylamine or preferably triethylamine is added and stirred for a period of 5 min to 1 h, preferably 30 min.
  • a neutral aprotic solvent such as THF or triethyl phosphate or similar solvent, but preferably THF
  • a non- nucleophilic base such as a tertiary amine or diisopropylethylamine or preferably triethylamine is added and stirred for a period of 5 min to 1 h, preferably 30 min.
  • the solution is then cooled to -100 °C to rt, or preferably -78 °C, and phosphorus oxychloride (phosphoryl chloride) of high quality is added
  • the reaction is stirred for 5 min to 2 h at temperatures from -100 °C to 0°C and optimally for 30 min at -78 °C, then warmed to ambient temperature for 5 min to 2 h, preferably 30 min forming compound (III).
  • the solution is further diluted with an aprotic solvent, preferably DCM, and a primary or secondary amine, such as the HC1 or tosylate salt of an amino acid ester, is added followed by the addition of a non-nucleophilic base such as a tertiary amine preferably triethylamine at reduced temperatures -78 °C to 5 °C and preferably at -78 °C.
  • reaction Scheme 2 illustrates a general method of preparation of asymmetrical phosphoramidates.
  • nucleoside (II) can be dissolved in a neutral aprotic solvent such as THF or triethyl phosphate or similar solvent, but preferably THF, and a non-nucleophilic base such as a tertiary amine or diisopropylethylamine or preferably triethylamine is added and stirred for a period of 5 min to 1 h, preferably 30 min.
  • a neutral aprotic solvent such as THF or triethyl phosphate or similar solvent, but preferably THF
  • a non-nucleophilic base such as a tertiary amine or diisopropylethylamine or preferably triethylamine is added and stirred for a period of 5 min to 1 h, preferably 30 min.
  • the solution is then cooled to -100 °C to rt, or preferably -78 °C, and phosphorus oxychloride (phosphoryl chloride) of high quality is added slowly to the solution with careful protection from moisture.
  • the reaction is stirred for 5 min to 2 h at temperatures ranging from -100 °C to 0 °C and optimally for 30 min at -78 °C, then warmed to ambient temperature for 5 min to 2 h, preferably 30 min forming compound (III).
  • the solution is further diluted with an aprotic solvent, preferably DCM, and one equivalent of a primary or secondary amine of formula (V), such as the HC1 or tosylate salt of an amino acid ester, is added followed by the addition of a non-nucleophilic base such as a tertiary amine preferably triethylamine at reduced temperatures -78 °C to 5 °C and preferably at -78°C.
  • a tertiary amine preferably triethylamine at reduced temperatures -78 °C to 5 °C and preferably at -78°C.
  • the solution is warmed to ambient temperature and stirred for 1 h to 48 h, preferably 24 h, forming phosphorodiamidate (IV).
  • a phosphorus NMR can be acquired to determine the status of the reaction.
  • the solution is then cooled to -100 °C to rt, or preferably -78 °C.
  • a primary or secondary amine of formula (VI) such as the HCl or tosylate salt of an amino acid ester
  • a non-nucleophilic base such as a tertiary amine, preferably triethylamine (5-10 equivalents) at reduced temperatures -78 °C to 5 °C and preferably at -78 °C.
  • the solution is warmed to ambient temperature and stirred for 1 h to 48 h, preferably 24 h, forming phosphorodiamidate (I).
  • reaction Scheme 3 illustrates an alternative method for synthesizing asymmetrical phosphorodiamidates.
  • This scheme describes a second general method for synthesizing asymmetrical phosphorodiamidates.
  • the nucleoside (II) can be dissolved in a neutral aprotic solvent such as THF or triethyl phosphate or similar solvent, but preferably THF.
  • a non-nucleophilic base such as a tertiary amine or diisopropylethylamine or preferably triethylamine is added in excess, preferably 1.2 equivalents.
  • the solution can be stirred at ambient temperature and 1 to 3 equivalents of an amino acid ester dichloridate (VII), can be added.
  • Compounds of the general structure (VII) can be synthesized using techniques familiar to one skilled in the art.
  • a phosphorus NMR can be acquired to determine the status of the formation of the compound of formula (IV)
  • the solution is then cooled to -100 °C to rt, or preferably -78 °C, and 1 to 10 equivalents, preferably 5 equivalents, of a primary or secondary amine of formula (VI) are added.
  • the solution is warmed to ambient temperature and stirred for 1 h to 48 h, preferably 24 h, forming phosphorodiamidate (I).
  • the reaction is worked up using standard methods familiar to one skilled in the art, for example extraction with a sodium chloride solution, drying with sodium sulfate and purification by silica gel chromatography. Changes to this procedure including solvent switches and optimization of the temperature, familiar to those skilled in the art of organic chemistry would be anticipated.
  • Suitable solvents include hydrocarbon solvents such as benzene and toluene; ether type solvents such as diethyl ether, tetrahydrofuran, diphenyl ether, anisole and dimethoxybenzene; halogenated hydrocarbon solvents such as methylene chloride, chloroform and chlorobenzene; ketone type solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; alcohol type solvents such as methanol, ethanol, propanol, isopropanol, w-butyl alcohol and iert-butyl alcohol; nitrile type solvents such as acetonitMRI, propionitrile and benzonitrile; ester type solvents such as ethyl acetate and butyl acetate; carbonate type solvents such as ethylene carbonate and propylene carbonate; and
  • inert solvent means a solvent inert under the conditions of the reaction being described in conjunction therewith including, for example, benzene, toluene, acetonitrile, tetrahydrofuran, dimethylformamide, chloroform, methylene chloride (or dichloromethane), diethyl ether, ethyl acetate, acetone, methylethyl ketone, methanol, ethanol, propanol, isopropanol, ie/t-butanol, dioxane, pyridine, and the like.
  • inert solvent means a solvent inert under the conditions of the reaction being described in conjunction therewith including, for example, benzene, toluene, acetonitrile, tetrahydrofuran, dimethylformamide, chloroform, methylene chloride (or dichloromethane), diethyl ether, ethyl acetate, acetone, methyleth
  • the effective amount will be that amount of the compound of this invention that would be understood by one skilled in the art to provide therapeutic benefits, i.e., the active ingredient, and will thus depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
  • the drug can be administered more than once a day, and in the preferred mode the drug is administered once or twice a day. As indicated above, all of the factors to be considered in determining the effective amount will be well within the skill of the attending clinician or other health care professional..
  • therapeutically effective amounts of compounds of Formula I may range from approximately 0.05 to 50 mg per kilogram body weight of the recipient per day; preferably about 0.1-25 mg/kg/day, more preferably from about 0.5 to 10 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 35-700 mg per day.
  • compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • the preferred manner of administration is oral using a convenient daily dosage regimen that can be adjusted according to the degree of affliction.
  • compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • Another preferred manner for administering compounds of this invention is inhalation. This is an effective method for delivering a therapeutic agent directly to the respiratory tract (see U.S. Pat. No. 5,607,915, said patent incorporated herein by reference).
  • the choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance.
  • the compound can be formulated as liquid solution, suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration.
  • suitable dispenser for administration There are several types of pharmaceutical inhalation devices- nebulizer inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI).
  • MDI metered dose inhalers
  • DPI dry powder inhalers
  • Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient's respiratory tract.
  • MDI's typically are formulation packaged with a compressed gas.
  • the device Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent.
  • DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the patient's inspiratory air- stream during breathing by the device.
  • the therapeutic agent In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose.
  • a measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation.
  • compositions in accordance with the invention generally comprise a compound of formulas (I- VI) in combination with at least one pharmaceutically acceptable carrier, excipient or diluent.
  • excipients are those that are non-toxic, will aid administration, and do not adversely affect the therapeutic benefit of the compound of the invention.
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients useful in the invention may include starch,
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of this invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
  • the amount of the compound in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % wherein the compound is a compound of formula I based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1-80 wt %.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of another active agent against RNA-dependent RNA virus and, in particular, against HCV.
  • Agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha- 1, an inhibitor of HCV NS3 serine protease, interferon-a, pegylated interferon-a (peginterferon-a), a combination of interferon-a and ribavirin, a combination of peginterferon-a and ribavirin, a combination of interferon-a and levovirin, and a combination of peginterferon- ⁇ and levovirin.
  • Interferon- ⁇ includes, but is not limited to, recombinant interferon-a2a (such as Roferon interferon available from Hoffman-LaRoche, Nutley, N.J.), interferon- a2b (such as Intron-A interferon available from Schering Corp., Kenilworth, N.J., USA), a consensus interferon, and a purified interferon- ⁇ product.
  • interferon-a2a such as Roferon interferon available from Hoffman-LaRoche, Nutley, N.J.
  • interferon-a2b such as Intron-A interferon available from Schering Corp., Kenilworth, N.J., USA
  • a consensus interferon such as Intron-A interferon available from Schering Corp., Kenilworth, N.J., USA
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of another agent active against hepatitis C virus.
  • agents include those that inhibit HCV proteases, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and inosine 5'-monophosphate dehydrogenase.
  • Other agents include nucleoside analogs for the treatment of an HCV infection.
  • Still other compounds include those disclosed in WO 2004/014313 and WO 2004/014852 and in the references cited therein.
  • Specific antiviral agents include Omega IFN (BioMedicines Inc.), BILN-2061 (Boehringer Ingelheim), Summetrel (Endo Pharmaceuticals Holdings Inc.), Roferon A (F. Hoffman-La Roche), Pegasys (F. Hoffman-La Roche), Pegasys/Ribaravin (F. Hoffman-La Roche), CellCept (F.
  • compositions and methods of the present invention contain a compound of formula I- VI and interferon.
  • the interferon is selected from the group consisting of interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon tau.
  • compositions and methods of the present invention utilize a combination of a compound of formula I- VI and a compound having anti- HCV activity such as those selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti- sense RNA, Imiqimod, ribavirin, an inosine 5' monophospate dehydrogenase inhibitor, amantadine, and rimantadine.
  • a compound having anti- HCV activity such as those selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti- sense RNA, Imiqimod, ribavirin, an inosine 5' monophospate dehydrogenase inhibitor, amantadine, and rimantadine.
  • WO 97/12033 relates to HCV polymerase assay that can be used to evaluate the activity of the of the compounds described herein.
  • Another HCV polymerase assay has been reported by Bartholomeusz, et al., Hepatitis C Virus (HCV) RNA polymerase assay using cloned HCV non- structural proteins; Antiviral Therapy 1996: 1 (Supp 4) 18-24.
  • HCV Hepatitis C Virus
  • dichloromethane were purchased from Aldrich and used directly.
  • the sugar derivative (2 l S',3R,4R,5R)-5-(benzoyloxymethyl)-3-methyltetrahydrofuran-2,3,4- triyl tribenzoate or equivalently: 2,3,4,5-tetra-0-benzoyl-2-C-methyl- ?-D- ribofuranose was purchased from CarboSynth Limited, 8&9 Old Station Business Park, Compton, Berkshire, RG20 6NE, UK.
  • the purine derivative 2-amino-6- chloropurine or equivalently, 6-chloro-9H-purin-2-amine was purchased from Aldrich.
  • 2'-C-Methylguanosine (2-amino-9-((3R,4R,5R)-3,4-dihydroxy-5- (hydroxymethyl)-3-methyltetrahydrofuran-2-yl)- lH-purin-6(9H)-one) is a commercial reagent and was purchased from CarboSynth Limited, 8&9 Old Station Business Park, Compton, Berkshire, RG20 6NE, UK. Salts of amino acid esters were prepared as described in PCT Int. Appl. (2010), WO 2010081082 A2 20100715. Column chromatography refers to flash column chromatography carried out using Merck silica gel 60 (40-60 ⁇ ) as stationary phase.
  • Coupling constants are referred to as J values.
  • Signal splitting patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), broad signal (br), doublet of doublet (dd), doublet of triplet (dt), or multiplet (m).
  • the electrospray source was operated at a temperature of 130 °C with a desolvation temperature of 300 °C, a capillary voltage of 3 kV, and cone voltage of 30 V. Data were collected in the continuum mode over the mass range 100-2000 amu and processed using Masslynx 4.1 software. Accurate mass measurements were facilitated by the introduction of a single lockmass compound of known elemental composition into the source concurrently with sample.
  • the reaction mixture was then heated at 65 °C for 4 to 6 h, allowed to cool down to room temperature, poured into saturated aqueous sodium bicarbonate (300 mL), and extracted with dichloromethane (3x150 mL). The combined organic phase was dried over sodium sulfate and evaporated under reduced pressure. The residue was precipitated from dichloromethane and methanol, filtrated, the solid was washed 2 times with methanol and dried to give the desired compound (8.5 g, 79 %) as a white solid (yields are from 65% (column) up to 90% (precipitation)).
  • Method D Asymmetrical phosphorodiamidates using amino acid ester phosphordichloridate
  • anhyd dichloromethane (4 mL), the hydrochloride salt of propyloxy-L- alanine (673 g, 4.02 mmol) and diisopropylethylamine (1.40 mL, 8.03 mmol) were added to the mixture obtained in step one.
  • silica gel column chromatography and preparative TLC 36 mg of the prodrug was obtained in 7.2% yield as an off white solid.
  • the phosphorodiamidate prodrug was synthesized using Method B.
  • a suspension of 6-0-methyl-2'-C-methylguanosine (250 mg, 0.803 mmole) in anhydrous tetrahydrofuran (4 mL) was reacted with triethylamine (135 ⁇ , 0.964 mmole) and phosphoryl chloride (89 ⁇ , 0.964 mmole).
  • Anhydrous dichloromethane (4 mL) the tosylate salt of isobutyloxy-L-alanine (1.27 g, 4.02 mmol) and triethylamine (1.12 mL, 8.03 mmol) were added.
  • silica gel column chromatography and preparative HPLC 66.1 mg of the prodrug was obtained in 13% yield as an off white solid.
  • the phosphorodiamidate prodrug was synthesized using Method B.
  • a suspension of 6-0-methyl-2'-C-methylguanosine (250 mg, 0.803 mmole) in anhydrous tetrahydrofuran (4 mL) was reacted with triethylamine (135 ⁇ , 0.964 mmole) and phosphorus oxychloride (89 ⁇ , 0.964 mmole).
  • Anhydrous dichloromethane (4 mL) the HCl salt of cyclobutyl-L-alanine (722.2 mg, 4.02 mmol) and triethylamine (1.12 mL, 8.03 mmol) were added to the previous mixture.
  • silica gel column chromatography and preparative HPLC 65.1 mg of the phosphorodiamidate was obtained in 13% yield as an off white solid.
  • anhyd dichloromethane (4 mL), the hydrochloride salt of cyclohexyloxy-L-alanine (834 mg, 4.02 mmol) and diisopropylethylamine (1.40 mL, 8.03 mmol) were added to the mixture obtained in step one.
  • 36.0 mg of the prodrug was obtained in 6.4% yield, as an off white solid.
  • anhyd dichloromethane (4 mL), the tosylate salt of (2 l S')-phenylethyloxy-L-alanine (1.46 g, 4.02 mmol) and diisopropylethylamine (1.40 mL, 8.03 mmol) were added to the mixture obtained in step one.
  • silica gel column chromatography and preparative TLC 27.1 mg of the prodrug was obtained in 4.5% yield as an off white solid.
  • Example 20 [00346]
  • the compound was prepared according to Method B from (2R,3R,4R,5R)-2-(2- amino-6-methoxy-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran- 3,4-diol, (Example 2, 250 mg, 0.80 mmol), POCl 3 (0.07 mL, 0.80 mmol), E t3 N (0.11 mL, 0.80 mmol), L-alanine 2-indanolyl ester tosylate salt (0.91g, 2.41 mmol), and Et 3 N (0.67 mL, 4.82 mmol) in 10 mL of 1 : 1 mixture of dry THF and DCM. Crude product was purified by column chromatography using a gradient of CHC1 3 to CHC1 3 : MeOH 95:5, to give a pure product as a white foam (52 mg, 9%).
  • the phosphorodiamidate prodrug was synthesized using Method C. [00369] A suspension of 6-O-methyl-2'-C-methylguanosine (250 mg, 0.803 mmole) in anhydrous tetrahydrofuran (4 mL) was reacted with triethylamine (135 ⁇ , 0.964 mmole) and phosphorus oxychloride (89 ⁇ , 0.964 mmole). Anhydrous dichloromethane (4 mL), the HCl salt of cyclohexyloxy-L-alanine (167 mg, 0.803 mmol) and triethylamine (224 ⁇ , 1.61 mmole) were added.
  • Example 23 [00374] (25 ieri-Butyl 2-((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4- dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(( l S')-l-(neopentyloxy)- l- oxopropan-2-ylamino)phosphorylamino)propanoate
  • Example 24 [00383] (25 Methyl 2-((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4- dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(( l S , )-l-(neopentyloxy)- l- oxopropan-2-ylamino)phosphorylamino)-3-methylbutanoate
  • Example 25 Methyl l-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4- methyltetrahydrofuran-2-yl)methoxy)(( l S')-l-(neopentyloxy)-l-oxopropan-2- ylamino)phosphoryl)pyrrolidine-2-carboxylate
  • the tosylate salt of neopentyloxy-L-alanine (1.33 g, 4.02 mmol) and triethylamine (1.12 mL, 8.03 mmol) were added to the mixture.
  • 71 mg of the prodrug was obtained in 14% yield as an off white solid.
  • the phosphorodiamidate prodrug was synthesized using Method C.
  • a suspension of 6-0-methyl-2'-C-methylguanosine (250 mg, 0.803 mmole) in anhydrous tetrahydrofuran (4 mL) was reacted with triethylamine (135 ⁇ , 0.964 mmole) and phosphorus oxychloride (89 ⁇ , 0.964 mmole).
  • aniline 73 ⁇ , 0.803 mmole
  • triethylamine (112 ⁇ , 0.803 mmole
  • HPLC i R 15.08 and 15.31 min (column: Varian Pursuit XRs 5, C 18 , 150x4.6 mm; method: linear gradient of ACN (10% to 100%) in H 2 0 in 30 min).
  • the tosylate salt of neopentyloxy-L-alanine (1.33 g, 4.02 mmol) and triethylamine (1.12 mL, 8.03 mmol) were added to the mixture.
  • silica gel column chromatography and preparative HPLC 9.3 mg of the prodrug was obtained in 2% yield as an off white solid.
  • HPLC t R 23.49 and 23.75 min (column: Varian Pursuit XRs 5, C 18 , 150x4.6 mm; method: linear gradient of CH 3 OH (10% to 100%) in H 2 0 in 30 min).
  • Step 2 The crude mixture from the above step was dissolved in dioxane (500 mL) followed by addition of HC1 (4M in dioxane) (5eq, 612 mL) at 0 °C and heated to 40 °C for 15 hrs. This mixture was cooled to room temperature and the volatiles were removed under reduced pressure. Trace amounts of dioxane was removed by azetroping with toluene (2 X 200 mL). To this solid was added anhydrous diethyl ether (1L) and stirred vigorously for lhr. The solids were filtered off and dried under vacuum to afford 87.3 gm of D-alanine neopentyl ester hydrochloride salt (3 in above scheme).
  • Example 37 [00515] (25,2'5)-Dineopentyl-((((2R,35,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)- 3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy) phosphoryl)-(2,2')-bis- amino-4-methylthiobutanoate
  • anhyd dichloromethane (4 mL), the tosylate salt of neopentyloxy-L-methionine (1.41 g, 4.02 mmol) and diisopropylethylamine (1.40 mL, 8.03 mmol) were added to the mixture obtained in step one.
  • silica gel column chromatography and preparative TLC 7 mg of the prodrug was obtained in 1.1% yield as an off white solid.
  • Example 42 [00559] (25,2'5)-Dibenzyl-((((2R,35,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4- dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy) phosphoryl)-bis-pyrrolidine-2- methanoate
  • anhyd dichloromethane (2.4 mL), the hydrochloride salt of benzyloxy-L-proline (583 mg, 2.41 mmol) and diisopropylethylamine (840 ⁇ , 4.82 mmol) were added to the mixture obtained in step one.
  • silica gel column chromatography and preparative TLC 8.4 mg of the prodrug was obtained in 2.3% yield as an off white solid.
  • HPLC t R 18.57 min (Varian Polaris C18-A (10 ⁇ ) column using a mobile phase of water/acetonitrile ingradient (90/10 to 0/100 v/v in 30 min, System 1)
  • the phosphorodiamidate was prepared according to Method C.
  • a solution of 6-O-methyl-2' -C-methylguanosine (550 mg, 1.76 mmol) in anhydrous tetrahydrofuran (8 mL) was allowed to react with triethylamine (300 ⁇ L, 2.11 mmol) and phosphorus oxychloride (200 ⁇ L, 2.11 mmole).
  • L-alanine cyclohexyl ester tosylate salt 370 mg, 1.76 mmol
  • triethylamine 0.5 mL, 3.52 mmol
  • Pentylamine (0.56 mL, 3.21mmoles) and triethylamine (0.67 mL, 3.21 mmol) were added. After work-up and silica gel column chromatography, 11 mg of phosphorodiamidate was obtained in 3% yield as an off white solid.
  • the phosphorodiamidate was prepared according to Method B.
  • a suspension of ((2R,3R,4R,5R)-2-(2-amino-6-methoxy-9H-purin-9- yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol 300 mg, 0.96 mmol
  • anhydrous tetrahydrofuran 5 mL
  • triethylamine 130 ⁇ L, 0.96 mmol
  • phosphorus oxychloride 90 ⁇ L, 0.96 mmol
  • a suspension of ((2R,3R,4R,5R)-2-(2-amino-6-methoxy-9H-purin-9- yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol 150 mg, 0.47 mmol
  • anhydrous tetrahydrofuran 2.5 mL
  • triethylamine 80 ⁇ , 0.56 mmol
  • phosphorus oxychloride 50 ⁇ , 0.56 mmol
  • a suspension of ((2R,3R,4R,5R)-2-(2-amino-6-methoxy-9H-purin-9- yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol 180 mg, 0.57 mmol
  • anhydrous tetrahydrofuran 3.0 mL
  • triethylamine 100 ⁇ , 0.69 mmol
  • phosphorus oxychloride 70 ⁇ , 0.69 mmol
  • the phosphorodiamidate was prepared according to the Method B. [00722] In a first step, a suspension of ((2R,3R,4R,5R)-2-(2-amino-6-methoxy-9H-purin-9- yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol (310 mg, 1.01 mmol) in anhydrous tetrahydrofuran (4.3 mL) was reacted with triethylamine (170 ⁇ L, 1.21 mmol) and phosphorus oxychloride (110 ⁇ L, 1.21 mmol).
  • a suspension of ((2R,3R,4R,5R)-2-(2-amino-6-methoxy-9H-purin-9- yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol 300 mg, 0.96 mmol
  • anhydrous tetrahydrofuran 5 mL
  • triethylamine 130 ⁇ , 0.96 mmol
  • phosphorus oxychloride 90 ⁇ , 0.96 mmol
  • the phosphorodiamidate was prepared according to Method B. [00750] In a first step, a suspension of ((2R,3R,4R,5R)-2-(2-amino-6-methoxy-9H-purin-9- yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol (300 mg, 0.96 mmol) in anhydrous tetrahydrofuran (5 mL) was reacted with triethylamine (130 ⁇ , 0.96 mmol) and phosphorus oxychloride (90 ⁇ , 0.96 mmol).
  • a suspension of ((2R,3R,4R,5R)-2-(2-amino-6-methoxy-9H-purin-9- yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol 300 mg, 0.96 mmol
  • anhydrous tetrahydrofuran 5 mL
  • triethylamine 130 ⁇ , 0.96 mmol
  • phosphorus oxychloride 90 ⁇ , 0.96 mmol
  • the phosphorodiamidate was prepared according to Method B. [00770] In a first step, a suspension of 6-O-methyl-2' -C-methylguanosine (300 mg, 0.96 mmol) in anhydrous tetrahydrofuran (5 mL) was reacted with triethylamine (130 ⁇ L, 0.96 mmol) and phosphorus oxychloride (90 ⁇ L, 0.96 mmol).
  • a suspension of ((2R,3R,4R,5R)-2-(2-amino-6-methoxy-9H-purin-9- yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol 300 mg, 0.96 mmol
  • anhydrous tetrahydrofuran 5 mL
  • triethylamine 130 ⁇ , 0.96 mmol
  • phosphorus oxychloride 90 ⁇ , 0.96 mmol
  • the phosphorodiamidate was prepared according to Method B. [00799] In a first step, a suspension of ((2R,3R,4R,5R)-2-(2-amino-6-methoxy-9H-purin-9- yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol (500 mg, 1.50 mmol) in anhydrous tetrahydrofuran (8 mL) was reacted with triethylamine (0.25 mL, 1.80 mmol) and phosphoryl chloride (0.13mL, 1.50 mmol).

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Abstract

La présente invention concerne de nouveaux composés de formule (I) ayant une structure utile dans le traitement d'infections virales chez les mammifères induites, au moins en partie, par un virus de la famille de virus des Flaviviridae. L'invention concerne également des procédés de traitement d'infections virales par le biais de l'administration de ces composés.
PCT/US2011/054945 2010-10-06 2011-10-05 Dérivés phosphorodiamidate de composés nucléosidiques à base de guanosine destinés à traiter des infections virales Ceased WO2012048013A2 (fr)

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Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012154321A1 (fr) * 2011-03-31 2012-11-15 Idenix Pharmaceuticals, Inc. Composés et compositions pharmaceutiques pour le traitement d'infections virales
US8507460B2 (en) 2011-10-14 2013-08-13 Idenix Pharmaceuticals, Inc. Substituted 3′,5′-cyclic phosphates of purine nucleotide compounds and pharmaceutical compositions for the treatment of viral infections
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