uracil spirooxethane nucleosides, their use, pharmaceutical composition and product comprising them

专利摘要:
"URACILA SPIROOXETAN NUCLEOSIDE". The present invention relates to compounds of formula I: (I) including any possible stereoisomers thereof, wherein R9 has the meaning as defined herein, or a pharmaceutically acceptable salt thereof or solvate. The present invention is also intended for processes for the preparation of said compounds, pharmaceutical compositions containing them and for their use, alone or in combination with other HCV inhibitors, in HCV therapy.
公开号:BR112014029185B1
申请号:R112014029185-3
申请日:2013-05-24
公开日:2020-07-21
发明作者:Ioannis Nicolaos Houpis；Tim Hugo Maria Jonckers；Pierre Jean-Marie Bernard Raboisson；Abdellah Tahri
申请人:Janssen Sciences Ireland Uc；
IPC主号:

专利说明:

[0001] [001] This invention is intended for spirooxethane nucleosides and nucleotides, which are inhibitors of the hepatitis C virus (HCV).
[0002] [002] HCV is a positive, single-stranded RNA virus, belonging to the family of Flaviviridae viruses of the genus Hepacivirus. The NS5B region of the RNA polygon encodes an RNA-dependent RNA polymerase (RdRp), which is essential for viral replication. After the initial acute infection, most infected individuals develop chronic hepatitis because HCV replicates, preferably, in hepatocytes, but is not directly cytopathic. In particular, the lack of a vigorous T-lymphocyte response and the high propensity of the virus to mutate appear to promote a high rate of chronic infection. Chronic hepatitis can progress to fibrosis of the liver, leading to cirrhosis, the final stage of liver disease and HCC (hepatocellular carcinoma), becoming the main cause of liver transplants. There are six main genotypes and more than 50 subtypes, which are differently distributed geographically. HCV genotype 1 is the predominant genotype in Europe and the USA. The extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, which may explain the difficulties in developing vaccines and the lack of response to current therapy.
[0003] [003] HCV transmission can occur through contact with contaminated blood or blood products, p. after blood transfusion or injecting drug use. The introduction of diagnostic tests used in blood screening has led to a downward trend in post-transfusion HCV incidence. However, given the slow progression to the final stage of liver disease, existing infections will continue to present a serious medical and economic burden for decades.
[0004] [004] Current HCV therapy is based on interferon-alpha (lazy-side) (IFN-α) in combination with ribavirin. This combination therapy produces a sustained virological response in more than 40% of patients infected with HCV genotype 1 and about 80% of those infected with genotypes 2 and 3. In addition to the limited effectiveness against HCV genotype 1, this combination therapy it has significant side effects and is poorly tolerated in many patients. The main side effects include flu-like symptoms, hematological abnormalities and neuropsychiatric symptoms. Therefore, there is a need for more effective, convenient and better tolerated treatments.
[0005] [005] Recently, the possibilities of therapy have been extended towards the combination of a HCV protease inhibitor (for example Telaprevir or boceprevir) and interferon-alpha (pegylated) (IFN-α) / ribavirin.
[0006] [006] Experience with anti-HIV drugs, in particular HIV protease inhibitors, has taught that suboptimal pharmacokinetics and that complex dosing regimes quickly result in inadvertent compliance failures. This in turn means that the minimum 24-hour concentration (the minimum plasma concentration) for the respective drugs in an HIV regimen often falls below the IC90 or ED90 threshold for much of the day. It is considered that in 24 hours, a minimum level of at least IC50, and more realistically, IC90 or ED90 is essential to slow the development of drug-resistant mutants. Achieving the required pharmacokinetics and drug metabolism allows these minimum levels to provide a rigorous challenge for drug planning.
[0007] [007] NS5B RdRp is essential for replication of the positive, single-stranded HCV RNA genome. This enzyme sustained significant interest among chemical drugs. Both nucleoside and non-nu-nucleoside NS5B inhibitors are known. Nucleoside inhibitors can act as a chain terminator or as a competitive inhibitor, or both. In order to be activated, nucleoside inhibitors have to be absorbed by the cell and converted in vivo to a triphosphate. This conversion to triphosphate is commonly mediated by cell kinases, which confer additional structural requirements on a potential inhibitor of the nucleoside polymerase. In addition, this limits the direct evaluation of nucleosides as inhibitors of HCV replication for assays based on cells capable of phosphorylation in situ.
[0008] [008] Several attempts have been made to develop nucleosides as HCV RdRp inhibitors, but although a group of compounds has progressed in clinical development, none have followed up for registration. Among the problems with nucleosides with HCV as an objective that have been found to date are toxicity, mutagenicity, lack of selectivity, low efficacy, low bioavailability, suboptimal dosing regimes and the consequent high load of pills and cost of goods .
[0009] [009] Spirooxetan nucleosides, in particular derivatives of 1- (8-hydroxy-7- (hydroxymethyl) -1,6-dioxaspospiro [3.4] octan-5-yl) pyrimidine-2,4-dione and their use as HCV inhibitors are known from WO2010 / 130726, and WO2012 / 062869, including CAS-1375074-52-4.
[0010] [0010] There is a need for HCV inhibitors that can overcome at least one of the disadvantages of current HCV therapy such as side effects, limited effectiveness, the appearance of resistance, and failures in compliance, or improve response sustained viral.
[0011] [0011] The present invention is aimed at a group of derivatives of uracil spirooxethane that inhibits HCV with useful properties in relation to one or more of the following parameters: antiviral efficacy in the sense of at least one of the following genotypes 1a, 1b, 2a , 2b, 3, 4 and 6, favorable resistance development profile, lack of toxicity and genotoxicity, favorable pharmacokinetics and pharmacodynamics and ease of formulation and administration. DESCRIPTION OF THE INVENTION
[0012] [0012] In one aspect, the present invention provides compounds that can be represented by formula I:
[0013] [0013] including any possible stereoisomer thereof, where:
[0014] [0014] R9 is C1-C6 alkyl, phenyl, C3-C7 cycloalkyl or C1-C3 alkyl substituted with 1, 2 or 3 substituents each independently selected from phenyl, naphthyl, C3-C6 cycloalkyl, hydroxy, or C1- C6 alkoxy;
[0015] [0015] or a pharmaceutically acceptable salt or solvate thereof.
[0016] [0016] Of particular interest are compounds of formula I, or subgroups thereof as defined in this document, which have a structure according to formula la:
[0017] [0017] In an embodiment of the present invention, R9 is C1-C6 alkyl, phenyl, C3-C7 cycloalkyl or C1-C3 alkyl substituted with 1 substituent selected from phenyl, C3-C6 cycloalkyl, hydroxy, or C1- C6 alkoxy. In another embodiment of the present invention, R9 in Formula I or la is C1-C6 alkyl or C1-C2 alkyl substituted with phenyl C1-C2 alkoxy or C3-C6 cycloalkyl. In a more preferred embodiment, R9 is C2-C4 alkyl and in a more preferred embodiment R9 is i-propyl.
[0018] [0018] A preferred embodiment according to the invention is Compound, according to formula lb:
[0019] [0019] including any pharmaceutically acceptable salt or sol-vato thereof and the use of compound (V) in the synthesis of a compound according to Formula I, la or lb.
[0020] [0020] The invention is also intended for compounds of formula V:
[0021] [0021] including any pharmaceutically acceptable salt or sol-vato thereof and the use of compound (V) in the synthesis of a compound according to Formula I, la or lb.
[0022] [0022] In addition, the invention is intended for a compound of formula VI:
[0023] [0023] including any stereochemical form and / or pharmaceutically acceptable salt or solvate thereof.
[0024] [0024] In addition, the invention is directed to a pharmaceutical composition comprising a compound according to Formula I, la or lb, and a pharmaceutically acceptable carrier. The invention is also intended for a product containing (a) a compound of formula I, la or lb, and (b) another HCV inhibitor, as a combined preparation for simultaneous, separate or sequential use in the treatment of HCV infections. .
[0025] [0025] Yet another aspect of the invention is directed to a compound according to Formula I, la or lb or a pharmaceutical composition according to the present invention for use as a medicament, preferably for use in preventing or treating HCV infection in a mammal.
[0026] [0026] In another aspect, the invention provides a compound of formula I, la or lb or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment or prophylaxis (or in the manufacture of a medicament for the treatment or prophylaxis) of HCV infection. Representative HCV genotypes in the context of treatment or prophylaxis according to the invention include, genotype 1b (predominant in Europe) or 1a (predominant in North America). The invention also provides a method for the treatment or prophylaxis of HCV infection, in particular of genotype 1a or 1b.
[0027] [0027] Of particular interest is the compound 8a mentioned in the "Examples" section, as well as the pharmaceutically acceptable acid addition salts of this compound.
[0028] The compounds of formula I have several chiral centers, in particular at the carbon atoms 1 ', 2', 3 ', and 4'. Although the stereochemistry in these carbon atoms is fixed, the compounds can have at least 75%, preferably at least 90%, such as in excess of 95%, or 98%, of enantiomeric purity in each of the chiral centers.
[0029] [0029] The phosphorus center can be present as RP or SP, or a mixture of these stereoisomers, including racemates. Diasteo-reisomers resulting from the chiral phosphorus center and a chiral carbon atom can also exist.
[0030] [0030] The compounds of formula I are represented as a defined stereoisomer, except for stereoisomerism in the phosphorus atom. The absolute configuration of these compounds can be determined using methods known in the art, such as, for example, X-ray diffraction or NMR and / or implication from starting materials of known stereochemistry. The pharmaceutical compositions according to the invention will preferably comprise stereoisomerically pure forms of the indicated stereoisomer of the particular compound of formula I.
[0031] [0031] The pure stereoisomeric forms of the compounds and intermediates as mentioned in this document, are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term "stereoisomerically pure" refers to compounds or intermediates that have a stereoisomeric excess of at least 80% (i.e., a minimum of 90% of an isomer and a maximum of 10% of the other possible isomers) to a stereoisomeric excess of 100% (that is, 100% of one isomer and none of the other), more in particular, compounds or intermediates that have a stereoisomeric excess of 90% to 100%, even more in particular with a stereoisomeric excess of 94% to 100 % and even more in particular having a stereoisomeric excess of 97% to 100%, or 98% to 100%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in a similar way, but taking into account the enantiomeric excess, and the diastereomeric excess, respectively, of the mixture in question.
[0032] [0032] Pure stereoisomeric forms of the compounds and intermediates of this invention can be obtained by applying procedures known in the art. For example, enantiomers can be separated from each other by selective crystallization of their diastereomeric salts with optically active acids or bases. Examples of these are tartaric acid, dibenzoyltartaric acid, ditoluoyl-tartaric acid and camphorsulfonic acid. Alternatively, enantiomers can be separated by chromatographic techniques using chiral stationary phases. Such pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided the reaction occurs in a stereospecific manner. Preferably, if a specific stereoisomer is desired, said compound is synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
[0033] [0033] The diastereomeric racemates of the compounds of formula I can be obtained separately by conventional methods. Suitable physical separation methods that can be advantageously used are, e.g. selective selective crystallization and chromatography, e.g. column chromatography.
[0034] [0034] Pharmaceutically acceptable addition salts comprise therapeutically active non-toxic acid and base addition salt forms of the compounds of formula I. Of interest are the free forms, ie, non-salt forms, of the compounds of formula I, or any subgroup of compounds of formula I specified in this document.
[0035] [0035] Pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the base form with that appropriate acid. Suitable acids include, for example, inorganic acids, such as halide acids, e.g. eg, hydrochloric or hydrobromic, sulfuric, nitric, phosphoric acid and similar acids; or organic acids, such as, for example, acetic, proprionic, hydroxyacetic, lactic, pyruvic, oxalic (i.e., ethanedioic), malonic, succinic (i.e., butanedioic acid), maleic, fumaric, malic (i.e. is, hydroxybutanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, palmitic and similar acids. Conversely, said salt forms can be converted by treatment with an appropriate base in the form of the free base.
[0036] [0036] The compounds of formula I containing an acidic proton can also be converted to their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Suitable base salt forms comprise, e.g. e.g., ammonia salts, alkali and alkaline earth metal salts, e.g. e.g., lithium, sodium, potassium, magnesium, calcium and the like salts, salts with organic bases, e.g. , the benza-tine, N-methyl-D-glucamine salts, hydrabamine salts, and salts with amino acids, such as, e.g. , arginine, lysine and the like.
[0037] [0037] The term "solvates" encompasses any pharmaceutically acceptable solvates that the compounds of formula I, as well as their salts, are capable of forming. Such solvates are, e.g. hydrates, al-coolates, e.g. , ethanolates, propanolates, and the like.
[0038] [0038] Some of the compounds of formula I can also exist in their tautomeric forms. For example, the tautomeric forms of the amide groups (-C (= O) -NH-) are imino alcohols (-C (OH) = N-), which can become stabilized in aromatic rings. The uridine base is an example of one of these forms. These forms, although not explicitly indicated in the structural formulas represented in this document, are intended to be included within the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWING
[0039] [0039] Figure 1: In vivo efficacy of compound 8a and CAS-1375074-52-4 as determined in a humanized model of rat hepatocytes. DEFINITIONS
[0040] [0040] As used in this document, the term "C1-Cn alkyl", as a group or part of a group, defines hydrocarbon radicals of saturated linear or branched chain having from 1 to n carbon atoms. Thus, "C1-C4 alkyl" as a group or part of a group defines saturated straight chain or branched chain hydrocarbon radicals, which have between 1 to 4 carbon atoms, such as, for example, methyl, ethyl, 1 -propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl. "C1-C6 alkyl" encompasses C1-C4 alkyl radicals and their higher counterparts, therefore having 5 or 6 carbon atoms, such as, for example, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl , 2-hexyl, 2-methyl-1-butyl, 2-methyl-1-pentyl, 2-ethyl-1-butyl, 3-methyl-2-pentyl, and the like. Of interest among C1-C6 alkyl is C1-C4 alkyl.
[0041] [0041] 'C1-Cn alkoxy' means an -O-C1-Cn alkyl radical where C1-Cn alkyl is as defined above. Thus, 'C1-Cn alkoxy' means a -O-C1-C6 alkyl radical in which C1-C6 alkyl is as defined above. Examples of C1-C6 alkoxy are methoxy, ethoxy, n-propoxy, or isopropoxy. Of interest is ‘C1-C2 alkoxy’, encompassing methoxy and ethoxy.
[0042] [0042] 'C3-C6 cycloalkyl' includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[0043] [0043] In one embodiment, the term "phenyl-C1-C6 alkyl" is benzyl.
[0044] [0044] As used in this document, the term '(= O)' or 'oxo' forms a carbonyl moiety when attached to a carbon atom. It should be noted that an atom can only be replaced with an oxo group when the valence of that atom allows it.
[0045] [0045] The term "monophosphate, diphosphate or triphosphate ester" refers to groups:
[0046] [0046] Where the position of a radical in a molecular moiety is not specified (for example, a phenyl substituent) or is represented by a floating bond, that moiety can be positioned on any atom of that moiety, as long as the resulting structure is chemically stable. When any variable is present more than once in the molecule, each definition is independent.
[0047] [0047] Whenever used in this document, the term 'compounds of formula I', or 'the compounds present' or similar terms, if intended to include compounds of Formula I, la, and lb, including stereochemically possible isomeric forms, and their pharmaceutically acceptable salts and solvates.
[0048] [0048] The present invention also includes compounds labeled with isotopes of formula I or any subgroup of formula I, in which one or more of the atoms is replaced by an isotope which differs from that normally found in nature. Examples of such isotopes include isotopes of hydrogen, such as 2H and 3H; carbon, such as 11C, 13C and 14C; nitrogen, such as 13N and 15N; oxygen, such as 15O, 17O and 18O; phosphorus, such as 31P and 32P, sulfur, such as 35S; fluorine, such as 18F; chlorine, such as 36CI; bromine such as 75Br, 76Br, 77Br and 82Br; and iodine, such as 123l, 124l, 125l and 1311. The isotope-labeled compounds of the invention can be prepared by processes analogous to those described herein, using the appropriate isotope-labeled reagents or starting materials, or by techniques known in the art. technical. The choice of the isotope included in an isotope-labeled compound depends on the specific application of that compound. For example, for tissue distribution assays, a radioactive isotope such as 3H or 14C is incorporated. For radio imaging applications, a positron emitting isotope, such as 11C, 18F, 13N or 15O, will be useful. The incorporation of deuterium can confer greater metabolic stability, resulting in, for example, an in vivo increase in the half-life of the compound or in the reduction of dosage requirements. GENERAL SYNTHETIC PROCEDURES
[0049] [0049] The following schemes are intended to be illustrative only and are in no way limiting the scope.
[0050] [0050] The starting material 1 - [(4R, 5R, 7R, 8R) -8-hydroxy-7- (hydroxymethyl) -1,6-dioxaspiro [3.4] octan-5-yl] pyrimidine-2,4 (1H , 3H) -dione (1) can be prepared as exemplified in WO2010 / 130726. Compound (1) is converted to the compounds of the present invention through a protected derivative of p-methoxybenzyl (4), as exemplified in the following Scheme 1.
[0051] [0051] In Scheme 1, R9 can be C1-C6 alkyl, phenyl, naphthyl, C3-C7 cycloalkyl or C1-C3 alkyl substituted with 1, 2 or 3 substituents each independently selected from phenyl, C3-C6 cycloalkyl, hydroxy, or C1-C6 alkoxy, preferably R9 is C1-C6 alkyl or C1-C2 alkyl substituted with phenyl, C1-C2 alkoxy or C3-C6 cycloalkyl, even more preferably R9 is C2-C4 alkyl and most preferably R9 is i-propyl.
[0052] [0052] In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, as specified herein, and a pharmaceutically acceptable carrier. Said composition can contain from 1% to 50%, or from 10% to 40% of a compound of formula I and the rest of the composition is said vehicle. The therapeutically effective amount in this context is an amount sufficient to act prophylactically against HCV infection, inhibit HCV, stabilize or reduce HCV infection, in infected individuals or individuals at risk of being infected. In yet another aspect, this invention is intended for a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound of formula I, as specified herein. .
[0053] [0053] The compounds of formula I or any subgroup can be formulated in various dosage forms for the purpose of administration. As appropriate compositions, all compositions normally used for systemic drug administration can be cited. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in the form of an addition salt or metal complex, as the active ingredient is combined in admixture with a pharmaceutically acceptable carrier, the carrier of which can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unit dosage form suitable, particularly, for administration by oral, rectal, percutaneous, or parenteral injection. For example, in the preparation of compositions in oral dosage form, any of the usual pharmaceutical means, such as, for example, water, glycols, oils, alcohols and the like in the case of liquid oral preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid vehicles such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Due to their ease of administration, tablets and capsules represent the most advantageous unitary oral dosage form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the vehicle will usually comprise sterile water, at least in large part, although other ingredients, for example, to aid solubility, may be included. Injectable solutions can be prepared, for example, in which the vehicle comprises saline, glucose solution or a mixture of saline and glucose. Injectable suspensions can also be prepared, in which case appropriate liquid vehicles, suspending agents and the like can be used. Also included are preparations in solid form with the intention of being converted, just before use, to preparations in liquid forms. In compositions suitable for percutaneous administration, the vehicle optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minimal proportions, the additives of which do not introduce significant deleterious effects on the skin. The compounds of the present invention can also be administered via oral inhalation or insufflation, in the form of a solution, a suspension or a dry powder, using any delivery system known in the art.
[0054] [0054] It is especially advantageous to formulate the above mentioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The unit dosage form as used in this document refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in combination with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including grooved or coated tablets), capsules, pills, suppositories, powder packs, wafers, injectable solutions and suspensions and the like, and their multiple secretions.
[0055] [0055] The compounds of formula I show activity against HCV and can be used in the treatment and / or prophylaxis of HCV infection or diseases associated with HCV. The latter include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease and HCC. In addition, the compounds of this invention are believed to be active against mutated strains of HCV and have a favorable pharmacokinetic profile and have attractive properties in terms of bioavailability, including an acceptable half-life, AUC (area under the curve) and peak values and lack of unfavorable phenomena such as insufficient rapid onset and tissue retention.
[0056] [0056] The in vitro antiviral activity against HCV of compounds of formula I can be tested in a cellular HCV replicon system based on Lohmann et al. (1999) Science 285: 110-113, with the additional modifications described by Krieger et al. (2001) Journal of Virology 75: 4614-4624 (incorporated herein by reference), which is further exemplified in the examples section. This model, while not a complete HCV infection model, is widely accepted as the most robust and efficient model of autonomous HCV RNA replication currently available. It will be appreciated that it is important to distinguish between compounds that specifically interfere with HCV functions from those that exert cytotoxic or cytostatic effects on the HCV replicon model, and as a result cause a decrease in HCV RNA or bound reporter enzyme concentration. The assays are known in the art for the evaluation of cell cytotoxicity based, for example, on the activity of mitochondrial enzymes using fluorogenic redox dyes, such as resazurin. In addition, cell count screens exist for the assessment of non-selective inhibition of linked reporter gene activity, such as firefly luciferase. Suitable cell types can be equipped by stable transfection with a luciferase reporter gene, the expression of which is dependent on a constitutively active gene promoter, and these cells can be used as in screening the count to eliminate non-selective inhibitors.
[0057] [0057] Due to their anti-HCV properties, compounds of formula I, including any possible stereoisomers, their pharmaceutically acceptable addition salts or solvates, are useful in the treatment of warm-blooded animals, in particular humans, infected with HCV , and in the prophylaxis of HCV infections. The compounds of the present invention can therefore be used as a medicine, in particular as an anti-HCV or HCV-inhibiting medicine. The present invention is also intended for the use of the present compounds in the manufacture of a medicament for the treatment or prevention of HCV infection. In a further aspect, the present invention is intended for a method of treating a warm-blooded animal, in particular a human being, infected with HCV, or being at risk of becoming infected with HCV, said method comprises administering a effective amount of anti-HCV of a compound of said formula I, as specified herein. Said use as a medicine or treatment method comprises systemic administration, to subjects infected with HCV or to subjects susceptible to HCV infection of an amount effective to combat the conditions associated with HCV infection.
[0058] [0058] In general, it is contemplated that an effective antiviral daily amount would be from about 1 to about 30 mg / kg, or about 2 to about 25 mg / kg, or about 5 to about 15 mg / kg , or about 8 to about 12 mg / kg of body weight. Average daily doses can be obtained by multiplying these daily amounts by about 70. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals during the day. Said underdoses can be formulated as unit dosage forms containing, for example, about 1 to about 2000 mg, or about 50 to about 1500 mg, or about 100 to about 1000 mg, or about 150 to about 600 mg, or about 100 to about 400 mg of active ingredient per unit dosage form.
[0059] [0059] As used in this document the term "about" has the meaning known to the person skilled in the art. In certain embodiments, the term "about" can be left out and the exact amount is intended. In other modalities the term "about" means that the numeric after the term "about" is in the range of ± 15%, or ± 10%, or ± 5%, or ± 1%, of that value numeric. EXAMPLES
[0060] [0060] Compound (2) can be prepared by dissolving compound (1) in pyridine and adding 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane. The reaction was stirred at room temperature until complete. The solvent is removed and the product was redissolved in CH2 Cl2 and washed with a saturated solution of NaHCO3. Drying over MgSO4 and removing the solvent gives compound (2). Compound Synthesis (3)
[0061] [0061] Compound (3) is prepared by reacting compound (2) with p-methoxybenzyl chloride in the presence of DBU as the base in CH3CN. Compound Synthesis (4)
[0062] [0062] Compound (4) is prepared by cleavage of the bis-silyl protecting group in compound (3) using TBAF as the fluoride source. Synthesis of the compound (6a)
[0063] [0063] A solution of isopropyl alcohol (3.86 ml, 0.05 mol) and triethylamine (6.983 ml, 0.05 mol) in dichloromethane (50 ml) was added dropwise to a stirred solution of POCI3 (5 ) (5.0 ml, 0.0551 mol) in DCM (50 ml) over a period of 25 min at -5 ° C. After the mixture was stirred for 1 h, the solvent was evaporated, and the residue was suspended in ether (100 ml). The triethylamine hydrochloride salt was filtered and washed with ether (20 ml). The filtrate was concentrated, and the residue was distilled to give (6) as a colorless liquid (6.1 g, 69% yield). Synthesis of the compound (7a)
[0064] [0064] To a stirred suspension of (4) (2.0 g, 5.13 mmol) in dichloromethane (50 ml), triethylamine (2.07 g, 20.46 mmol) was added at room temperature. The reaction mixture was cooled to -20 ° C and then (6a) (1.2 g, 6.78 mmol) was added dropwise over a period of 10 min. The mixture was stirred at this temperature for 15 min and then NMI (0.84 g, 10.23 mmol) was added dropwise over a period of 15 min. The mixture was stirred at -15 ° C for 1 h and then slowly warmed to room temperature over 20 h. The solvent was evaporated, the mixture was concentrated and purified by column chromatography using petroleum ether / EtOAc (10: 1 to 5: 1 as a gradient) to give (7a) as a white solid (0.8 g , 32% yield). Synthesis of the compound (8a)
[0065] [0065] To a solution of (7a) in CH3CN (30 ml) and H2O (7 ml) was added the CAN portion just below 20 ° C. The mixture was stirred at 15-20 ° O for 5 h under N2. Na2SO3 (370 ml) was added dropwise to the reaction mixture below 15 ° C, and then Na2CO3 (370 ml) was added. The mixture was filtered and the filtrate was extracted with CH2 Cl2 (100 ml * 3). The organic layer was dried and concentrated to give the residue. The residue was purified by column chromatography to give the target compound (8a) as a white solid. (Yield: 55%)
[0066] [0066] 1H NMR (400 MHz, CHLOROPHORMUM-d) δ ppm 1.45 (dd, J = 7.53, 6.27 Hz, 6 H), 2.65 - 2.84 (m, 2 H), 3, 98 (td, J = 10.29, 4.77 Hz, 1 H), 4.27 (t, J = 9.66 Hz, 1 H), 4.43 (ddd, J = 8.91, 5, 77, 5.65 Hz, 1 H), 4.49 - 4.61 (m, 1 H), 4.65 (td, J = 7.78, 5.77 Hz, 1 H), 4.73 ( d, J = 7.78 Hz, 1 H), 4.87 (dq, J = 12.74, 6.30 Hz, 1 H), 5.55 (br. s., 1 H), 5.82 (d, J = 8.03 Hz, 1 H), 7.20 (d, J = 8.03 Hz, 1 H), 8.78 (br. s., 1 H); 31P NMR (D-CHLOROPHORM) δ ppm -7.13; LC-MS: 375 (M + 1) +
[0067] [0067] Compound (1), CAS 1255860-33-3 (1200 mg, 4.33 mmol) and 1,8-bis (dimethylamine) naphthalene (3707 mg, 17.3 mmol) were dissolved in 24.3 ml trimethylphosphate. The solution was cooled to 0 ° C. Compound (5) (1.21 ml, 12.98 mmol) was added, and the mixture was stirred well maintaining the temperature at 0 ° C for 5 hours. The reaction was quenched by adding 120 ml of tetraethylammonium bromide solution (1M) and extracted with CH2 Cl2 (2x80 ml). Purification was carried out by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10µm, 30x150mm, mobile phase: NH4HCO3 solution 0.25% in water, CH3CN), obtaining two fractions. The purest fraction was dissolved in water (15 ml) and passed through a manually packed Dowex column (H +) by eluting with water. The end of the elution was determined by determining the UV absorption of the elution fractions. The combined fractions were frozen at -78 ° C and lyophilized. Compound (9) was obtained as a soft white solid (303 mg, (0.86 mmol, 20% yield), which was used immediately in the next reaction. Step 2: Preparation of the compound (VI)
[0068] [0068] Compound (9) (303 mg, 0.86 mmol) was dissolved in 8 ml of water and to this solution was added N, N'-Dicyclohexyl-4-morpholine carboxamidine (253.8 mg, 0 , 86 mmol) dissolved in pyridine (8.4 ml). The mixture was kept for 5 minutes and then evaporated to dryness, dried overnight in vacuo overnight at 37 ° C. The residue was dissolved in pyridine (80 ml). This solution was added dropwise to DCC (892.6 mg, 4.326 mmol) vigorously stirred in pyridine (80 ml) at reflux temperature. The solution was kept at reflux for 1.5 h, during which some turbidity in the solution was observed. The mixture was cooled and evaporated to dryness. Diethyl ether (50 ml) and water (50 ml) were added to the solid residue. N'N-dicyclohexylurea was removed by filtration, and the aqueous fraction was purified by preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10µm, 30x150mm, mobile phase: 0.25% NH4HCO3 solution in water, CH3CN ), obtaining a white solid which was dried overnight under vacuum at 38 ° C. (185 mg, 0.56 mmol, 65% yield). LC-MS: (M + H) +: 333.
[0069] [0069] 1H NMR (400 MHz, DMSO-d6) d ppm 2.44 - 2.59 (m, 2 H) signals fall within the DMSO signal, 3.51 (td, J = 9.90, 5.50 Hz, 1 H), 3.95 - 4.11 (m, 2 H), 4.16 (d, J = 10.34 Hz, 1 H), 4.25 - 4.40 (m, 2 H) , 5.65 (d, J = 8.14 Hz, 1 H), 5.93 (br. S., 1 H), 7.46 (d, J = 7.92 Hz, 1 H), no 2Hs observed. BIOLOGICAL EXAMPLES Replicon Assay
[0070] [0070] The compounds of formula I were examined for activity in inhibiting HCV RNA replication in a cell assay. The assay was used to demonstrate that the compounds of formula I inhibited a functional HCV replication cell line, also known as HCV replicons. The cell assay was based on a bicistronic expression construct, as described by Lohmann et al. (1999) Science vol. 285 pg. 110-113 with modifications described by Krieger et al. (2001) Journal of Virology 75: 4614-4624) in a multi-target screening strategy. Replicon Assay (A)
[0071] [0071] In essence, the method was as follows. The assay used the stably transfected cell line Huh-7 luc / neo (hereinafter referred to as Huh-Luc). This cell line has an RNA that encodes a bicistronic expression construct comprising the HCV type 1b wild-type NS3 to NS5B regions translated from an internal ribosomal entry site (IRES; "Internai Ribosome Entry Site") of the encephalomyocarditis virus (EMCV), prescribed by a portion of the reporter gene (FfL-luciferase) and a portion of the selection marker (neoR, neomycin phosphotransferase). The construction is delimited by 5 'and 3' NTRs (untranslated regions) of the HCV genotype 1b. Continuation of replicon cell culture in the presence of G418 (neoR) is dependent on HCV RNA replication. Stably transfected cells containing the replicon, which express HCV RNA, which replicate autonomously and at high levels, encoding luciferase, among others, were used for the screening of antiviral compounds.
[0072] [0072] The replicon cells were plated in 384-well plates, in the presence of the test and control compounds that were added in various concentrations. Following a three-day incubation, HCV replication was measured by assaying luciferase activity (using luciferase assay substrates and reagents and a Perkin Elmer ViewLux ™ ul-traHTS microplate imager). The replicon cells in the control cultures have a high expression of luciferase in the absence of any inhibitor. The compound's inhibitory activity on luciferase activity was monitored in Huh-Luc cells, allowing a dose response curve for each test compound. EC50 values were calculated, whose values represent the amount of compound needed to decrease the level of luciferase activity detected by 50%, or more specifically, the ability of the genetically linked HCV RNA replicon to replicate. Results (A)
[0073] [0073] Table 1 shows the results of the replicon (EC50, replicon) and the results of cytotoxicity (CC50 (μΜ) (Huh-7)), obtained for the compound of the examples given above.
[0074] [0074] Other replicon assays with compound 8a were carried out of which the protocols and results are disclosed below. TEST 1
[0075] [0075] The anti-HCV activity of compound 8a was tested in cell culture with replicon cells generated using reagents from the Bartenschlager laboratory (the HCV subgenomic HCV 1b subgenomic luciferase reporter clone). The protocol included a 3-day incubation period with 2500 replicon cells in a 384-well format in a nine-point 1: 4 dilution series of the compound. Dose response curves were generated based on the firefly luciferase reading. In a variation of this assay, a 3-day incubation with 3000 cells in a 96-well format in a series of nine-point dilutions was followed by Taqman detection of qRT-PCR from the HCV genome, and normalized for cell transcription, RPL13 (from the ribosomal subunit of the RPL13 gene) as a control for inhibition of the cell transcriptional compound. TEST 2
[0076] [0076] The anti-HCV activity of compound 8a was tested in cell culture with replicon cells generated using reagents from the Bartenschlager laboratory (the replicon replicon clone of the bi-conditional subgenomic ET luciferase HCV 1b or Huh-Luc-Neo). The protocol included a 3-day incubation period with 2 x 104 replicon cells in a 96-well format in a six-point 1: 5 dilution series of the compound. Dose response curves were generated based on the luciferase reading. TEST 3
[0077] [0077] The anti-HCV activity of compound 8a was tested in cell culture with replicon cells generated using reagents from the Bartenschlager laboratory (the replicon replicon clone of the bi-conditional subgenomic ET luciferase HCV 1b or Huh-Luc-Neo). The protocol included either a 3-day incubation period with 8 x 103 or 2 x 104 cells in a 96-well format in a 1: 5 dilution series of eight points of the compound. Dose response curves were generated based on the luciferase reading. RESULTS
[0078] [0078] Table 2 shows the average replicon results (EC50, replicon) obtained for compound 8a following assays as shown above.
[0079] [0079] The anti-HCV activity of compound 8a was determined in an in vitro primary human hepatocyte assay. The protocols and results are disclosed below. PROTOCOL Hepatocyte isolation and culture
[0080] [0080] Primary human hepatocytes (PHH) were prepared from patients undergoing partial hepatectomy for metastases or benign tumors. Fresh human hepatocytes were isolated from encapsulated liver fragments using a two-step modification of the collagenase digestion method. Briefly, the encapsulated liver tissue was placed in a custom-made perfusion device and the hepatic vessels were cannulated with tubing fixed to the multichannel collector. The liver fragment was initially perfused for 20 min with a pre-heated (37 ° C) calcium-free buffer, supplemented with ethylene glycol tetra-acetic acid (EGTA), followed by perfusion with a pre-heated (37 ° C) buffer containing calcium (CaCI 2, H2O2) and 0.05% collagenase for 10 min. Then, the liver fragment was gently agitated to release the liver cells in Hepatocyte Washing Medium. The cell suspension was filtered through a gauze-lined funnel. The cells were centrifuged at low speed centrifugation. The supernatant, containing damaged or killed hepatocytes, non-parenchymal cells and debris were removed and the pelleted hepatocytes were resuspended in Hepatocyte Washing Medium. Viability and cell concentration were determined by trypan blue exclusion test.
[0081] [0081] The cells were resuspended in complete hepatocyte medium consisting of William medium (Invitrogen) supplemented with 100 IU / I insulin (Novo Nordisk, France), and 10% fetal heat-inactivated bovine serum (Biowest, France ), and cultured at a density of 1.8 x 10 6 viable cells in 6-well plates, which had been pre-coated with calf skin type I collagen (Sigma-Aldrich, France). The medium was replaced 16-20 hours later with fresh complete hepatocyte medium supplemented with hydrocortisone hemisuccinate (SERB, Paris, France), and cells were left in this medium until HCV inoculation. The cultures were maintained at 37 ° C in a 5% humidified CO 2 atmosphere.
[0082] [0082] PHHs were inoculated three days after culture. The stocks of JFH1-HCVcc were used to inoculate PHHs for 12 hours, at a multiplicity of infection (MOI) of 0.1 ffu per cell. After a 12 hour incubation at 37 ° C, the nucleus was removed, and the monolayers were washed 3 times with phosphate buffered saline and incubated in complete hepatocyte medium containing 0.1% dimethylsulfoxide hepatocyte as the carrier vehicle. , 100 IU / ml IFNalpha as a negative control or increasing concentrations of compound 8a. The cultures were then maintained for 3 days. Quantification of HCV RNA
[0083] [0083] Total RNA was prepared from cultured cells or from filtered culture supernatants using the viral RNA minikit RNeasy or Qiamp respectively (Qiagen Sa, Courtaboeuf, France) according to the manufacturer's recommendations. HCV RNA was quantified in cells and culture supernatants using a specific real-time reverse chain PCR technique described previously (Carrière M et al 2007):
[0084] [0084] Reverse transcription was performed using previously described primers located in the 50 NCR region of the HCV genome, tag-RC1 (5'-GGCCGTCATGGTGGCGAATAAGTCTAG CCATGGCGTTAGTA-3 ') and RC21 (5'-CTCCCGGGGCACTCGCAAGC-3') for negative strings positive, respectively. After a denaturation step carried out at 70 ° C for 8 min, the RNA template was incubated at 4 ° C for 5 min in the presence of 200 ng of RC1 initiator tag and 1.25 mM of each deoxynucleotide triphosphate (dNTP) (Promega, Charbonnieres, France) in a total volume of 12 µl.
[0085] [0085] Reverse transcription was performed for 60 min at 60 ° C in the presence of 20 U of RNaseOut ™ (Invitrogen, Cergy Pontoise, France) and 7.5 U of Thermoscript ™ reverse transcriptase (Invitrogen), in the buffer recommended by the manufacturer . An additional treatment was applied by adding 1 μΙ (2U) RNaseH (Invitrogen) for 20 min at 37 ° C.
[0086] [0086] The first round of PCR was performed with 2 μΙ of cDNA obtained in a total volume of 50 μΙ, containing 3 U of Taq polymerase (Promega), 0.5 mM dNTP, and 0.5 μΜ of RC1 primers ( 5'-GTCTAGCCATGGCGTTAGTA-3 ') and RC21 for amplification of the positive strand, or Tag primers (5'-GGCCGTCATGGTGGCGAATAA-3') and RC21 for amplification of the negative strand. The PCR protocol consisted of 18 cycles of denaturation (94 ° C for 1 min), tie-down (55 ° C for 45 sec) and extension (72 ° C for 2 min). The obtained cDNA was purified using the Qiagen kit, according to the manufacturer's instructions.
[0087] [0087] The purified product was then subjected to real-time PCR. The reaction was carried out using the LightCycler 480 SYBR Green I Master Kit (2x con) (Roche, Grenoble, France), with LC480 instruments and technology (Roche Diagnostics). The PCR amplifications were performed in a total volume of 10 μΙ, containing 5 μΙ of Sybrgreen I Master Mix (2x), and 25 ng of the 197R primers (5'- CTTTCGCGACCCAACACTAC-3 ') and 104 (5'- AGAGCCATAGTGGTCTGCGG-3 '). The PCR protocol consisted of an initial denaturation step for 10 min at 94 ° C, followed by 40 denaturation cycles (95 ° C for 15 sec), matched (57 ° C for 5 sec), and extension (72 ° C for 8 s and g).
[0088] [0088] Quantification of 28Sr RNA using specific RT-PCR was used as an internal standard to express the results of positive or negative HCV chains per µg of total hepatocyte RNA. The specific primers for 28 S RNAr were designed using the Oligo6 software 5'-TTGAAAATCCGGGGGAGAG-3 '(nt2717-2735) and 50-ACATTGTTCCAACATGCCAG-30 (nt 28162797). Reverse transcription was performed using AMV reverse transcriptase (Promega), and the PCR protocol consisted of an initial denaturation step for 8 min at 95 ° C, followed by 40 cy-denaturation cycles (95 ° C for 15 sec ), tied hamento (54 ° C for 5 sec), and extension (7210 for 5 sec). RESULTS
[0089] [0089] Table 3 shows the anti-HCV activity of compound 8a as determined in the primary human hepatocyte in vitro assay described above. The numbers are expressed as 106 copies of HCV RNA / µg of total RNA. The results of two independent levels of experimentation (Exp 1 and Exp 2) are presented. Experimental data are the average of the two measurement levels.
[0090] [0090] Table 3: Effect of compound 8a on HCV RNA positive chain levels in primary human hepatocytes (expressed as 106 copies of HCV RNA / µg of total RNA.
[0091] [0091] The in vivo efficacy of compound 8a and CAS-1375074-52-4 was determined in a model of humanized mouse hepatocytes (mouse PBX) as previously described by Inoue et. al (Hepatology. 2007 abr; 45 (4): 921-8) and Tenato et. al. (Am J Pathol 2004; 165-901-912) with the following specification: Test animals: PXB mice infected with HCV G1a, male or female,> 70% human hepatocyte replacement index. Dosing was carried out for 7 days at doses indicated below where QD represents a single dose per day, BID represents two doses per day.
[0092] [0092] The effectiveness of compound 8a was compared with CAS-1375074-52-4. The results are shown in Figure 1. The Figure shows the HCV viral RNA log after administration over a 7-day period.
[0093] [0093] Figure 1 clearly shows that a dosage of 100 mg / kg QD for CAS 1375074-52-4 (indicated as n = 4) does not result in a significant decrease in the HCV viral RNA record. This contrasts sharply with each of the dosage regimens indicated for compound 8a, in which a clear log record is observed for 100 mg / kg QD (indicated as ♦, n = 3), 200 mg / kg QD (indicated as •, n = 4), 50 mg / kg BID (indicated as ■, n = 4). The effect of the most pronounced logging on viral RNA is observed after a 7-day dosage of compound 8a at 100 mg / kg BID (indicated as n = 4).

权利要求:
Claims (15)
[0001]
Compound, characterized by the fact that it presents formula I:
[0002]
Compound, according to claim 1, characterized by the fact that it has the formula la:
[0003]
Compound according to claim 1 or 2, characterized in that R9 is C1-C6 alkyl or C1-C2 alkyl substituted with phenyl, C1-C2 alkoxy or C3-C6 cycloalkyl.
[0004]
Compound according to any one of claims 1 to 3, characterized by the fact that R9 is C2-C4alkyl.
[0005]
Compound according to any one of claims 1 to 4, characterized in that R9 is i-propyl.
[0006]
Compound according to any one of claims 1 to 5, characterized by the fact that it has the formula lb:
[0007]
Compound, characterized by the fact that it presents the formula V:
[0008]
Use of the compound (V), characterized by the fact that it is in the synthesis of a compound, as defined in any one of claims 1 to 6 according to the following 2 steps:
[0009]
Use according to claim 8, characterized by the fact that it is in the following process:
[0010]
Compound, characterized by the fact that it presents the formula VI:
[0011]
Pharmaceutical composition, characterized in that it comprises a compound, as defined in any one of claims 1 to 6, and a pharmaceutically acceptable carrier.
[0012]
Compound according to any one of claims 1 to 6, and 10, or a pharmaceutical composition according to claim 11, characterized (a) in that it is for use as a medicament.
[0013]
Compound according to any one of claims 1 to 6 and 10, or a pharmaceutical composition according to claim 11, characterized (a) in that it is for use in preventing or treating an HCV infection in a mammal .
[0014]
Product, characterized in that it contains (a) a compound of formula I, as defined in any of claims 1 to 6 and 10, and (b) another HCV inhibitor, as a combined preparation for simultaneous, separate or sequential use in the treatment of HCV infections.
[0015]
Use of a compound, as defined in any of claims 1 to 7 and 10, characterized by the fact that it is for the preparation of a pharmaceutical composition in the prevention or treatment of an HCV infection.

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法律状态:
2017-12-12| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2018-02-27| B25A| Requested transfer of rights approved|Owner name: JANSSEN SCIENCES IRELAND UC (IE) |

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2018-03-06| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-03-13| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-03-20| B06I| Publication of requirement cancelled [chapter 6.9 patent gazette]|Free format text: ANULADA A PUBLICACAO CODIGO 6.6.1 NA RPI NO 2462 DE 13/03/2018 POR TER SIDO INDEVIDA. |

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2019-04-16| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-08-13| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-05-12| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-07-21| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 24/05/2013, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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EP12169425|2012-05-25|

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EP12169425.1|2012-05-25|

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PCT/EP2013/060704|WO2013174962A1|2012-05-25|2013-05-24|Uracyl spirooxetane nucleosides|

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