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WO2007065883A1 - Derives antiviraux des azanucleosides - Google Patents

Derives antiviraux des azanucleosides Download PDF

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Publication number
WO2007065883A1
WO2007065883A1 PCT/EP2006/069288 EP2006069288W WO2007065883A1 WO 2007065883 A1 WO2007065883 A1 WO 2007065883A1 EP 2006069288 W EP2006069288 W EP 2006069288W WO 2007065883 A1 WO2007065883 A1 WO 2007065883A1
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Prior art keywords
virus
group
compounds
use according
hydroxy
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PCT/EP2006/069288
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English (en)
Inventor
Ugo Chiacchio
Antonio Mastino
Pedro Merino
Giovanni Romeo
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Istituto di Ricerche di Biologia Molecolare P Angeletti SpA
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Istituto di Ricerche di Biologia Molecolare P Angeletti SpA
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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
    • 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

  • the present invention relates to the field of pharmaceutical chemistry and in particular to the preparation of compounds with azanucleoside structure and their use as medicaments, and more in particular for the treatment of viral infections. Background of the invention
  • Hepatitis C virus causes a persistent infection in 50% of the infected indi- viduais.
  • a rational approach for treatment of said pathology is the development of agents that can specifically act against viral targets, including RNA-dependent RNA polymerase coded by NSB5 of HCV which is responsible for viral genome replication.
  • NSB5 is a good target for investigating new drugs.
  • RJNA polymerase inhibitors are well-known in the art. Said inhibitors have different chemical structures and can be classified as nucleoside derivatives and non-nucleoside derivatives. Recently, compounds being analogue of nucleosides have been disclosed as useful anti C hepatitis agents.
  • Said nucleosides have three key features: a) a hydroxymethyl group that undergoes to J 1 W vivo phosphorylation by kinases giving nucleotides triphosphate b) the purine and/or pyrimidine base that is essential for specific enzymatic recognition and complementarity with the nucleic acid strain during protein synthesis c) the ribose ring, or a similar heterocyclic group, can be considered as a spacer group which maintains a) and b) groups in the right position, a) and b) groups tolerate few structural changes, while drastic modification of the spacer group are often present.
  • nucleoside derivatives are disclosed in WO 02/057287 (Merck & Co. e ISIS PHARMACEUTICALS), where the c) element is a ribose residue.
  • I Qiu, Xiao-Long and Qing, Feng-Ling J. Org, Chem., 2005, 70, 3826-3837) disclose the synthesis of 3'-deoxy-3'-difluoromethyl azanucleosides from trans A- hydroxy L-proline. A possible antiviral activity of said compounds is cited but no indication is given on their efficacy.
  • modified nucleosides active on HCV it must be taken into consideration that the recognition of the nucleosides by the viral polymerase is strictly linked to the presence of the pharmacophore group on CT, i.e. hydroxy or meth- oxy.
  • hepatitis C virus polymerase is an RNA polymerase having ribonucleoside triphosphates as natural substrate, said hydroxy group on C2' recognises said compounds from deoxyribonucleotides, which are DNA-polymerase substrates.
  • Current therapy combines subcutaneous administration of pegylated D -interferon with oral administration of nucleoside ribavirin. Said treatment gives positive results only in 50% of the cases and only after six months.
  • RNA-dependent viral polymerase responsible for viral genome replication is particularly felt the need of improving therapy efficacy and security.
  • One possible approach is based on the development of an antiviral chemotherapy, based on the design of new agents, in particular on the HCV NS5B target: RNA- dependent viral polymerase responsible for viral genome replication.
  • the new nucleosides of the present invention specifically and effectively solve this need.
  • One feature of said compounds is ribose ring, the sugar unit, substituted with an alternative heterocyclic system derived from proline. Said compounds can be classified as azanucleosides.
  • hydroxy group in position 2' is responsible for the recognition by polymerase, while the hydroxy group in position 3' has been deleted, in order to avoid RNA, DNA growing chain elongation. Therefore, compounds of formula (I) are an object of the present invention:
  • B is an aromatic or non-aromatic heterocyclic base, in particular a nucleobase
  • Ri is hydrogen, C 1 -C 6 linear or branched, saturated or unsaturated alkyl, C 3 -C O saturated or unsaturated cycloalkyl;
  • R 3 is hydrogen or a group that can be converted in vivo into hydrogen or a phosphate containing group
  • R 6 is hydrogen, Ci-C 6 linear or branched, saturated or unsaturated alkyl, C 2 -C 6 linear or branched, saturated or unsaturated acyl;
  • R 2 is (-CO-X) n -R 4 , wherein X is O, S or N, or is absent; and R 4 is Ci-C 6 linear or branched alkyl, C 6 -CiO aryl, benzyl; n is 0 or 1 ; their salts, in particular their pharmaceutically acceptable salts, solvates, single enantiomers, diastereoisomers, and their mixtures.
  • the compounds of the present invention have an interesting antiviral activity; therefore they are useful as active ingredients for the preparation of medicaments for human or animal use. Said class of compounds has never been disclosed in literature and consequently it represents a new class of modified nucleosides.
  • the disclosed compounds can be combined with other active agents in cocktail therapies.
  • a further object of the present invention is a process for the preparation of the compounds of formula (I).
  • a further object of the present invention is the use of the compounds of formula (I) for the preparation of medicaments, in particular for the treatment of viral infections.
  • the group B is a heterocyclic base, aromatic or non aromatic.
  • the heterocyclic ring can also contain other heteroatoms, like oxygen and/or sulphur, on condition that they do not cancel ring basicity.
  • the heterocyclic base can be aromatic or non aromatic depending on the presence of unsaturations and conjugations.
  • Examples are aziridine group, oxaziridine group, azetidine group, pyrrole group, isoxazole, oxazole, thiazole and imidazole, pyridine or pyrimidine fused with one or more benzene ring.
  • Preferred examples are typical nucleotide bases, also known as nucleobases, adenine, guanine, thymine and uracil.
  • Heterocyclic bases, and preferred nucleobases can also have one or more substituents on the ring, such as C 1 -C 6 linear or branched, saturated or unsaturated alkyl, C 3 -C O cycloalkyl, hydroxy, Ci -C 6 linear or branched, saturated or unsaturated alkoxy, halogen.
  • a preferred example is 5-fiuorouracyl.
  • Ci -C 6 Alkyl group means methyl, ethyl, propyl, butyl, pentyl and hexyl and all their well-known position isomers.
  • C 3 -C 6 cycloalkyl group means cyclopropyl, cyclobutyl, cyclopentyl e cyclohexyl.
  • C 2 -C 6 acyl group means acetyl, propionyl, butirryl, pentanoyl and hexanoyl and all their position isomers.
  • the group that can be in vivo converted to hydrogen is a group which in cel- lular conditions restore the hydroxy or the phosphate-containing group, as phosphate or triphosphate, the group OR 3 can be phosphonate or phosphoamidate.
  • the compounds of the present invention can be prepared by an enantioselective synthetic process, following, for example, the scheme herein below.
  • the introduction of the heterocyclic base is carried out following a stereoselective synthesis pathway comprising a) oxidation of the carbon atom in position 5 to keto group;
  • the esterification in the first step is carried out by using the classic technique of acyl chloride in a suitable solvent, such as methanol, in suitable an- hydrous conditions.
  • a suitable solvent such as methanol
  • Reaction conditions, time, temperature and reagent ratio can be determined by the skilled person in view of the ester. It is convenient to prepare the methyl ester, for yield reason, and isolation of the desired product.
  • the nitrogen atom of proline is functionalised with the R 4 -X-CO group by using conventional method.
  • a preferred group is ter-butoxycarboxyl. Protection of the hydroxy group in position 4 of the proline ring is not difficult and a preferred method is silylation for example with ter-butyldimethylsilyl- chloride.
  • the carbon atom in position 5 of the proline ring undergoes oxidation
  • differ- ent systems can be used, for example a rutenium oxide/sodium periodate system, transforming the methylene group into a keto group.
  • the carbonyl is reduced to hydroxy, preferably with LiEt 3 BH.
  • the group protecting the hydroxy in 4 can be removed, for example with TBAF (tetrabutylammonium fluoride).
  • TBAF tetrabutylammonium fluoride
  • the introduction of the heterocyclic base can be carried out in different known ways, for example, soon after having re -protected the free hydroxy groups with an acyl group, such as acetyl, the selected base is introduced in position 5.
  • the described method uses the process designed by Vorbruggen (H. Vorbruggen et al, Chem. Ber., 1981, 114, 1234-1255). Finally, the carboxylic group, or its ester, is reduced to primary alcohol.
  • the stereochemical configuration of the compounds of the present invention is important for the activity. Consequently, it is important to have a process which leads to final products having the desired configuration, without needing any further technique for the separation and isolation of the active diastereoisomer.
  • the important point is the stereospecific introduction of the heterocyclic base in position 5 of the proline ring.
  • the -OAc group in position 4 of the pyrrolidine nucleus which is in trans with respect to the carboxylic group in C-2, controls the stereochemical course of the nucleosidation process, with the exclusive formation of the derivatives which have trans heterocyclic base with respect to the substituents in C-4 and cis with respect to carboxyethyl in C-2.
  • Process stereoselectivity is controlled by the steric center in C-4 and will lead to the formation of nucleosides having the desired ⁇ .-configuration
  • the compounds of the present invention have pharmaceutical activity hence are useful for the preparation of medicaments.
  • the compounds of the present invention have antiviral activity, therefore, the medicament containing at least one compound of formula (I) as active agent is suitable for the treatment of viral infections.
  • the compounds of the present invention show an interesting antiviral activity against RNA viruses, at non toxic concentrations equal or less than 100 ⁇ M.
  • HCV hepatitis C virus
  • the antiviral effect is expressed by the "inhibitory con- centration 50 %" (IC50) of the viral protein presence, measured as the value of ab- sorbance by optical reading, evaluated by linear regression of values from wells with treated cells and control wells with untreated cells, followed by calculation of Pearson's correlation coefficients.
  • IC50 inhibitory con- centration 50 %
  • the above disclosed compounds are suitable inhibitors of RNA-dependent viral RNA-polymerase, of viral replication of RNA viruses and/or for the treatment of RNA virus infections.
  • Examples of viral infections are infections caused by Flaviviridae o Picornaviridae viruses.
  • Picornaviridae viruses are, for example, rhinovirus, poliovirus, and hepatitis A virus.
  • Flaviviridae viruses are, for example, Hepatitis C Virus (HCV), yellow fever virus, dengue virus , west Nile virus, Japanese encephalitis virus, Banzi virus, BVDV - Bovine Viral Diarrhoea Virus.
  • RNA viruses such as influenza virus (Orthomyxoviridae), for example human influenza A and B virus, avian influenza A virus, pig influenza A virus; Rheoviridae family viruses (human Rotavirus and ovine bluetongue virus) Bunyaviridae family viruses (many viruses transmitted by insects, hantavirus and flebovirus) and Retroviridae family viruses (HIV-I, HIV-2, HTLV-I e HTL V-2).
  • influenza virus Orthomyxoviridae
  • human influenza A and B virus avian influenza A virus
  • pig influenza A virus avian influenza A virus
  • Rheoviridae family viruses human Rotavirus and ovine bluetongue virus
  • Bunyaviridae family viruses many viruses transmitted by insects, hantavirus and flebovirus
  • Retroviridae family viruses HIV-I, HIV-2, HTLV-I e HTL V-2).
  • Another aspect of the present invention is the use of the compounds of formula (I) for the inhibition of HCV NS5B.
  • An additional aspect of the present invention is the inhibition of virus replication or the treatment of the viral infection thereof.
  • Said aspects refer also to the use of compounds of formula (I) in the laboratory practice, where they can be used as reagents and optionally prepared with common additives or in titrated solutions.
  • compounds of (I) in particular for the treatment of viral infections, they can be the only active agent having antiviral activity or, as a further object of the invention, they can be combined with other active agents with specific antiviral activity or having different pharmaceutical ac- tivities, suitably chosen in consideration of the present clinic state.
  • the compounds of the invention can be used alone or in combination with other medicaments commonly used for the treatment of said pathology.
  • medicaments are, HCV NS5B po- lymerase inhibitors, such as ribavirin, levovirin, viramidine, ⁇ -1 thymosin, pegy- lated or non pegylated interferon ⁇ , , their combinations, such as pegylated or non pegylated interferon ⁇ and ribavirin or levovirin.
  • Interferon ⁇ comprises interferon ⁇ 2a (for example Roferon ® ), also pegylated (PegasysTM); consensus recombinant interferon (for example alphacon-1); being a product of purified interferon.
  • the combination of compounds of formula (I) can be done with active agents of NS3 HCV serine protease, such as inhibitors based or not on the substrate, such as for example disclosed in WO 98/22496, WO 98/46630, WO 99/07733, WO 99/07734, WO 99/3888, WO 99/50230, WO 99/64442, WO 00/09543, WO 00/59929 e GB 2337262.
  • the compounds of the present invention are used for the production of a medicament suitable for the treatment of viral infections. Said medicament will be administered to a subject in need thereof, according to conventional human or animal medicine.
  • the kind of treatment, the therapeutic protocol, and the posology will be deter- mined by the person skilled in the art, in this case the doctor, considering the type of infection, patient's conditions, and doctor's experience.
  • Posology will be determined by the methods commonly used in clinical trials.
  • Administration in combination with different active agents can be done using single components alone or combined together in single or divided doses.
  • the compounds of the present invention can be formulated in well known conventional pharmaceutical compositions.
  • the pharmaceutical compositions contain at least one active ingredient in an amount such to obtain a significant therapeutic effect.
  • compositions according to the present invention are obtained by using methods conventionally used in the pharmaceutical industry, as for example, those described in Remington 's Pharmaceutical Science Handbook, Mack Pub. N. Y. - last edition. In view of the selected administration protocol, the composition will be in solid or liquid form, suitable for oral, parenteral and intravenous administration. Formulations suitable for inhalation are also mentioned.
  • the compositions according to the present invention comprise, together with the active agent, at least one pharmaceutically acceptable vehicle or excipient.
  • Formulation co-adjuvants can be particularly useful, such as for examples, solubilizing agents, dispersing agents, suspending agents, or emulsifying agents.
  • compositions comprise formulations for oral administration, tablets, pills, rigid or soft capsules, powders, wafers, powders for solutions or extemporary suspensions, drinkable solutions or suspensions, chewable tablets, syrups, elixirs, sublingual tablets, oral adhesive forms or slow release forms, foams and aerosol.
  • formulations for enteral administration are suppositories.
  • examples of pharmaceutical composition for parenteral administration are solutions or apirogen injectable suspensions.
  • pharmaceutical compositions for topical administration are creams, ointments, patches, also with systemic effect.
  • formulations for administration in the respiratory tract are sprays, aerosol, and formulations for inhalation. Formulations for ophthalmic administration are also mentioned.
  • the active agent dose can be indicated as from 0.01 to 1000, preferably from 0.1 to 100, more preferably from 0.5 to 20 mg/kg of body weight.
  • Example 1 The invention is further illustrated by the following examples.
  • Example 1 The invention is further illustrated by the following examples.
  • Acetyl chloride (4.14 g, 52.8 mmol) is dropped into a three neck round bottom flask containing anhydrous methanol (33 ml) in ice bath and under N 2 flux.
  • [(2S,4R)-(-)-4-Hydroxypyrrolidine-2-carboxylic acid (1) (5.0 g, 37.7 mmol) is added and the so obtained reaction mixture is firstly brought to room temperature (r.t.) then refluxed for 8 hours. Afterwards, the reaction is brought to room temperature and diethyl ether is added till complete precipitation of the reaction product, which, after Buchner filtration, is (2S,4R)-4-hydroxy-2-(methoxy- carbonyl)pyrrolidine chloride (2).
  • Triethylamine (10.1 g, 100 mmol), then di-ter-butyl-dicarbonate (8.3 g, 38.0 mmol) are added to the suspension of (2S,4R)-4-hydroxy-2-(methoxycarbonyl)- pyrrolidine chloride (2) (6.32 g, 34.8 mmol) in 45 ml of anhydrous CH 2 Cl 2 at 0 0 C.
  • the reaction is carried out in ice/salt bath for 12 hours under N 2 flux. Then, the reaction mixture is treated with a 1 M H 3 PO 4 solution (158 ml), then with a Na- HCO 3 saturated solution (3x45 ml).
  • Imidazole (7.15 g, 105 mmol) is added to the solution of l-ter-butyl-2 -methyl (2S,4R)-4-hydroxypir-rolidin-l,2-dicarboxylate (3) (11.7 g, 47.7 mmol) in 60 ml of anhydrous CH 2 Cl 2 .
  • the so obtained solution is treated with ter-butyl- dimethylsilylchloride (7.91 g, 52.5 mmol) in 40 ml anhydrous CH 2 Cl, drop by drop, at 0 0 C.
  • the reaction is left overnight at r.t.
  • the obtained organic phase is separated from the aqueous phase and treated with a saturated solution OfNaHSO 3 (3x60 ml), filtered through celite, dried over sodium sulfate and evaporated to dryness, and l-ter-butyl-2-methyl (2S,4R) -4- ⁇ [ter-butyl(dimethyl)- silyl]-oxy ⁇ -5-oxypyrrolidine-l,2-dicarboxylate (5) is obtained. Yellow oil, yield 60% (calculated by 1 R NMR).
  • Lithium triethyl borohydrate (0.51 g, 4.83 mmol) is dripped into the solution of 1- ter-butyl-2 -methyl (2S,4R)-4- ⁇ [ter-butyl-(dimethyl)silyl]oxy ⁇ -5-oxypyrrolidine- 1,2-dicarboxylate (5) (3.6 g, 9.66 mmol) in 90 ml anhydrous THF, at -78°C under N 2 flux. Reaction is carried out for 1 hour, then hydride (0.72 g, 6.76 mmol) is further added. After 45 minutes, the reaction is stopped and 160 OfH 2 O added.
  • nucleobase suspension (0,06 g, Cytosine; 0,07 g, Thymine; 0,06 g Uracil; 0,55 mmol
  • anhydrous CH 3 CN N,O-bis-trimethylsilylacetamide (0,45 g, 2,23 mmol) is added drop by drop and re-precipitating for 15 minutes.
  • the reaction mixture is brought to r.t. and l-ter-butyl-2 -methyl (2S,4R)-4,5-bis(acetyl- oxy pyrrolidine- 1,2-dicarboxylate solution is dropped
  • modified nucleosides 9a-d (0,11 mmol; 0,05 g, of 9a; 0,05 g, of 9d; 0,05 g, of 9b; 0,04 g, of 9c) in 10 ml dioxane/water 1:1 solid NaBH 4 (0,04 g, 1 ,05 mmol) is added.
  • the obtained suspension is reacted overnight at r.t. Then the reaction is stopped, filtered and the solvent eliminated with the rotavapor.
  • 10 ml of CH 2 Cl 2 added , the organic phase is washed with H 2 O (3x10 ml), dried over sodium sulfate, evaporated to dryness and the obtained residues are purified by flash chromatography.
  • Lithium triethyl borohydride (0.5 g, 6.9 mmol) was dropped into the solution of (2S,4R)-1 -ethyl 2-methyl 4-(ter-butyldimethylsilyloxy)-5-oxopyrrolidine-l,2-di- carboxylate (5) (4.8 g, 13.75 mmol) in 1280 ml of anhydrous THF, at -78°C under N 2 flux. Reaction was left for 1 h, then a second portion of hydride was added thereto (0.7 g, 9.6 mmol). After 45 min, reaction was stopped and H 2 O was added.

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Abstract

La présente invention concerne des composés à structure d'azanucléoside de formule (I), dans laquelle les groupes sont tels que définis plus bas. Lesdits composés ont une activité antivirale et, en particulier, ils inhibent les polymérases virales qui dépendent de l'ARN.
PCT/EP2006/069288 2005-12-06 2006-12-04 Derives antiviraux des azanucleosides Ceased WO2007065883A1 (fr)

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ITRM2005A000611 2005-12-06
IT000611A ITRM20050611A1 (it) 2005-12-06 2005-12-06 Derivati azanucleosidici ad attivita' antivirale.

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WO2007065883A1 true WO2007065883A1 (fr) 2007-06-14

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009040698A (ja) * 2007-08-07 2009-02-26 Nagasaki Univ 光学活性プロリンエステル誘導体およびｎ−ホルミル光学活性プロリン誘導体の製造方法
WO2009076747A1 (fr) 2007-12-19 2009-06-25 Boehringer Ingelheim International Gmbh Inhibiteurs de polymérase virale
WO2010080874A1 (fr) 2009-01-07 2010-07-15 Scynexis, Inc. Dérivé de cyclosporine convenant au traitement de l'infection par vhc et vih
CN104435222A (zh) * 2014-12-01 2015-03-25 登封市博爱农林牧开发有限公司 防治羊蓝舌病的中药制剂

Citations (2)

* Cited by examiner, † Cited by third party
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WO2002018371A1 (fr) * 2000-08-29 2002-03-07 Industrial Research Limited Inhibiteurs du metabolisme des nucleosides
WO2006002231A1 (fr) * 2004-06-22 2006-01-05 Biocryst Pharmaceuticals, Inc. Azanucleosides, leur preparation et leur utilisation comme inhibiteur des arn polymerases virales

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002018371A1 (fr) * 2000-08-29 2002-03-07 Industrial Research Limited Inhibiteurs du metabolisme des nucleosides
WO2006002231A1 (fr) * 2004-06-22 2006-01-05 Biocryst Pharmaceuticals, Inc. Azanucleosides, leur preparation et leur utilisation comme inhibiteur des arn polymerases virales

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHAND, P. ET AL.: "Synthesis of (2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)-3-methylpyrrolidine-3,4,-diol, an analog of potent HCV inhibitor", COLLECTION SYMP. SER., 2005, pages 329 - 332, XP009082877 *
COSTENARO, E. R. ET AL: "Stereoselective synthesis of aza-nucleosides aza-stavudine (aza-D4T), aza-2',3'-didehydro-3'-deoxyuridine (aza-D4U), and its hydrogenated analogs from an endocyclic enecarbamate", TETRAHEDRON LETTERS , 42(9), 1599-1602 CODEN: TELEAY; ISSN: 0040-4039, 2001, XP002431010 *
PICKERING, LEA ET AL: "4'-Methyloxycarbamyl-3'-deoxy-5-methyl uridine; synthesis of a novel nucleoside analog", TETRAHEDRON , 51(9), 2719-28 CODEN: TETRAB; ISSN: 0040-4020, 1995, XP004104737 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009040698A (ja) * 2007-08-07 2009-02-26 Nagasaki Univ 光学活性プロリンエステル誘導体およびｎ−ホルミル光学活性プロリン誘導体の製造方法
WO2009076747A1 (fr) 2007-12-19 2009-06-25 Boehringer Ingelheim International Gmbh Inhibiteurs de polymérase virale
WO2010080874A1 (fr) 2009-01-07 2010-07-15 Scynexis, Inc. Dérivé de cyclosporine convenant au traitement de l'infection par vhc et vih
CN104435222A (zh) * 2014-12-01 2015-03-25 登封市博爱农林牧开发有限公司 防治羊蓝舌病的中药制剂

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