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WO1998046597A1 - Inhibiteurs de serines proteases - Google Patents

Inhibiteurs de serines proteases Download PDF

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Publication number
WO1998046597A1
WO1998046597A1 PCT/US1998/007709 US9807709W WO9846597A1 WO 1998046597 A1 WO1998046597 A1 WO 1998046597A1 US 9807709 W US9807709 W US 9807709W WO 9846597 A1 WO9846597 A1 WO 9846597A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
hydrogen
iii
independently selected
Prior art date
Application number
PCT/US1998/007709
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English (en)
Inventor
Dennis C. Liotta
Neysa Nevins
James P. Snyder
Dawei Zhang
Krista Kasdorf
Original Assignee
Emory University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Emory University filed Critical Emory University
Priority to AU71272/98A priority Critical patent/AU7127298A/en
Publication of WO1998046597A1 publication Critical patent/WO1998046597A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Proteases are essential enzymes in the life cycle of many viruses and also play a role in various physiological processes. Many of the proteases developed by viruses are so specialized that they differ substantially from the enzymes to be found in the host, and such specialization makes the viral protease an attractive target of drug therapy. Proteases are also used by the body to regulate various processes and an unbalancing of these mechanisms leads to many disease states. Inhibition of protease, such as serine protease, is considered an ideal chemotherapy in such cases.
  • Viruses suitable for serine protease inactivation include hepatitis C virus (HCV), [Love, R. A., et al.; Cell 87, 331 (1996); Kim, J. L., et al., Cell 87, 343 (1996)], human cytomeglavirus (HCMV) [ Stevens, J. T., et al, Ewr. J. BioChem. 226, 361 (1994)], various flaviviruses, e.g., yellow fever, various encephalitises [ Fraenkel- Conrat, H., et al., Virology, 2nd Ed., Prentice Hall ⁇ nglewood Cliffs, pp. 102-103 (1998)], as well as HSV-1, HSV-2, VZV, ⁇ BV, HHV-6, and HHV-7.
  • HSV-1, HSV-2, VZV, ⁇ BV, HHV-6, and HHV-7 as well as HSV-1, HSV-2,
  • human leukocyte elastase is a serine protease which is involved in diseases such as pulmonary emphysema, [Lungarella, G., et al., Exp. Mol. Pathol. 42, 44 (1985); Powers, J. C. Trends BioChem. Sci., I (9), 211 (1976)], arthritis [JanofF, A. et al. (eds.) Neutral Proteases in Human Polymorphonuclear Leukocytes, Urban and Schwartzenberg, Baltimore, p. 390-417, (1978); JanofF, A.
  • compounds of formulas I-III are suitable, either as compounds, pharmaceutically acceptable salts or hydrates, pharmaceutical composition ingredients, whether or not as combination with other antivirals, immunomodulators, antibiotics or vaccines.
  • Methods of treating infection by such viruses, and methods of preventing infection by such viruses are also disclosed.
  • HSV Herpes Simplex Virus in various serotypes, e.g., HSV-1, HSV-2
  • This invention relates to compounds of formula I-III, combinations thereof, or pharmaceutically acceptable salts or hydrates thereof, in the inhibition of serine protease encoded by HCV, HCMV, HSV, VZV, EBV, HHV, and flaviviruses involved with yellow fever or encephalitis.
  • the compounds of the present invention are also useful for treating diseases without apparent viral etiology, including pulmonary emphysema, cardiovascular disease, cancer, rheumatoid arthritis and immune nephritis.
  • X is a single or a double bond
  • X is C or N
  • R 1 and R 4 are ! independently selected from the groups consisting of
  • R 3 is H or (CH 2 ) n -Q, wherein n is an integer between 1 and 5 and Q is
  • R 3 is absent; when either Yi or Wi are hydrogen or Yt and Wi are both hydrogens, then Zi is absent, Yi and Wi are not joined to each other and are independently selected from:
  • ( ⁇ i) aryl when Yi and Wi are both not hydrogen, they are selected independently from: (i) -CH 2 -; (ii) -CHR 1 -; or (iii) -CR*R 4 -; when either Y 2 or W 2 are hydrogen or Y 2 and W 2 are both hydrogens, then Z 2 is absent, Y 2 and W are not joined to each other and are independently selected from:
  • aryl when Y 2 and W 2 are both not hydrogen, they are selected independently from: (i) -CH 2 -; (ii) -CHR 1 -; or (Hi) -CR'R 4 -;
  • W 3 is selected from:
  • R 1 and R 4 are independently selected from the groups consisting of
  • R 3 is H or (CH 2 ) consult-Q, wherein n is an integer between 1 and 5 and Q is
  • Zi and Z 2 are 5 both -CH 2 -; or pharmaceutically acceptable salts or hydrates thereof.
  • R 1 is independently selected from the groups consisting of
  • Compound A is preferred and is defined as follows:
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising any compound of the present invention, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention is useful in the treatment of infections associated with hepatitis C and human cytomeglavirus, encephalitis, pulmonary emphysema, cardiovascular disease, cancer, rheumatoid arthritis and immune nephritis.
  • the pharmaceutical composition of the present invention is useful in the inhibition of the serine proteases of HCV, HCMV, HSV, VZV, EBV and HHV.
  • the preferred compound of the present infection is compound A, shown below
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers or enantiomers, with all isomeric forms being included in the present invention.
  • alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl).
  • aryl is intended to mean phenyl (Ph) or naphthyl.
  • the pharmaceutically-acceptable salts of the compounds of Formulas I- III include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methansulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and unde
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • Schemes I-V for preparing the novel compounds of this invention are presented below.
  • Schemes I-V are not limited by any particular substituents employed in the schemes for illustrative purposes. The examples specifically illustrate the application of the following schemes to specific compounds.
  • the corresponding alpha-furfuryl amide 11 is synthesized as an intermediate.
  • the asymmetric synthesis of the alpha furfuryl amide is carried out by first subjecting 2-furaldehyde 1 to enantioselective alkylation with a chiral sulfonamide-titanate complex, formed with 2, to give 3 ( in the S configuration) with typically high enantiomeric excess. See, e.g., Takahashi, H. et al., Tetrahedron Lett. 30, 7095 (1989), and Yoshioka, M. et al.,
  • Scheme II sets forth three racemic pathways for the synthesis of intermediate racemate 9.
  • furan 7 is acylated with catalyst ZnCl 2 according to Harough, H.D. et al., J.Am.Chem.Soc. 69, 1012 (1947).
  • the acylated furan 8 is then reacted with hydroxylamine to form the corresponding oxime, which in turn is reduced with lithium aluminum hydride (LAH) to give the racemic amine 9.
  • LAH lithium aluminum hydride
  • racemic amine 9 In a second pathway to synthesize racemic amine 9, 2-fi ⁇ raldehyde 1 is first reacted with the appropriate Grignard reagent to give the racemic alcohol 10. Conversion to the azide, followed by reduction to give racemic amine 9 is accomplished by the method of Thompson, A. et al., J.Org.Chem. 5_8, 5886 (1993).
  • a third method of synthesizing racemic amine 9 involves reacting the nonenolizable aldehyde 1 with 1,1,1,3,3,3-hexamethyldisilazane (LiHMDS) to give the corresponding N-trimethylsilyl imine, which is then treated with the appropriate Grignard reagent to give 9. Tosylation of amine 9 gives 11 in Scheme III.
  • Oxidative rearrangements of 11 are carried out to isolate 13. See, for example, Scheme III.
  • TBHP tert-butyl hyrdoperoxide
  • L-(+)-DIPT gives a mixture of 12 in the S configuration and 13 in the R configuration.
  • Amide couplings used to form the compounds of this invention are typically performed by the carbodiimide method with reagents such as dicyclohexylcarbodiimide, or l-ethyl-3-(3-dimethylaminopropyl) carbodiimide.
  • Other methods of forming the amide or peptide bond include, but are not limited to the synthetic routes via an acid chloride, azide, mixed anhydride or activated ester.
  • solution phase amide coupling are performed, but solid-phase synthesis by classical Merrified techniques may be employed instead. The addition and removal of one or more protecting groups is also typical practice.
  • the compounds of the present invention are useful in the inhibition of viral serine proteases, the prevention or treatment of infection by the human viruses encoding serine proteases, and the treatment of consequent pathological conditions such as Hepatitis C, yellow fever, viral encephalitis, herpes infection.
  • the compounds of the present invention are also useful in the treatment of diseases without apparent viral etiology, including, but not limited to pulmonary emphysema, cardiovascular disease, cancer, rheumatoid arthritis and immune nephritis.
  • the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, topically, intravitreously, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
  • a method of treating and a pharmaceutical composition for treating infection by human viruses encoding serine proteases involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • compositions may be in the form of orally- administrable suspensions or tablets; nasal sprays; sterile injectable preparations, for example, as sterile injectable aqueous or oleaginous suspensions or suppositories.
  • these compositions When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents known in the art.
  • these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
  • these compositions When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • the injectable solutions or suspensions may be formulated according to known art, using suitble non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • suitble non-toxic, parenterally-acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • compositions When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidity and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidity and/or dissolve in the rectal cavity to release the drug.
  • Dosage levels of the order of 0.02 to 5.0 or 10.0 grams-per-day are useful in the treatment or prevention of the above-indicated conditions, with oral doses two-to-five times higher.
  • infection by Hepatitis C virus is effectively treated by the administration of from 10 to 50 milligrams of the compound per kilogram of body weight from one to three times per day.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • the present invention is also directed to combinations of the viral serine protease inhibitory compounds with one or more agents useful in the treatment of such viruses.
  • the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of antivirals, immunomodulators, anti-infectives, or vaccines known to those of ordinary skill in the art.
  • antivirals, immunomodulators, anti-infectives, or vaccines include in principle any combination with any pharmaceutical composition useful for the treatment of diseases resulting from infection by viruses encoding serine protease.
  • 2-Isopropyl-2'-furyl carbinol 2-Furaldehyde (18.25 g, 0.19 mol, 1.00 eq) was dissolved in THF (35 mL) and cooled to 0°C. To this solution, isopropyl magnesium chloride (99.71 mL, 0.21 mol, 2.0 M in THF, 1.05 eq) was added dropwise. After 2 h, TLC followed the consumption of the starting material, ice-cold NH 4 CI (5%; 50 mL) was added. The reaction solution was extracted with EtOAc (150 mL), washed with water (3 x 50 mL), dried (MgSU 4 ) and concentrated to a light yellow oil.
  • 2-Isopropyl-2'-furylmethylamine Following the procedure of Thompson, A.S., et al., J. Org. Chem. 58, 5886 (1993), 2-isopropyl-2-furylmethylazide (3.00 g, 18.16 mmol, 1.00 eq) was dissolved in THF (40 mL) and cooled to 0°C. To this solution, LAH (36.00 mL, 36.32 mmol, 2.00 eq) was added dropwise. After 2 h, the reaction was warmed to room temperature. The reaction was cooled to -78°C and quenched with water (50 mL).
  • N-(L-Alanyl-L-alanine acetate)-2-isopropyl-2'-furylmethylamine L-Alaninyl-L-alanine acetate (1.00 g, 4.95 mmol, 1.00 eq) was dissolved in DMF (15 mL) and THF (30 mL). The reaction mixture was cooled to - 20 °C (acetone/dry ice) and N-methyl morpholine (1.09 mL, 9.91 mmol, 2.00 eq) was added, followed by slow addition of iso-butyl chloroformate (0.70 mL, 5.40 mmol, 1.09 eq).
  • N-(L-Prolyl-L-alanine acetate)-2-isopropyl-2'-furylmethylamine L-Prolyl-L-alanine Acetate (0.78 g, 3.42 mmol, 1.00 eq) was dissolved in DMF (35 mL). The reaction mixture was cooled to - 20 °C (acetone/dry ice), and N-methyl morpholine (0.75 mL, 6.84 mmol, 2.00 eq) was added followed by slow addition of iso-butyl chloroformate (0.44 mL, 3.42 mmol, 1.00 eq).
  • L-Prolyl - L-alaninyl-L-alanine acetate (0.72 g, 2.41 mmol, 1.00 eq) was dissolved in DMF (50 mL). The reaction mixture was cooled to - 20 °C (acetone/dry ice), and N-methyl morpholine (0.58 mL, 5.29 mmol, 2.20 eq) was added followed by slow addition of iso- butyl chloroformate (0.31 mL, 2.41 mmol, 1.00 eq).
  • N-(L-alanyl-L-alanine acetate)-2-isopropyl-6-hydroxy-l ,6-dihydro-3-piperidone N-(L-alanyl-L- alanine acetate)-2-isopropyl-2'-fiuylme1hylarnine (18 mg, 0.06 mmol, 1.00 eq) was dissolved in dichloromethane (10 mL). To this solution, MCPBA (9.4 mg, 0.06 mmol, 1.00 eq) was added via four portions over 10 minutes intervals. After 10 hrs, the solvent was removed and the residue was passed through a pad of silica gel.
  • N-(L-Prolyl-L-alanine acetate)-2-isopropyl-6-hydroxy- 1 , 6-dihydro-3 -piperidone N-(L- Prolyl-L-alanine acetate)-2-isopropyl-2'-furylmethylamine (35 mg, 0.10 mmol, 1.00 eq) was dissolved in dichloromethane (10 mL). To this solution, MCPBA (17 mg, 0.10 mmol, 1.00 eq) was added, After 1.2 hr, the solvent was removed and the residue was passed through a pad of silica gel. EtOAc (50 mL) was used to washed away the impurities followed by washing with acetone (25 mL).
  • N- ( ⁇ -Prolyl-L-ala nyl-L-alanine acetate)-2-isopropyl-2-furylmethylamine 46 mg, 0.11 mmol, 1.00 eq
  • dichloromethane 10 mL
  • MCPBA 24 mg, 0.14 mmol, 1.25 eq
  • porcine pancreatic elastase was performed substantially according to Powers, J.C. et al. Biochemistry 29 3108. (1990). Porcine pancreatic elastase (PPE), Suc-Ala-Ala-Ala-NA (N-succinyl-a anyl-alanyl-alanine ?- nitroanilide.), and Hepes were obtained from Sigma Chemical Co., St. Louis, MO.
  • a volume of 50 ⁇ L of DMSO and a 50 ⁇ L aliquot of PPE solution (5.0 mg PPE dissolved in 5.0 mL 1 mmol HC1) were added to 0.5 mL Hepes buffer (0.1 M Hepes, 0.5 M NaCl, pH 7.5).
  • a 50 ⁇ L aliquot of this solution was added to a solution of a 50 ⁇ L aliquot of substrate solution (20 mmol Suc-Ala-Ala-Ala-NA in DMSO) in 2.0 mL Hepes buffer.
  • a 50 ⁇ L aliquot of inhibitor solution (20 mmole in DMSO) and a 50 ⁇ L aliquot of PPE solution were added to 0.5 mL Hepes buffer.
  • Compound A was active in the assay, and showed about 20% inhibition at about 17 ⁇ M.

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Abstract

L'invention concerne des composés tels que (A) ou leurs sels ou hydrates pharmaceutiquement acceptables, qui inhibent les sérines protéases virales et humaines, et conviennent au traitement des infections dues au virus de l'hépatite C, des infections à Cytomégalovirus humain, de la fièvre jaune, de l'encéphalite à virus, de l'emphysème pulmonaire, des maladies cardiovasculaires, du cancer, de la polyarthrite rhumatoïde, de l'herpès, et de l'immuno-néphrite.
PCT/US1998/007709 1997-04-14 1998-04-14 Inhibiteurs de serines proteases WO1998046597A1 (fr)

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AU71272/98A AU7127298A (en) 1997-04-14 1998-04-14 Serine protease inhibitors

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US4364097P 1997-04-14 1997-04-14
US60/043,640 1997-04-14

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WO2000051625A1 (fr) * 1999-03-05 2000-09-08 The Trustees Of University Technology Corporation Inhibiteurs d'activite de serine protease, methodes et compositions de traitement de virus de l'herpes
US6143715A (en) * 1997-08-11 2000-11-07 Boehringer Ingelheim (Canada) Ltd. Hepatitis C inhibitor peptide analogues
WO2000051623A3 (fr) * 1999-03-05 2000-12-14 Trustees Of University Technol Inhibiteurs d'activite de serine protease, methodes et compositions de traitement des etats cliniques dus au bioxyde d'azote
WO2000051624A3 (fr) * 1999-03-05 2000-12-28 Trustees Of University Technol Methodes et compositions utiles a l'inhibition de l'apoptose
WO2000052034A3 (fr) * 1999-03-05 2001-01-11 Trustees Of University Technol Inhibiteurs d'activite de serine protease, methodes et compositions de traitement d'infections virales
US6608027B1 (en) 1999-04-06 2003-08-19 Boehringer Ingelheim (Canada) Ltd Macrocyclic peptides active against the hepatitis C virus
US6642204B2 (en) 2002-02-01 2003-11-04 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor tri-peptides
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WO2007044893A2 (fr) 2005-10-11 2007-04-19 Intermune, Inc. Composés et méthodes pour l'inhibition de la réplication du virus de l'hépatite c
WO2007119889A1 (fr) 2006-04-18 2007-10-25 Japan Tobacco Inc. Nouveau compose de piperazine et son utilisation en tant qu'inhibiteur de la polymerase du vhc
US7309708B2 (en) 2003-11-20 2007-12-18 Birstol-Myers Squibb Company Hepatitis C virus inhibitors
US7323447B2 (en) * 2005-02-08 2008-01-29 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
BG65356B1 (bg) * 1999-04-06 2008-03-31 Boehringer Ingelheim (Canada) Ltd. Макроциклени пептиди, активни срещу вируса на хепатит с, фармацевтични състави, които ги съдържат, методи за получаване и използването им
US7504378B2 (en) 2002-10-25 2009-03-17 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
US7511157B2 (en) 2004-07-20 2009-03-31 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor dipeptide analogs
US7585845B2 (en) 2003-05-21 2009-09-08 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor compounds
EP2103623A2 (fr) 2005-07-25 2009-09-23 Intermune, Inc. Nouveaux inhibiteurs macrocycliques de la multiplication du virus de L'Hépatite C
US7642235B2 (en) 2003-09-22 2010-01-05 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
US7659263B2 (en) 2004-11-12 2010-02-09 Japan Tobacco Inc. Thienopyrrole compound and use thereof as HCV polymerase inhibitor
US7696242B2 (en) 2004-07-20 2010-04-13 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor peptide analogs
US7749961B2 (en) 2004-01-21 2010-07-06 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
EP2206715A1 (fr) 2004-02-24 2010-07-14 Japan Tobacco, Inc. Composé héterotétracycliques fusionnés et leur utilisation en tant qu'inhibiteurs de la polymérase du HCV
US20110046066A1 (en) * 2008-01-11 2011-02-24 Genentech, Inc. Inhibitors of iap
US7977331B1 (en) 2004-02-24 2011-07-12 Japan Tobacco Inc. Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor
EP2399575A2 (fr) 2006-08-11 2011-12-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés, utilisations et compositions pour le traitement d'une infection par un virus de la famille de Flaviviridae par l'inhibition de récepteur farnésoïde X (FXR)
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EP2399575A2 (fr) 2006-08-11 2011-12-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés, utilisations et compositions pour le traitement d'une infection par un virus de la famille de Flaviviridae par l'inhibition de récepteur farnésoïde X (FXR)
US8907092B2 (en) 2007-04-30 2014-12-09 Genentech, Inc. Inhibitors of IAP
US8513186B2 (en) 2007-06-29 2013-08-20 Gilead Sciences, Inc. Antiviral compounds
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US8809266B2 (en) 2007-06-29 2014-08-19 Gilead Sciences, Inc. Antiviral compounds
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