WO2006122207A1 - 6-hydrazinopurine 2'-methyl ribonucleosides et nucleotides pour le traitement de hcv - Google Patents

6-hydrazinopurine 2'-methyl ribonucleosides et nucleotides pour le traitement de hcv Download PDF

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Publication number
WO2006122207A1
WO2006122207A1 PCT/US2006/018135 US2006018135W WO2006122207A1 WO 2006122207 A1 WO2006122207 A1 WO 2006122207A1 US 2006018135 W US2006018135 W US 2006018135W WO 2006122207 A1 WO2006122207 A1 WO 2006122207A1
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WIPO (PCT)
Prior art keywords
methyl
mmol
hcv
amino
reaction mixture
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PCT/US2006/018135
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English (en)
Inventor
Esmir Gunic
Frank Rong
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Valeant Research & Development
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Publication of WO2006122207A1 publication Critical patent/WO2006122207A1/fr

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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

Definitions

  • the invention is in the fields of nucleoside chemistry, pharmacology, and the therapeutic treatment of hepatitis C virus (HCV) infection.
  • HCV hepatitis C virus
  • nucleoside analogues have been used as antimetabolites for treatment of cancers and viral infections. After entry into the cell, many nucleoside analogues can be phosphorylated to monophosphates by nucleoside kinases, and then further phosphorylated by nucleoside monophosphate kinases and nucleoside diphosphate kinases to give nucleoside triphosphates. Once a nucleoside analogue is converted to its triphosphate inside the cell, it can be incorporated into DNA or RNA.
  • nucleic acid replicates or transcripts can interrupt gene expression by early chain termination or by interfering with the function of the modified nucleic acids.
  • nucleoside analogue triphosphates are very potent, competitive inhibitors of DNA or RNA polymerases, which can significantly reduce the rate at which the natural nucleoside can be incorporated.
  • anti-HIV nucleoside analogues fall into this category, including 3'-C- azido-3'-deoxythymidine (AZT), 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddl), and 2 ' ,3 ' -didehydro-2 ' ,3 ' -dideoxythymidine (d4T).
  • AZT 3'-C- azido-3'-deoxythymidine
  • ddC 2',3'-dideoxycytidine
  • ddl 2',3'-dideoxyinosine
  • d4T 2 ' ,3 ' -didehydro-2 ' ,3 ' -dideoxythymidine
  • nucleotide analogs for the treatment of HCV is at present accepted in clinical practice.
  • the combination of the pyrimidine nucleoside analog ribavirin (l- ⁇ -D-ribofuranosyl-lH-l,2,4-triazole-3-carboxamide) and ⁇ -interferon has been the accepted therapy for HCV.
  • the search for more potent analogs having fewer side effects has been continuing.
  • These efforts have involved not only base analogs, such as ribavirin, but also modification of the ribofuranose moiety.
  • Nucleosides and nucleotides derived from 2'methylribofuranosyl are described in WO 01/90121 and WO 01/92282 (now U.S. patent No. 6,812,219 to Idenix) by Sommoadossi and LaCoIIa.
  • the 2'methylribonucleotides and ribonucleosides disclosed were those with 6-alkylamino-substitutions, 6-alkylamino and 8 amino substitutions and 6-alkylamino and 2- amino substitutions.
  • the ' 121 publication reports that the phosphorylation of 2'methyl adenosine, i.e., the production of active triphosphate, occurs readily in comparison to the phosphorylation of the 2'methylguanosine.
  • a further group of purine nucleotides and nucleosides for the treatment of HCV was disclosed in WO 02/18404 by Devos et al. (to F. Hoffmann-LaRoche).
  • the nucleotides disclosed by Devos include purines having 2-amino-N 6 -substituted amino bases and having 2'-difluoro or 2'-deoxy ribofuranosyl.
  • SATE prodrug nucleotides were generically disclosed in U.S. patent No. 5,770,725 and related patents.
  • Other neutral nucleotide prodrugs for the treatment of viral diseases are disclosed in U.S. patent No 6,312,662 by Erion et al. (assigned to Metabasis), and No. 6,455,513 by McGuigan and Balzarini, assigned to University College Cambridge Consultants Ltd.
  • N 6 substituted adenosines and N 6 substituted-2-amino adenosines were reported in WO 2003/039050 by Loakes et al, assigned to the Med. Research Council of Great Britain.
  • 2-amino-N 6 methyl-N 6 amino adenosine was reported in WO 2003/039050 by Loakes et al, assigned to the Med. Research Council of Great Britain.
  • 2-amino-N 6 methyl-N 6 amino adenosine 2-amino-N 6 methyl-N 6 amino adenosine.
  • the invention is based on a first surprising discovery, that the N 6 -methyl-N 6 - methylsulfonamido derivatives of an adenine-2'-methylribofunanosyl nucleosides are superior as inhibitors of HCV replication to the corresponding compounds lacking the N 6 - methyl.
  • the invention accordingly provides compounds of formula I
  • Z 2 is H and Z 6 is -N(Me)NHSO 2 CH 3 and R is H or any suitable synthetic protecting group, including but not limited to acetyl, benzoyl, trialkylsilyl, isopropylidine, BOC or CBZ groups.
  • each R independently, is preferably H or a substituted or unsubstituted acyl group.
  • acyl groups include Ci- Cio aliphatic acyl groups (formyl, acetyl, etc.), benzoyl groups, pyridinecarbonyl groups, and other acyl groups that are removable in vivo.
  • Substituted acyl groups may be substituted with one or more of methyl, halogen, methoxy, hydroxy, nitro, cyano, methylsulfonyl, aminosulfonyl, sulfonylamino, and the like.
  • the invention is also based on a second surprising discovery, which is that 2-amino substituted 6-hydrazino purine -2'methylribonucleosides have superior activity to the 2- usubstituted 6-hydrazino purine nucleosides.
  • the invention extends to the related mono- di- and triphosphonucleotides which result from either in vitro or in vivo phosphorylation or from in vivo processing of a prodrug.
  • Such mono-phosphonucleotides may result from either in vitro or in vivo phosphorylation or from in vivo processing of a prodrug.
  • the invention further provides the combination of 6-hydrazino and 2-amino-6- hydrazino purine 2'methylnucleosides with 7-deaza and 7-substituted -7-deaza 2'methylnucleotides according to formula III.
  • Z 2 is H, NH 2 , NHMe, or NMe 2
  • Z 6 is NR 1 NH 2 , NR 1 NMeH, NR 1 NMe 2 , NRiNHSO 2 CH 3 , NRiN(Me)SO 2 CH 3 , wherein R 1 is Ci -4 alkyl and Z 7 is H, F, Cl, Br, or CN and related phosphonucleotides.
  • the compounds of the invention can be presented by three formulae.
  • the invention provides for particular nucleosides, including protected synthetic intermediates, according to formula I. wherein Z 2 is H or NH 2 .
  • Z 2 is NH 2
  • Z 6 is -N(Me)NHSO 2 CH 3 or -N(Me)NH 2 .
  • Z 2 is H
  • Z 6 -N(Me)NHSO 2 CH 3 .
  • R can be H, a synthetic protecting group, or an acyl group as defined above.
  • the invention further provides nucleotides according to Formula II
  • Z 2 is H, NH 2 , NHMe, or NMe 2 ; and Z 6 is NR 1 NH 2 , NR 1 NMeH, NR 1 NMe 2 , NR 1 NHSO 2 CH 3 , OrNRiN(Me)SO 2 CH 3 , wherein Ri is C M alkyl.
  • Particular embodiments consist of the compounds where Z 2 is NH 2 and Ri is CH 3 .
  • an embodiment provides that Z 2 is H and Z 6 is NMeNHSO 2 CH 3 or NMeNH 2 .
  • Z 2 is H, NH 2 , NHMe, or NMe 2 ;
  • Z 6 is NRjNH 2 , NRiNMeH, NRiNMe 2 , NRiNHSO 2 CH 3 , NRiN(Me)SO 2 CH 3 , wherein Ri is C M alkyl; and
  • Z 7 H, F, Cl, Br 3 or CN and R is as above.
  • the pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
  • compositions for parenteral injection preferably comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, cetyl alcohol and glycerol monostearate
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
  • Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq.
  • the salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid.
  • acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
  • Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting an acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals and nontoxic quaternary ammonia and amine cations.
  • dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration. Dose-ranging studies are routine in the pharmaceutical art. Generally, dosage levels of about 1 to about 500, more preferably of about 5 to about 50 mg of an active compound per kilogram of body weight per day are administered orally to a mammalian patient. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g., two to four separate doses per day.
  • the invention also provides methods for the treatment of HCV viral infection in a mammal by administration of the compounds of the invention, pharmaceutical compositions comprising one or more compounds of the invention, a method of inhibiting replication of HCV comprising contacting a compound of the invention with the replicating HCV, and the use of compounds of the invention for the preparation of a pharmaceutical composition for treatment of HCV.
  • the invention also provides a method of treating a patient suffering from HCV infection, comprising administering to the patient a therapeutically effective amount of a compound of the invention.
  • reaction mixture was warmed to 5 0 C for one hour to complete the reaction.
  • One hundred ml of 20 % aq. H 2 SO 4 (360 mmol) was slowly added dropwise, with good stirring to the reaction mixture. Rapid gas evolution was observed.
  • the reaction mixture was extracted with 6 x 60 ml CHCl 3 , organic layers were dried with sodium sulfate and solvent removed in vacuo, to give 12.5 g of crude product. Distillation at 40-55 0 C and 5-10 mm Hg provided 7 g product.
  • reaction was quenched by adding 15 ml of water, and extracted with ethyl acetate (30 ml x 3), washed with brine (20 ml x 3) and water, then dried over anhydrous sodium sulfate. After evaporation of solvents, the residue was purified by flash chromatography on a silica gel column, eluting with 1 to 12% methanol in chloroform to provide the product as a light yellow powder in 26% yield: silica gel TLC R f 0.55 (1 : 8 methanol-chloroform).
  • the reaction mixture was poured into a 30 ml ice water and extracted with 5X20 ml of chloroform. Solvents were removed in vacuo and the residue chromatographed with 3/15/82 methanol/acetone/chloroform to give 48 mg of the acetone hydrazone of 17.
  • the hydrazine 17 was generated by treatment with 15 ml of 60 % Aq HOAc for 15 minutes. After removal of solvent, 17 was recovered, 95 % pure by HPLC, with NMR and MS consistent with structure.
  • reaction mixture was cooled to -60 0 C, then 0.162 ml (0.81 mmol) 5M t- butylhydroperoxide was added, drop wise with stirring. After 2 hours the reaction mixture was warmed to room temperature and kept at room temperature for 2 hours. The mixture was poured into 100 ml of ice water then extracted with 5 x 50 ml of CHCl 3 . Solvent was removed in vacuo and the residue subjected to silica gel chromatography with 4% MeOH/CHCl 3 , to yield 101 mg 20, having NMR and MS consistent with the structure shown.
  • the replicon cells (Huh- 7) contain replicating HCV replicon RNA, modified by replacing the structural region with a neomycin resistance marker.
  • Survival of the replicon cells under G418 selection relies on the replication of HCV RNA and subsequently expression of neomycin phosphoryltransferase.
  • the ability of modified nucleoside libraries and compounds to suppress HCV RNA replication was determined using the QuantigeneTM Assay Kit from Bayer. The assay measures the reduction of HCV RNA molecules in the treated cells.
  • Replicon cells were incubated at 37°C for 3 days in the presence of nucleoside libraries and compounds before being harvested for detection.
  • HCV subgenomic replicon cell line was provided by Dr. Bartenschlager. The assay protocol was modified based on the literature procedure
  • Bovine viral diarrhea virus (BVDV) (strain NADL) was provided by Dr. Ruben Donis and propagated in MDBK cells (ATCC).
  • the nucleoside compounds were tested utilizing the modified protocol (V. B. Vassilev, M. S. Collett, R. O. Donis, J. Viol. 1997, 71, 471-478; S. G. Bagginski, D. C. Pevear, M. Seipel, S. C. C. Sun, C. A. Benetatos, S. K. Chunduru, C. M. Rice, M. S. Collett, Proc. Natl. Acad. ScI U. S. A. 2000, 97, 7981-7986)
  • SPTE bis-pivaloyl SATE derivatives
  • Sl-13 was significantly more active than SPTE Sl-18 and further found that the SPTE of the disubstituted N 6 -methyl-N 6 -methylsulfoamido 2'MA (S2-1) was comparable in strength to SPTE of Sl-13.
  • the unsubstituted hydrazino 2'MA was not tested as a prodrug due to the instability of the hydrazine.
  • Table II shows the activity gains due to the presence of a 2-amino substitution (compounds S2-2 - S2-4).

Abstract

L'invention concerne des composés de formule I, utilisés comme inhibiteurs du virus de l'hépatite C.
PCT/US2006/018135 2005-05-10 2006-05-10 6-hydrazinopurine 2'-methyl ribonucleosides et nucleotides pour le traitement de hcv WO2006122207A1 (fr)

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US60/679,780 2005-05-10

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010514768A (ja) * 2006-12-28 2010-05-06 イデニク プハルマセウティカルス，インコーポレイテッド ウイルス感染の治療のための化合物、及び医薬組成物
WO2014008236A1 (fr) 2012-07-03 2014-01-09 Bristol-Myers Squibb Company Procédé de préparation de dérivés de phosphoramidates enrichis en diastéréo-isomères de composés de nucléosides, destinés au traitement d'infections virales

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002057287A2 (fr) * 2001-01-22 2002-07-25 Merck & Co., Inc. Derives de nucleoside servant d'inhibiteurs de l'arn polymerase virale arn dependante

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002057287A2 (fr) * 2001-01-22 2002-07-25 Merck & Co., Inc. Derives de nucleoside servant d'inhibiteurs de l'arn polymerase virale arn dependante

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010514768A (ja) * 2006-12-28 2010-05-06 イデニク プハルマセウティカルス，インコーポレイテッド ウイルス感染の治療のための化合物、及び医薬組成物
JP2014139218A (ja) * 2006-12-28 2014-07-31 Idenix Pharmaceuticals Inc ウイルス感染の治療のための化合物、及び医薬組成物
KR101508018B1 (ko) * 2006-12-28 2015-04-08 아이데닉스 파마슈티칼스, 인코포레이티드 바이러스 감염의 치료를 위한 화합물 및 제약 조성물
WO2014008236A1 (fr) 2012-07-03 2014-01-09 Bristol-Myers Squibb Company Procédé de préparation de dérivés de phosphoramidates enrichis en diastéréo-isomères de composés de nucléosides, destinés au traitement d'infections virales

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