WO2010031832A9 - Combinaisons synergiques d'un inhibiteur macrocyclique de hcv et d'un dérivé d'acide thiophène-2-carboxylique - Google Patents
Combinaisons synergiques d'un inhibiteur macrocyclique de hcv et d'un dérivé d'acide thiophène-2-carboxylique Download PDFInfo
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- WO2010031832A9 WO2010031832A9 PCT/EP2009/062101 EP2009062101W WO2010031832A9 WO 2010031832 A9 WO2010031832 A9 WO 2010031832A9 EP 2009062101 W EP2009062101 W EP 2009062101W WO 2010031832 A9 WO2010031832 A9 WO 2010031832A9
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- hcv
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Definitions
- the present invention relates to synergistic combinations of a macrocyclic NS3/4A protease inhibitor of HCV and a HCV NS5B polymerase inhibiting nucleoside.
- HCV Hepatitis C virus
- Flaviviridae family of viruses in the hepacivirus genus is the leading cause of chronic liver disease worldwide.
- HCV Hepatitis C virus
- HCV is mainly transmitted by blood contact. Following initial acute infection, a majority of infected individuals develops chronic hepatitis because HCV replicates preferentially in hepatocytes but is not directly cytopathic. Over decades, a
- liver fibrosis fibrosis, cirrhosis and hepatocellular carcinoma, with chronic HCV infection being the leading cause for liver
- HCV NS3/4A serine protease and its associated cofactor HCV NS3/4A serine protease and its associated cofactor
- NS4A HCV NS3/4A serine protease and its associated cofactor
- NS5B polymerase Another essential enzyme in this process is NS5B polymerase. Both NS3/4A serine protease and NS5B polymerase are considered to be essential for viral replication and inhibitors of these enzymes are considered drug candidates for HCV treatment.
- WO 05/073195 discloses linear and macrocyclic NS3 serine protease inhibitors with a central substituted proline moiety and WO 05/073216 with a central cyclopentyl moiety. Amongst these, the macrocyclic derivatives are attractive due to their potency and interesting pharmacokinetic profile.
- WO 2007/014926 discloses a series of macrocyclic NS3 serine protease inhibitors. Of these, the compound
- RNA-dependent RNA polymerase NS5B is essential for replication of the RNA genome.
- Both nucleoside and non-nucleoside inhibitors of this enzyme are known. A number of the latter have been described for example in WO 2002/100851, which discloses substituted thiophene-2-carboxylic acids. One of these compounds is
- the present invention relates to a synergistic combination comprising the compound of formula I:
- 1,4-trans cyclohexyl isomer in particular the 1,4-trans cyclohexyl isomer; or a pharmaceutically acceptable salt thereof.
- the compounds of formula I or formula II may be used in pharmaceutically acceptable salt forms or in free (i.e. non-salt) form. Salt forms can be obtained by treating the free form with an acid or base.
- the pharmaceutically acceptable acid and base addition salts which are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compounds of formula I and II are able to form.
- the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the free form with such appropriate acid.
- Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, such as hydrobromic acid, or in particular hydrochloric acid; or sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic (i.e.
- the compounds of formula I or formula II may also be converted into the pharmaceutically acceptable metal or amine addition salt forms by treatment with appropriate organic or inorganic bases.
- Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, potassium, and in particular the sodium salt; and the magnesium, calcium salts, and the like; salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine, and the like.
- the term addition salt form is meant to also comprise any solvates that the compounds of formula I or formula II, as well as the salts thereof, may form. Such solvates are, for example, hydrates, alcoholates, e.g. ethanolates, and the like. Of interest are the free (i.e. non-salt) form of the compound of formula II.. Also of interest are the pharmaceutically acceptable salt forms of the compound of formula I.
- the EC50 ratio between both active ingredients I and II in the combinations of the invention may vary. In one embodiment said ratio is in the range between 10: 1 to 1 : 10, or between 5 : 1 to 1 :5, or between 3 : 1 to 1 :3, or between 2: 1 to 1 :2. In a particular embodiment said ratio is about 1 : 1.
- the term "EC50 ratio” refers to the ratio of the EC50 value of the compound of formula I to the EC50 value of the compound of formula II, said EC50 value being obtained in the HCV replicon test. The latter in particular is the test method described hereinafter. In this test, the average EC50 value of compound I was found to be 8 nM and the average EC50 value of compound II to be 0.7 ⁇ .
- effective blood plasma levels can be determined by multiplying the EC50 values with a factor that expresses plasma protein binding and a factor that represents a safety margin.
- the latter factor can be set at about 10.
- Protein binding can be determined by measuring the amount bound to blood proteins such as human serum albumin, lipoprotein, glycoprotein, ⁇ , ⁇ , and ⁇ globulins.
- Effective blood plasma levels which can also be referred to as virological active doses, represent those doses that are needed to provide effective anti-viral activity, i.e. doses that effectively reduce viral load. The viral load is effectively reduced when it is reduced about two or more orders of magnitude, preferably below the detection limit of the virus.
- the dose (or amount of drug) to be administered can be calculated with the volume of distribution (V D ) , which is also known as apparent volume of distribution.
- V D volume of distribution
- the V D can be determined in animal models in which predetermined amounts of the active substance are
- the amounts of the compound of formula I in the combinations of the invention that are administered on a daily basis may vary from about 1 mg to about 2500 mg, about 5 mg to about 1000 mg, or from about 10 mg to about 500 mg, or from about 25 mg to about 250 mg, or from about 25 mg to about 200 mg.
- Examples of daily amounts of the compound of formula I are 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, and 400 mg.
- the amounts of the compound of formula II that are administered on a daily basis may vary from about 200 mg to about 5,000 mg, or from about 400 mg to about 3,000 mg, or from about 800 mg to about 2,400 mg, of the compound of formula II.
- Examples of daily amounts of the compound of formula II are 1200 mg, 1600 mg, 1800 mg, 2400 mg.
- the above values represent free-form equivalents, i.e. quantities as if the free form would be administered. If salts are administered the amounts need to be calculated in function of the molecular weight ratio between the salt and the free form.
- Exemplary combinations of the compound of formula I and of the compound of formula II in mg/mg per day include, for example, 25/1000; 25/2000; 50/1000, 50/2000, 100/1000, 100/2000, 200/1000, 200/2000.
- the above mentioned daily doses are calculated for an average body weight of about 70 kg and should be recalculated in case of paediatric applications, or when used with patients with a substantially diverting body weight.
- the dosage forms may be presented as one, two, three or four or more subdoses administered at appropriate intervals throughout the day.
- the unit dosage used preferably corresponds to the daily amount of the compound of formula I, or of the compound of formula II, mentioned above, or a subdose thereof, such as 1/2, 1/3, or 1/4 thereof.
- a unitary dosage form may contain the compound I or the compound II, or both, in an amount equal to the ranges or quantities mentioned in the previous paragraph, for example a unitary dosage form may contain 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, or 200 mg of compound I, or 250 mg, 500mg, 1000 mg, 1500 mg, or 2000 mg of compound II, either in separate formulations or in a combined formulation.
- the compound of formula I is administered once daily (q.d.), in particular as one unit dose per day, and the compound of formula II is administered once, or in particular, two, or more in particular, three times daily (b.i.d. or t.i.d.).
- q.d. once daily
- the compound of formula II is administered once, or in particular, two, or more in particular, three times daily (b.i.d. or t.i.d.).
- administered once daily this can be accomplished by administering two separate doses, one with compound I, the other with compound II, or by administering a combined dose containing both compound I and compound II.
- this can be accomplished by administering three or four separate doses, one with compound I, the others with compound II, or by administering a combined unit dose containing both compound I and compound II and, if desired, one or two additional unit doses with only
- the combinations of the invention may be administered once, twice, three, four, or if desired multiple times daily. In one embodiment, the combination is administered once daily. In another embodiment, the combination is administered twice daily, or three times per day. Administrations may be by separate dosage forms, i.e. dosage forms only containing compound I or only compound II; or by combined dosage forms containing both active ingredients I and II. Also, as mentioned above, a mix of using a combined dosage form and one, two or more dosage forms containing compound I or, preferably, containing compound II can be used. Dosage forms that can be
- oral dosage forms in particular tablets or capsules being preferred.
- Both active ingredients may be formulated in pharmaceutical compositions either separately or as a combined pharmaceutical composition.
- a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, and the compound of formula II, or a pharmaceutically acceptable salt thereof, the foregoing being as specified herein, and a pharmaceutically acceptable carrier.
- a therapeutically effective amount in this context is an amount sufficient to act in a prophylactic way against, or to stabilize or to reduce HCV infection, in infected subjects or subjects being at risk of being infected.
- Therapeutically effective amounts may in particular correspond to the amounts mentioned above for administration on a daily base or of the subdoses thereof in ease of multiple daily administrations.
- this invention relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the compound of formula II, or a pharmaceutically acceptable salt thereof.
- the combinations provided herein may also be formulated as a combined preparation for simultaneous, separate or sequential use in HCV therapy.
- the compound of formula I is formulated in a pharmaceutical composition containing other pharmaceutically acceptable excipients
- the compound of formula II is formulated separately in a pharmaceutical composition containing other pharmaceutically acceptable excipients.
- these two separate pharmaceutical compositions can be part of a kit for simultaneous, separate or sequential use.
- the individual components of the combination of the present invention can be administered simultaneously or separately at different times during the course of therapy or concurrently in divided or single combination forms.
- compositions suitable for administration purposes may be formulated into various pharmaceutical compositions suitable for administration purposes.
- a therapeutically effective amount of the particular compound, or of both compounds is combined with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
- Pharmaceutical compositions may be prepared as medicaments to be administered orally, parenterally (including subcutaneously, intramuscularly, and intravenously), rectally, transdermally, bucally, or nasally.
- suitable compositions for oral administration include powders, granulates, aggregates, tablets, compressed or coated pills, dragees, sachets, hard or gelatin capsules, syrups and suspensions.
- compositions for parenteral administration include aqueous or non-aqueous solutions or emulsions, while for rectal administration suitable compositions for administration include suppositories with a hydrophilic or hydrophobic vehicle.
- suitable transdermal delivery systems for topical administration there can be used suitable transdermal delivery systems and for nasal delivery there can be used suitable aerosol delivery systems.
- any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid compositions such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of solid compositions.
- the carrier will usually comprise sterile water, at least in large part, though other ingredients, such as solubilizers, emulsifiers or further auxiliaries may be added thereto.
- Injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of both.
- Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
- solid form preparations intended to be converted, shortly before use, to liquid form preparations such as powders for reconstitution.
- solid form preparations intended to be converted, shortly before use, to liquid form preparations such as powders for
- the carrier optionally comprises a skin penetration enhancing agent and/or a wetting agent, optionally combined with suitable skin-compatible additives in minor proportions.
- the compounds of formula I or II, or combinations thereof may also be administered via oral inhalation or insufflation by formulations suited for this type of administration such as a solution, a suspension or a dry powder.
- Suitable pharmaceutical compositions for administration in the form of aerosols or sprays are, for example, suspensions of the compound of formula I or II, or both, in a
- the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.
- Such a preparation customarily contains the active compound in a concentration from approximately 0.1 to 50%, in particular from approximately 0.3 to 3% by weight.
- compositions may contain the active ingredient of formula I, or of formula II, or both, in a concentration of about 0.1% to about 50%, or about 1% to about 30%), or about 3%> to about 20%>, or about 5%> to about 20%>, all percentages being by weight.
- the compound of formula I is present in a concentration of about 0.1% to about 50%, or about 1%> to about 30%>, or about 3%> to about 20%>, or about 5%> to about 20%>; and the compound of formula II is present in a concentration of about 1% to about 50%, or about 3%o to about 50%>, or about 5%> to about 50%>, or about 5%> to about 30%>, or about 10% to about 50%, or about 10% to about 30%.
- compositions may be conveniently presented in unit dosage form for ease of administration and uniformity of dosage. Examples include tablets
- solid dosage forms in unit dose form may be packed in any known package, blister packs being preferred, in particular for tablets and capsules.
- the compound of formula I and of formula II are formulated separately, they could be packed in separate blisters, but one blister could as well comprise unit dose forms of the compound I as of the compound II, for example one row with units of compound I and another with compound II, or one row with units of compound I and two with compound II .
- Other possibilities may be possible as well, for example for b.i.d.
- administration of the compound II one row of tablets with a combination dosage unit of both compounds I and II, and a row with the compound of formula II.
- the patient would then take, e.g. the combined dose in the morning and the compound of formula II dose in the evening.
- administration of the compound II one row of tablets with a combination dosage unit of both compounds I and II, and two rows with the compound of formula II.
- Other combinations may be possible as well.
- the combinations of this invention may be used to treat HCV infections as well as diseases associated with HCV.
- the diseases associated with HCV include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, and HCC (hepatocellular carcinoma).
- the in vitro antiviral activity against HCV of the compound of formula I or of formula II can be tested in a cellular HCV replicon system based on Lohmann et al. (1999) Science 285: 110-113, with the further 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 infection model for HCV, is widely accepted as the most robust and efficient model of autonomous HCV R A replication currently available.
- the in vitro antiviral activity against HCV can also be tested by enzymatic tests.
- the combination of the compound of formula I and the compound of formula II, as specified herein, is useful in the treatment of warm-blooded animals, in particular humans, infected with HCV, and for the prophylaxis of HCV infections.
- the present invention therefore furthermore relates to a method of treating a warmblooded animal, in particular a human, infected by HCV, or being at risk of infection by HCV, said method comprising the administration of an anti-HCV effective amount of a combination of the compound of formula I and the compound of formula II, as specified herein.
- the present invention provides as well a method of treating
- HCV-related conditions or preventing HCV-related conditions in a mammal comprising administering an anti-virally effective amount of a combination of the compound of formula I and the compound of formula II, as specified herein.
- the combinations of the present invention may be used as medicaments.
- the present invention also relates to the use of a combination, as described herein, for the manufacture of a medicament for the treatment or the prevention of HCV infection or HCV related conditions.
- the invention relates to a product containing the compound of formula I and the compound of formula II, and optionally another anti-HCV
- combinations of the present invention in turn may be combined with one or more further anti-HCV compounds.
- combinations with IFN-a (pegylated or not) and/or ribavirin are combinations with IFN-a (pegylated or not) and/or ribavirin.
- the other agents that may be co-administered with the combinations of the present invention may be administered as separate formulations or may be co-formulated with one or both of the active ingredients of formula I or of formula II .
- the combinations of the present invention including those with other anti-HCV agents, may also be combined with an agent that has a positive effect on drug metabolism and/or pharmacokinetics that improve bioavailabilty, e.g. ritonavir or a
- the ritonavir may be used as separate formulation, or may be co-formulated with one or more of the active agents of the combinations of the present invention.
- the weight ratio of the compound of formula I or of the compound of formula II to ritonavir may be in the range of from about 10: 1 to about 1 : 10, or from about 6: 1 to about 1 :6, or from about 1 : 1 to about 10: 1, or from about 1 : 1 to about 6: 1 , or from about 1 : 1 to about 4: 1 , or from about 1 : 1 to about 3:1, or from about 1 : 1 to about 2: 1.
- Example 1 Activity of the compounds of formula I and II
- the compounds of formula I were examined for activity in the inhibition of HCV RNA replication in a cellular assay.
- the assay demonstrated that the compounds of formula I exhibited activity against HCV replicons functional in a cell culture.
- the cellular assay was based on a bicistronic expression construct, as described by Lohmann et al. (1999) Science vol. 285 pp. 110-113 with modifications described by Krieger et al. (2001) Journal of Virology 75: 4614-4624, in a multi-target screening strategy. In essence, the method was as follows.
- the assay was based on the stably transfected cell line Huh-7 luc/neo (hereafter referred to as Huh-Luc).
- Huh-Luc This cell line harbors an RNA encoding a bicistronic expression construct comprising the wild type NS3-NS5B regions of HCV type lb translated from an Internal Ribosome Entry Site (IRES) from encephalo myocarditis virus (EMCV), preceded by a reporter portion (FfL-luciferase), and a selectable marker portion (neo R , neomycine phosphotransferase).
- IRS Internal Ribosome Entry Site
- EMCV encephalo myocarditis virus
- FfL-luciferase reporter portion
- neo R neomycine phosphotransferase
- the replicon cells were plated in 384 well plates in the presence of the test and control compounds which were added in various concentrations. Following an incubation of three days, HCV replication was measured by assaying luciferase activity (using standard luciferase assay substrates and reagents, and a Perkin Elmer ViewLux Tm ultraHTS microplate imager). Replicon cells in the control cultures have high luciferase expression in the absence of any inhibitor. The inhibitory activity of the compound was monitored on the Huh-Luc cells, enabling a dose-response curve for each test compound.
- EC50 values were then calculated, which value represents the amount of the compound required to decrease by 50% the level of detected luciferase activity, or more specifically, the ability of the genetically linked HCV replicon RNA to replicate.
- Example 2 Determination of effect when combining the compounds of formula I and II The presence or absence of synergy was determined using the Loewe model.
- the Loewe additivity Liewe S, Muischnek H. Effect of combinations: mathematical basis of problem. Arch Exp Pathol Pharmakol 1926;114:313-326
- dose addition is based on the concept that zero interaction occurs when the response produced by dose A plus the response produced by dose B is equal to the response produced by dose A + B.
- CalcuSyn (Biosoft, Ferguson, Mo.) was used to analyze HCV replicon inhibition data for the Loewe additivity model. CI values of ⁇ 0.9, 0.9-1.1, and > 1.1 indicate synergy, an additive effect, or antagonism, respectively.
- the combination index (CI) value for an effective dose of 50%, 75%, or 90% inhibition was calculated.
- Five separate tests with combinations of the compound of formula I and the compound of formula II were conducted. One test was with four test plates; a second with five test plates; a third, a fourth and a fifth with three test plates.
- the median ED 50 , ED 75 and ED 90 values (CI values) as well as the standard deviations (SD values) were calculated and these are listed in the following table. These values indicate a synergistic relationship.
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Abstract
La présente invention concerne une combinaison synergique du composé de formule (I) ou d'un de ses sels pharmaceutiquement acceptables, et du composé de formule (II) ou d'un de ses sels pharmaceutiquement acceptables.
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US8492386B2 (en) | 2011-10-21 | 2013-07-23 | Abbvie Inc. | Methods for treating HCV |
SE1450131A1 (sv) | 2011-10-21 | 2014-05-07 | Abbvie Inc | DAA-kombinationsbehandling (t.ex. med ABT-072 eller ABT-333)för användning vid behandling av HCV |
US8466159B2 (en) | 2011-10-21 | 2013-06-18 | Abbvie Inc. | Methods for treating HCV |
ES2572328B1 (es) | 2011-10-21 | 2017-08-24 | Abbvie Inc. | Combinación de al menos dos agentes antivirales de acción directa y ribavirina pero no interferón, para su uso en el tratamiento del vhc |
PT2909205T (pt) | 2012-10-19 | 2017-02-06 | Bristol Myers Squibb Co | Derivados de carbamato de hexadecahidrociclopropa(e)pirrolo(1,2- a)(1,4)diazaciclopentadecinilo substituídos com 9-metilo como inibidores da protease não estrutural 3 (ns3) para o tratamento de infeções por vírus da hepatite c |
US9643999B2 (en) | 2012-11-02 | 2017-05-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
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US9409943B2 (en) | 2012-11-05 | 2016-08-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2014137869A1 (fr) | 2013-03-07 | 2014-09-12 | Bristol-Myers Squibb Company | Inhibiteurs du virus de l'hépatite c |
JP7129703B2 (ja) | 2016-04-28 | 2022-09-02 | エモリー ユニバーシティー | アルキン含有ヌクレオチド及びヌクレオシド治療組成物並びにそれらに関連した使用 |
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