NZ720391B2 - Methods for treating HCV - Google Patents

Methods for treating HCV Download PDF

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Publication number
NZ720391B2
NZ720391B2 NZ720391A NZ72039112A NZ720391B2 NZ 720391 B2 NZ720391 B2 NZ 720391B2 NZ 720391 A NZ720391 A NZ 720391A NZ 72039112 A NZ72039112 A NZ 72039112A NZ 720391 B2 NZ720391 B2 NZ 720391B2
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compound
hcv
combination
mmol
human
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NZ720391A
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NZ720391A (en
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Iv William E Delaney
John O Link
David W Oldach
Adrian S Ray
William J Watkins
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Gilead Pharmasset Llc
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Priority claimed from NZ623396A external-priority patent/NZ623396A/en
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Publication of NZ720391B2 publication Critical patent/NZ720391B2/en

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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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    • 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
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    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
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Abstract

This disclosure relates to combinations of therapeutic molecules useful for treating hepatitis C virus infection. In one embodiment the combination comprises (S)-2-{[(1R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-(R)-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-yl-methoxy]-phenoxyphosphorylamino}-propionic acid isopropyl ester (compound 10), and 5-(3,3-dimethylbut-1-yn-1-yl)-3-[(cis-4-hydroxy-4-{[(3S)-tetrahydrofuran-3-yloxy]methyl}cyclohexyl){[(1R)-4-methylcyclohex-3-en-1-yl]carbonyl}amino]thiophene-2-carboxylic acid (compound 5) or (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methylbutyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1 ]heptane-2-carbonyl}-2-methyl-propyl)carbamic acid methyl ester (compound 6).The present disclosure relates to methods, uses, dosing regimens, and compositions. lamino}-propionic acid isopropyl ester (compound 10), and 5-(3,3-dimethylbut-1-yn-1-yl)-3-[(cis-4-hydroxy-4-{[(3S)-tetrahydrofuran-3-yloxy]methyl}cyclohexyl){[(1R)-4-methylcyclohex-3-en-1-yl]carbonyl}amino]thiophene-2-carboxylic acid (compound 5) or (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methylbutyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1 ]heptane-2-carbonyl}-2-methyl-propyl)carbamic acid methyl ester (compound 6).The present disclosure relates to methods, uses, dosing regimens, and compositions.

Description

METHODS FOR TREATING HCV This application is a divisional of New Zealand patent application no. 623396, the entire sure of which is incorporated herein by nce.
PRIORITY OF INVENTION This application claims priority to United States Provisional Application Number 61/535,885, filed 16 September 2011; and to United States Provisional Application Number 61/561,753, filed 18 November 2011. The entire t of each of these provisional applications is hereby incorporated herein by nce.
FIELD OF THE INVENTION This ion relates to combinations of therapeutic molecules useful for treating hepatitis C virus infection. The present invention relates to methods, uses, dosing regimens, and compositions.
OUND OF THE INVENTION Hepatitis is a disease occurring throughout the world. Hepatitis is generally of viral nature, although, if ered a state of chronic inflammation of the liver, there are other known, noninfectious causes. Viral hepatitis is by far the most common form of hepatitis. The U.S. Centers for Disease Control has estimated that at least 1.8% of the U.S. population has serologic evidence of HCV infection, in the majority of cases associated with c active ion. HCV is a positive-stranded RNA virus belonging to the Flaviviridae family and has closest relationship to the iruses that include hog cholera virus and bovine viral diarrhea virus.
The HCV genome is a single-stranded, positive-sense RNA of about 9,600 bp coding for a polyprotein of 3009-3030 amino acids, which is cleaved co- and post-translationally by cellular and two viral proteinases into mature viral proteins (core, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B). The structural proteins, E1 and E2, are believed to be embedded into a viral lipid envelope and form stable heterodimers. The structural core protein is believed to interact with the viral RNA genome to form the nucleocapsid. The nonstructural proteins designated NS2 to NS5 include proteins with enzymatic functions involved in virus replication and protein sing including a polymerase, protease, and helicase. HCV replicates through the production of a complementary ve-strand RNA template.
HCV is a genetically diverse virus. Within a single infected patient, many variant viruses can be identified, leading to the description ‘viral swarm’, or viral quasispecies. Within the global human population, HCV is also genetically diverse, with at least 6 major ‘genotypes’ identified (Genotypes 1-6), and numerous subtypes (i.e., HCV Genotype 1a and 1b). HCV genotypes are defined by genomic phylogenetic analysis, and sed (in a given patient) by HCV RNA sequence-based diagnostic assays.
The main route of infection with HCV is blood re. The ude of the HCV infection as a health problem is illustrated by the prevalence among high-risk groups. For example, in some surveys, 60% to 90% of hemophiliacs and more than 80% of intravenous drug abusers in western countries had chronic HCV infection. For intravenous drug s, the ence varies from about 28% to 80% depending on the population studied. The tion of new HCV infections associated with blood or blood product transfusion has been markedly d due to pharmaceutical advances and read use of sensitive gic and RNA detection assays used to screen blood donors, however, a large cohort of aging, chronically infected persons is already established.
One available treatment for HCV infection is pegylated interferon-α (PEG-IFN α1a or PEG-IFN α1b), which is, under current treatment guidelines, stered weekly by subcutaneous injection for 24 to 48 weeks, dependent upon the HCV viral genotype being treated. Although greater than 50% of patients with Genotype 1 HCV infection may be expected to have suppression of HCV viremia at the completion of 48 weeks therapy, a significant proportion of these patients will have viral relapse. Accordingly, a Sustained Virologic Response (SVR, defined as HCV RNA negativity 24 weeks post treatment cessation, and considered tantamount to ‘cure’) is only achieved in 30-40% of Genotype 1 HCV infections treated with PEG-IFN alone. In addition, ent with PEG-IFN + RBV is not well tolerated, with an e event profile that includes flu-like symptoms, thrombocytopenia, anemia, and serious atric side effects. While treatment with the current standard of care is suboptimal, many patients are precluded from ever starting therapy due to comorbidities common in HCV-infected populations, including psychiatric disorders, advanced liver disease, and substance abuse.
Ribavirin is a nucleoside analog antiviral drug. Ribavirin is typically taken orally (by mouth) twice a day. The exact mechanism for ribavirin is unknown. However, it is believed that when ribavirin enters a cell it is orylated; it then acts as an inhibitor of e 5’- monophosphate dehydrogenase (IMPDH). IMPDH inhibitors such as rin reduce the intracellular synthesis and storage of guanine, a nucleotide “building block” necessary for DNA and RNA production, thus inhibiting viral ation. IMPDH inhibitors also interfere with the reproduction of rapidly proliferating cells and cells with a high rate of protein turnover.
Treatment with ribavirin erapy has little effect on HCV RNA levels, but is associated with a decline in serum alanine transferase (ALT). This observation suggests that ribavirin may not be acting as an antiviral agent, but rather as a modulator of immune system function. Ribavirin is only approved for use, for HCV infection, in ation with IFN.
Treatment with the combination of PEG-IFN plus ribavirin improves SVR rates over those observed with PEG-IFN alone, in large part due to reduction in the frequency of viral relapse at the cessation of therapy. Large clinical trial SVR rates for PEG-IFN/ribavirin treated patients with HCV Genotype 1 infection have ranged from 40-55%. At the present time, PEGIFN irin therapy is considered the ‘standard-of-care’ ent for chronic HCV infection.
The standard of care is, however, expected to change y in the near future with approval of direct acting antiviral agents which will, initially, be used in combination with PEG-IFN/ribavirin.
Unfortunately, different genotypes of HCV respond ently to PEG-IFN/ribavirin therapy; for example, HCV genotype 1 is more resistant to therapy than types 2 and 3.
Additionally, many current treatments for HCV produce unwanted side effects. Thus, there is currently a need for new anti-viral therapies. In ular there is a need for new antiviral therapies that produce fewer unwanted side-effects, that are more effective t a range of HCV genotypes, or that have less complicated dosing schedules, i.e. that require administration of agents fewer times during a day.
SUMMARY OF THE INVENTION The present invention provides compositions and therapeutic methods that are useful for treating viral infections (e.g. HCV). Certain compositions and methods of the invention produce fewer unwanted ffects, are more effective t a range of HCV genotypes, reduce the potential for viral rebound due to resistance selection and have ned less complicated dosing schedules than currently ble therapies.
Accordingly, in one embodiment the invention provides a composition comprising two or more compounds selected from Compound 1, Compound 2, Compound 3, Compound 4, nd 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16 and pharmaceutically acceptable salts thereof.
In r embodiment the invention provides a method of treating an HCV infection in a human, comprising administering two or more compounds selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16 and pharmaceutically able salts f to the human.
In another embodiment the invention provides a method for ameliorating one or more symptoms of an HCV infection in a human, sing administering two or more nds selected from nd 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16 and pharmaceutically acceptable salts thereof to the human.
In another embodiment the invention provides a method for reducing viral load in a human with HCV, comprising administering two or more compounds selected from nd 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16 and ceutically acceptable salts thereof to the human.
In another embodiment the ion provides a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents in a human, comprising administering two or more compounds selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, nd 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16 and pharmaceutically acceptable salts thereof to the human.
In r embodiment the invention provides the use of two or more compounds selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, nd 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16 and pharmaceutically acceptable salts thereof in medical therapy.
In another embodiment the invention provides the use of two or more compounds selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16 and ceutically acceptable salts thereof for the prophylactic or therapeutic treatment of a viral (e.g. HCV) infection.
In another embodiment the invention provides the use of a composition of the invention for the prophylactic or therapeutic treatment of a viral (e.g. HCV) infection.
In another embodiment the ion provides the use of two or more compounds selected from Compound 1, nd 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, nd 12, nd 13, Compound 14, nd 15 and nd 16 and pharmaceutically acceptable salts thereof to prepare a medicament for treating a viral (e.g. HCV) infection in a human.
In another embodiment the invention provides the use of a composition of the invention to prepare a medicament for treating a viral (e.g. HCV) infection in a human.
In another embodiment the invention provides the use of two or more compounds selected from nd 1, Compound 2, Compound 3, Compound 4, Compound 5, nd 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and nd 16 and pharmaceutically acceptable salts thereof to prepare a medicament for ameliorating one or more symptoms of a viral (e.g. HCV) infection in a human.
In r embodiment the invention provides the use of a composition of the invention to prepare a medicament for ameliorating one or more symptoms of a viral (HCV) infection in a human.
In another embodiment the invention provides the use of two or more compounds ed from Compound 1, nd 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and nd 16 and pharmaceutically acceptable salts thereof to prepare a ment for reducing viral load in a human.
In r embodiment the invention provides the use of a composition of the invention to prepare a medicament for reducing viral load in a human.
In another embodiment the ion provides the use of two or more nds selected from Compound 1, nd 2, nd 3, Compound 4, Compound 5, Compound 6, Compound 7, nd 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, nd 15 and Compound 16 and pharmaceutically acceptable salts thereof to prepare a medicament for reducing emergence of HCV quasispecies with resistance to nistered oral antiviral agents in a human.
In another embodiment the invention provides the use of a composition of the invention to prepare a medicament for reducing emergence of HCV pecies with resistance to coadministered oral antiviral agents in a human.
The compositions and methods of the invention may provide "synergy" and "synergistic effects", i.e. the effect achieved when the active ingredients (including two or more Combination Compounds) are used together is greater than the sum of the effects that s from using the compounds separately.
The compositions and s of the invention are beneficial because they provide treatments for a wide range of HCV genotypes and because they cause fewer or less serious side effects than current HCV therapies (e.g. treatments that e the administration of interferon). Additionally, certain combinations of compounds (e.g. Compounds 10 and 5, Compounds 10 and 6, and Compounds 10, 5, and 6) may provide a Sustained Virological Response (SVR) that is a significantly higher than that achieved by t therapies (e.g. HCV therapies). For example, some combinations of compounds may provide an SVR that is at least about 70% or at least about 80%.
DETAILED DESCRIPTION OF THE INVENTION Definitions Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings. The fact that a particular term or phrase is not specifically defined should not be correlated to indefiniteness or lacking clarity, but rather terms herein are used within their ordinary meaning. When trade names are used herein, applicants intend to independently include the trade name product and the active pharmaceutical ingredient(s) of the trade name product.
As used herein the term “Combination Compounds” refers to Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, nd 10, Compound 11, Compound 12, Compound 13, Compound 14, nd 15 and Compound 16.
As used herein, Compound 1 is: N N Compound 1 may also be referred to as 5-((6-(2,4-bis(trifluoromethyl)phenyl)pyridazin hyl)(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine or 5H-imidazo[4,5-c]pyridine, 5-[[6-[2,4- bis(trifluoromethyl)phenyl]pyridazinyl]methyl](2-fluorophenyl).
As used herein, Compound 2 is: .
Compound 2 may also be referred to as (2R,6S,13aR,14aS,16aS)(8-chloro(2- (isopropylamino)thiazolyl)methoxyquinolinyloxy)(cyclopentyloxycarbonylamino)- ,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-14a-yl(2,6- diflurobenzyl)phosphinic acid.
As used herein, Compound 3 is: O N N OH O N O As used herein, Compound 4 is: O O N N P O N O H O N O OH As used , Compound 5 is: .
As used herein, Compound 6 is: O F F N H NH N HN O As used , Compound 7 is: As used herein, Compound 8 is: N O O N N As used herein Compound 9 (diastereomer at P) is: H O O O N N P O O O HO F With regard to Compound 9, reference is made to US 7,964,580 and US 2010/0298257, (both of which are incorporated by reference) with regard to manufacture and purification of Compound 9.
As used herein, Compound 10 (S-isomer of Compound 9) is: H O O O N N P O O O HO F 10 .
With regard to Compound 10, nce is made to US 7,964,580 and US 2010/0298257, (both of which are incorporated by reference) with regard to manufacture and cation of Compound 10.
As used herein, Compound 11 is: O N NH2 O O F With regard to Compound 11, reference is made to US 2010/0081628 (which is hereby orated by reference) with regard to manufacture and purification of Compound 11.
As used herein, Compound 12 (diastereomer at P) is: O N O N NH2 O P O HO F With regard to nd 12, reference is made to US 20110015146 (which is hereby incorporated by reference) with regard to manufacture and purification of Compound 12.
As used herein, Compound 13 (S-diastereomer of Compound 12 at P) is: O N O N NH2 O P O HO F With regard to Compound 13, reference is made to US 20110015146 (which is hereby incorporated by reference) with regard to manufacture and purification of Compound 13.
As used herein, Compound 14 is: O O N N P O O O HO F 14.
With regard to Compound 14, nce is made to US 7,964,580 (which is hereby incorporated by nce) with regard to manufacture and purification of Compound 14.
As used herein, Compound 15 is: O O N N P O O O HO F F 15.
With regard to Compound 15, nce is made to US 7,964,580 (which is hereby incorporated by nce) with regard to cture and purification of Compound 15.
As used herein, nd 16 is: O N HO F 16.
With regard to Compound 16, reference is made to US 7,429,572 (which is hereby incorporated by reference) with regard to manufacture and purification of Compound 16.
With regard to ribavirin, reference is made to EP 0 093 401 B1, herein incorporated by reference with regard to a process for manufacture as well as to nomenclature concerning ribavirin. As used herein, ribavirin refers to: O N NH2 HO N HO OH Ribavirin.
Ribavirin is also referred to as 1-β-D-ribofuranosyl-1H-1,2,4-Triazolecarboxamide, 1- β-D-ribofuranosyl-1,2,4-triazolcarboxyamide; 1-β-D-Ribofuranosyl-1,2,4-triazole amide; COPEGUS (Roche); DRG-0028; HSDB 6513; ICN 1229; MegaRibavirin (e.g. in formulations of 100 mg of ribavirin/mL); NSC 163039; RAVANEX (BioPartners); REBETOL (Schering-Plough; Aesca; Bayer Schering Pharma; Essex; Pfizer; Trading Pharma; g Pharma); Ribamide; RIBAMIDIL (Biopharma, Russia); RIBASPHERE (Three Rivers Pharmaceuticals); Ribavarin; Ribavirina; Tribavirin; VILONA (Valeant Pharmaceuticals; ICN Pharmaceuticals); VIRAMID (ICN Pharmaceuticals ; Alfa Wassermann); VIRAZOLE (Valeant Pharmaceuticals); and VIRIZADOLE (Uci-farma, Sao Bernardo do Campo, Sao Paulo, Brazil).
In addition, as used herein ribavirin includes analogs of ribavirin, including taribavirin (VIRAMIDINE, ICN 3142).
The term “interferon” includes 1) interferons, e.g., pegylated rIFN-alpha 2b (PEG-Intron, Merck & Co., Inc.), pegylated rIFN-alpha 2a (PEGASYS, Hoffmann-La Roche Inc.), rIFN-alpha 2b (INTRON® A, Merck & Co., Inc.), rIFN-alpha 2a (Roferon®-A, Hoffmann-La Roche Inc.), eron alpha (MULTIFERON® Viranative AB Corporation, OPC-18, Alfaferone, Alfanative, subalin), eron alfacon-1 (Valeant), interferon alpha-n1 (Wellferon™, Glaxo Wellcome), interferon alpha-n3 (ALFERON®-Hemispherx Biopharma, Inc.), interferon-beta-1a (AVONEX® Biogen Idec, DL-8234 Daiichi Pharmaceutical Co. Ltd), eron-omega (omega DUROS®, Alza Corporation, Intarcia Therapeutics, Inc.; Biomed 510, Intarcia Therapeutics, Inc.), erferon alpha-2b (ALBUFERON®, Human Genome Sciences, INC.), IFN alpha-2b XL, 3 (LOCTERON®, Biolex Therapeutics, INC.), DA-3021, glycosylated interferon alpha-2b (AVI-005), PEG-INFERGEN®, Amgen, Inc., Pegylated interferon lambda-1(type III) ated IL-29), and BELEROFON®, us Biotech.
The term “combination therapy” means compositions or methods or uses or the like that incorporate two or more of the Combination Compounds. ation therapy may also incorporate other active ingredients in on to the two or more of the ation Compounds including, but not limited to: ribavirin, an interferon, an alpha-glucosidase 1 inhibitor, a hepatoprotectant, a Toll-like receptor (TLR)-7 agonist, a cyclophilin inhibitor, an HCV viral entry inhibitor, an HCV maturation inhibitor, and an HCV IRES inhibitor.
The term “active ingredient” means a ent of a combination therapy that a exerts or is capable of exerting a pharmaceutical effect including any of the Combination Compounds, ribavirin, an interferon, an alpha-glucosidase 1 tor, a hepatoprotectant, a TLR-7 agonist, a hilin inhibitor, an HCV viral entry inhibitor, an HCV maturation inhibitor, and an HCV IRES inhibitor.
The term “treating” and grammatical equivalents thereof, when used in the context of treating a disease, means slowing or stopping the ssion of a disease, or rating at least one symptom of a disease, more ably ameliorating more than one symptom of a e. For example, an HCV patient may ence an improvement in one or all of the following symptoms that can be associated with HCV infection: increase in alanine aminotransferase (ALT) levels, fever, headache, muscle aches, jaundice, fatigue, loss of appetite, nausea, vomiting and diarrhea. Treatment of a hepatitis C virus infection can include reducing the HCV viral load in an HCV infected human being.
Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple isomers. The scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or omerically/diastereomerically enriched mixtures. Also included within the scope of the invention are the individual s of the compounds represented by the formulae shown herein, as well as any wholly or partially brated mixtures thereof. The present invention also includes the individual isomers of the compounds represented by the formula shown herein as mixtures with isomers thereof in which one or more chiral centers are inverted. chemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York, herein incorporated by reference in its entirety.
Many organic nds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the le about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory.
A specific stereoisomer may also be referred to as an omer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
Combinations The present invention encompasses combinations of two or more of the Combination Compounds. Table I showing le two-way (Combinations 1-21), three-way (Combinations 22-56), four-way (Combinations 57-92) and five-way (Combinations 93-113) combinations of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, nd 10, Compound 11, Compound 12, Compound 13, nd 14, Compound 15 and nd 16 of the invention is provided below.
Compound 4, nd 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16 are side inhibitors of HCV NS5b polymerase and combinations of Combination Compounds will most often include only one of nd 4, nd 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16 (See Column 6 of Table I).
TABLE I Compound 4 Compound 9 Compound 10 Compound 11 Or Compound 12 Compound 13 Or Compound 14 Or Compound 15 Compound Compound Compound Or Compound Compound Compound 1 2 3 Compound 16 5 6 7 Combination 1 X X Combination 2 X X Combination 3 X X Combination 4 X X ation 5 X X Combination 6 X X Combination 7 X X Combination 8 X X Combination 9 X X Combination 10 X X Combination 11 X X Combination 12 X X Combination 13 X X Combination 14 X X Combination 15 X X Combination 16 X X Combination 17 X X Combination 18 X X Combination 19 X X Combination 20 X X Combination 21 X X ation 22 X X X Combination 23 X X X Combination 24 X X X Combination 25 X X X Combination 26 X X X Combination 27 X X X Combination 28 X X X Combination 29 X X X Combination 30 X X X Combination 31 X X X Combination 32 X X X Combination 33 X X X Combination 34 X X X Combination 35 X X X ation 36 X X X Combination 37 X X X ation 38 X X X ation 39 X X X Combination 40 X X X Combination 41 X X X Combination 42 X X X Combination 43 X X X Combination 44 X X X Combination 45 X X X ation 46 X X X Combination 47 X X X Combination 48 X X X Combination 49 X X X Combination 50 X X X Combination 51 X X X Combination 52 X X X Combination 53 X X X Combination 54 X X X Combination 55 X X X Combination 56 X X X Combination 57 X X X X Combination 58 X X X X Combination 59 X X X X Combination 60 X X X X Combination 61 X X X X Combination 62 X X X X Combination 63 X X X X Combination 64 X X X X Combination 65 X X X X Combination 66 X X X X Combination 67 X X X X Combination 68 X X X X Combination 69 X X X X Combination 70 X X X X Combination 71 X X X X Combination 72 X X X X Combination 73 X X X X Combination 74 X X X X Combination 75 X X X X ation 76 X X X X Combination 77 X X X X ation 78 X X X X Combination 79 X X X X Combination 80 X X X X Combination 81 X X X X Combination 82 X X X X Combination 83 X X X X Combination 84 X X X X Combination 85 X X X X Combination 86 X X X X Combination 87 X X X X ation 88 X X X X Combination 89 X X X X Combination 90 X X X X ation 91 X X X X Combination 92 Combination 93 X X X X X Combination 94 X X X X X Combination 95 X X X X X Combination 96 X X X X X Combination 97 X X X X X Combination 98 X X X X X Combination 99 X X X X X Combination 100 X X X X X Combination 101 X X X X X ation 102 X X X X X Combination 103 X X X X X Combination 104 X X X X X Combination 105 X X X X X Combination 106 X X X X X Combination 107 X X X X X Combination 108 X X X X X Combination 109 X X X X X ation 110 X X X X X Combination 111 X X X X X Combination 112 X X X X X Combination 113 X X X X X Compositions One aspect of the present invention includes a composition, e.g. a pharmaceutical composition, the composition comprising Compound 1 and further comprising a second compound selected from the group consisting of Compound 2, nd 3, Compound 4, nd 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, nd 12, Compound 13, nd 14, Compound 15 and Compound 16. In one specific embodiment of the invention, the second compound may be nd 2, Compound 3, Compound 4, Compound 5 or Compound 6.
Another aspect of the present invention includes a composition, e.g. a pharmaceutical composition, the composition sing Compound 2 and further comprising a second compound selected from the group consisting of Compound 1, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. In one specific embodiment of the invention, the second compound may be Compound 4. In one specific embodiment of the invention, the second compound may be Compound 3. In one specific embodiment of the ion, the second compound may be Compound 5.
Another aspect of the present invention includes a composition, e.g. a pharmaceutical ition, the composition comprising nd 3 and further comprising a second compound selected from the group consisting of Compound 1, Compound 2, Compound 4, nd 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, nd 15 and Compound 16. In one specific embodiment of the invention, the second compound may be Compound 1. In one specific embodiment of the invention, the second compound may be Compound 4. In one specific embodiment of the invention, the second compound may be Compound 5. In one specific embodiment of the invention, the second compound may be Compound 6.
Another aspect of the present invention includes a composition, e.g. a pharmaceutical ition, the composition comprising a first compound selected from the group consisting of nd 4 and r comprising a second compound selected from the group consisting of Compound 1, Compound 2, Compound 3, nd 5, Compound 6 and Compound 7. In one specific embodiment of the invention, the second compound may be Compound 1 or Compound 2 or Compound 3 or nd 6. In one specific embodiment of the invention, the second compound may be Compound 1. In one specific embodiment of the invention, the second compound may be Compound 2. In one ic embodiment of the invention, the second compound may be Compound 3. In one specific embodiment of the invention, the second compound may be Compound 5. In one specific embodiment of the invention, the second compound may be Compound 6.
Another aspect of the present invention includes a composition, e.g. a pharmaceutical composition, the ition comprising Compound 5 and further comprising a second compound selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. In one ic ment of the invention, the second compound may be Compound 1. In one specific embodiment of the invention, the second compound may be Compound 6.
Another aspect of the present invention includes a composition, e.g. a pharmaceutical composition, the composition comprising Compound 6 and further sing a second compound selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. In one specific embodiment of the invention, the second compound may be nd 1. In one specific embodiment of the invention, the second compound may be nd 2. In one specific embodiment of the invention, the second compound may be Compound 3. In one specific embodiment of the invention, the second compound may be nd 4.
Another aspect of the present invention includes a composition, e.g. a pharmaceutical composition, the composition comprising nd 7 and further comprising a second compound selected from the group ting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16.
Another aspect of the present invention es a composition, e.g. a pharmaceutical composition, the composition comprising a first compound selected from the group consisting of Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, nd 14, Compound 15 and nd 16 and further comprising a second compound selected from the group consisting of nd 1, nd 2, Compound 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the present ion includes a composition, e.g. a pharmaceutical composition, the composition comprising Compound 1 and further comprising a second compound and a third compound each selected from the group consisting of Compound 2, Compound 3, Compound 4, Compound 5, nd 6, Compound 7, Compound 9, Compound 10, nd 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 3, or Compound 4, or Compound 5 or Compound 6. The second compound may be Compound 2 and the third compound may be Compound 4. The second compound may be Compound 3 and the third compound may be Compound 4. The second compound may be Compound 2 and the third compound may be Compound 6. The second compound may be Compound 3 and the third compound may be Compound 6. The second compound may be nd 4 and the third compound may be Compound 6. The second compound may be Compound 2 and the third compound may be nd 3. The second nd may be Compound 2 and the third nd may be Compound 5. The second compound may be Compound 3 and the third compound may be Compound 5.
Another aspect of the present invention es a composition, e.g. a pharmaceutical composition, the composition comprising Compound 2 and further comprising a second compound and a third compound each selected from the group consisting of Compound 1, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, nd 15 and Compound 16. The second compound may be Compound 4. The second compound may be Compound 1 and the third compound may be Compound 4. The second compound may be nd 1 and the third compound may be Compound 6. The second compound may be Compound 4 and the third compound may be Compound 6. The second compound may be Compound 3 and the third compound may be Compound 4. The second compound may be Compound 3 and the third compound may be nd 5. The second compound may be Compound 3 and the third compound may be Compound 6.
Another aspect of the present invention includes a ition, e.g. a pharmaceutical composition, the composition comprising Compound 3 and further comprising a second compound and a third compound each selected from the group consisting of Compound 1, Compound 2, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, nd 13, Compound 14, Compound 15 and Compound 16. The second compound may be nd 1 or Compound 6. The second nd may be Compound 1 and the third compound may be Compound 4. The second compound may be Compound 1 and the third compound may be Compound 6. The second compound may be Compound 4 and the third compound may be Compound 6. The second compound may be Compound 4 and the third nd may be Compound 5.
Another aspect of the present invention includes a composition, e.g. a ceutical composition, the composition sing a first compound selected from the group consisting of Compound 4 and further comprising a second compound and a third compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7. The second compound may be Compound 1, Compound 2, Compound 3 or Compound 6. The second compound may be nd 1 and the third compound may be Compound 2. The second compound may be Compound 1 and the third compound may be Compound 3. The second compound may be Compound 1 and the third compound may be Compound 6. The second compound may be Compound 2 and the third compound may be nd 6. The second nd may be Compound 3 and the third compound may be Compound 6. The second compound may be Compound 1 and the third compound may be Compound 5. The second compound may be Compound 2 and the third compound may be Compound 5.
Another aspect of the present invention includes a composition, e.g. a pharmaceutical composition, the composition comprising Compound 5 and further comprising a second compound and a third nd each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and nd 16. The second compound may be Compound 1.
Another aspect of the present invention includes a ition, e.g. a pharmaceutical composition, the composition comprising Compound 6 and further comprising a second nd and a third compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, nd 5, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, nd 13, Compound 14, Compound 15 and Compound 16. The second compound may be nd 1, Compound 2, Compound 3 or Compound 4. The second nd may be Compound 1 and the third compound may be Compound 2. The second compound may be Compound 1 and the third compound may be Compound 3. The second compound may be Compound 4 and the third compound may be Compound 6. The second compound may be Compound 2 and the third compound may be Compound 4. The second nd may be Compound 3 and the third compound may be Compound 4. The second compound may be Compound 1 and the third compound may be Compound 5. The second compound may be nd 2 and the third compound may be Compound 5. The second compound may be Compound 3 and the third compound may be Compound 5.
Another aspect of the present ion includes a composition, e.g. a pharmaceutical composition, the composition comprising Compound 7 and further comprising a second compound and a third nd each ed from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 9, Compound 10, nd 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16.
Another aspect of the present invention includes a composition, e.g. a pharmaceutical composition, the composition comprising a first compound ed from the group consisting of Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16 and further comprising a second compound and a third compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the present ion includes a composition, e.g. a pharmaceutical composition, the composition comprising Compound 1 and further comprising a second compound, a third nd and a fourth compound each selected from the group consisting of Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 3, Compound 4, Compound 5, or Compound 6. The second compound may be Compound 2 and the third compound may be Compound 4. The second compound may be Compound 3 and the third compound may be Compound 4. The second compound may be Compound 2 and the third compound may be nd 6. The second compound may be Compound 3 and the third compound may be Compound 6. The second nd may be nd 4 and the third compound may be Compound 6. The second compound may be Compound 2, the third compound may be Compound 4, and the fourth compound may be Compound 6. The second compound may be Compound 3, the third compound may be Compound 4, and the fourth compound may be nd 6.
Another aspect of the present invention includes a composition, e.g. a pharmaceutical composition, the composition comprising Compound 2 and further comprising a second compound, a third compound and a fourth nd each selected from the group consisting of Compound 1, Compound 3, Compound 4, nd 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, nd 14, Compound 15 and Compound 16. The second compound may be Compound 4. The second compound may be Compound 1 and the third compound may be nd 4. The second compound may be Compound 1 and the third compound may be Compound 6. The second compound may be nd 4 and the third nd may be Compound 6.
Another aspect of the present invention includes a composition, e.g. a pharmaceutical composition, the composition comprising Compound 3 and further comprising a second compound, a third compound and a fourth compound each selected from the group consisting of Compound 1, Compound 2, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second nd may be Compound 1 or Compound 6. The second nd may be Compound 1 and the third compound may be Compound 4.
The second nd may be Compound 1 and the third compound may be Compound 6.
The second compound may be Compound 4 and the third compound may be Compound 6.
The second compound may be nd 4, the third compound may be Compound 5, and the fourth compound may be Compound 6.
Another aspect of the present invention includes a composition, e.g. a pharmaceutical composition, the composition comprising a first compound selected from the group consisting of Compound 4 and further comprising a second compound, a third compound and a fourth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7. The second compound may be nd 1, nd 2, Compound 3, or Compound 6. The second compound may be Compound 1 and the third compound may be Compound 2. The second compound may be Compound 1 and the third compound may be Compound 3. The second compound may be Compound 1 and the third compound may be Compound 6. The second compound may be Compound 2 and the third compound may be Compound 6. The second compound may be Compound 3 and the third compound may be Compound 6.
Another aspect of the present invention includes a composition, e.g. a ceutical composition, the composition comprising Compound 5 and further sing a second compound, a third compound and a fourth compound each selected from the group ting of Compound 1, Compound 2, nd 3, Compound 4, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, nd 15 and Compound 16. The second compound may be Compound 1.
Another aspect of the present invention includes a composition, e.g. a pharmaceutical composition, the composition comprising Compound 6 and further comprising a second compound, a third compound and a fourth compound each ed from the group consisting of nd 1, Compound 2, nd 3, Compound 4, Compound 5, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1, nd 2, Compound 3, or Compound 4. The second compound may be Compound 1 and the third compound may be Compound 2. The second compound may be Compound 1 and the third compound may be Compound 3. The second compound may be Compound 4 and the third compound may be Compound 6. The second compound may be Compound 2 and the third nd may be Compound 4. The second compound may be Compound 3 and the third compound may be nd 4.
Another aspect of the present invention includes a composition, e.g. a pharmaceutical composition, the composition comprising Compound 7 and further comprising a second compound, a third compound and a fourth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, nd 4, Compound 5, Compound 6, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, nd 14, Compound 15 and Compound 16.
Another aspect of the present invention includes a ition, e.g. a pharmaceutical composition, the composition comprising a first compound selected from the group ting of Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16 and r comprising a second compound, a third compound and a fourth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the present invention includes a composition, e.g. a pharmaceutical composition, the composition comprising Compound 1 and further comprising a second nd, a third compound, a fourth compound and a fifth nd each selected from the group ting of Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 3, Compound 4, Compound 5 or Compound 6. The second compound may be Compound 2 and the third compound may be Compound 4. The second compound may be Compound 3 and the third compound may be nd 4. The second compound may be Compound 2 and the third compound may be Compound 6. The second compound may be Compound 3 and the third compound may be Compound 6. The second compound may be Compound 4 and the third compound may be Compound 6.
Another aspect of the present invention includes a composition, e.g. a pharmaceutical ition, the composition comprising Compound 2 and r comprising a second compound, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, nd 11, nd 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 4. The second compound may be Compound 1 and the third compound may be Compound 4.
The second compound may be Compound 1 and the third nd may be nd 6.
The second compound may be Compound 4 and the third compound may be Compound 6.
Another aspect of the t invention includes a composition, e.g. a pharmaceutical composition, the composition comprising Compound 3 and further comprising a second compound, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 2, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, nd 11, nd 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1 or Compound 6. The second compound may be nd 1 and the third compound may be Compound 4. The second compound may be Compound 1 and the third compound may be Compound 6. The second compound may be Compound 4 and the third compound may be Compound 6.
Another aspect of the present invention includes a composition, e.g. a pharmaceutical composition, the composition comprising a first compound selected from the group consisting of Compound 4 and further comprising a second compound, a third nd, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 2, nd 3, Compound 5, nd 6 and Compound 7. The second compound may be Compound 1, Compound 2, Compound 3 or Compound 6. The second compound may be Compound 1 and the third compound may be Compound 2. The second compound may be Compound 1 and the third compound may be Compound 3. The second compound may be Compound 1 and the third compound may be Compound 6. The second compound may be Compound 2 and the third compound may be Compound 6. The second compound may be Compound 3 and the third nd may be Compound 6. r aspect of the present invention includes a composition, e.g. a pharmaceutical composition, the composition comprising Compound 5 and further comprising a second compound, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16.
The second compound may be Compound 1.
Another aspect of the t invention includes a composition, e.g. a pharmaceutical composition, the composition sing Compound 6 and further comprising a second compound, a third compound, a fourth compound and a fifth compound each ed from the group ting of Compound 1, nd 2, Compound 3, Compound 4, nd 5, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1, Compound 2, Compound 3, and Compound 4. The second compound may be nd 1 and the third compound may be Compound 2. The second compound may be Compound 1 and the third compound may be Compound 3. The second compound may be Compound 4 and the third nd may be Compound 6. The second compound may be nd 2 and the third compound may be Compound 4. The second compound may be Compound 3 and the third compound may be Compound 4.
Another aspect of the present invention includes a composition, e.g. a pharmaceutical ition, the composition sing Compound 7 and further comprising a second compound, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16.
Another aspect of the present invention includes a composition, e.g. a pharmaceutical composition, the composition comprising a first compound selected from the group consisting of nd 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16 and further comprising a second compound, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, nd 5, Compound 6 and nd 7.
Salts The Combination Compounds and other active ingredients can be in the form of a salt. lly, but not absolutely, the salts of the Combination Compounds and other active ingredients are pharmaceutically acceptable salts. Salts assed within the term aceutically acceptable salts" refer to xic salts of the Combination Compounds and/or other active ingredients. Examples of suitable pharmaceutically acceptable salts e inorganic acid addition salts such as chloride, bromide, sulfate, phosphate, and nitrate; organic acid addition salts such as e, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ate; salts with acidic amino acid such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; organic basic salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, and N,N'-dibenzylethylenediamine salt; and salts with basic amino acid such as lysine salt and arginine salt. The salts may be in some cases hydrates or ethanol solvates.
Pharmaceutical Formulations The Combination Compounds and/or other active ingredients can be formulated with conventional carriers or excipients, which can be selected in accord with ordinary practice.
Tablets typically contain excipients, glidants, fillers, binders and the like. Aqueous formulations can be prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986), herein orated by reference in its entirety. Excipients include ascorbic acid and other idants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to While it is le for an active ingredient to be administered alone it may be preferable to t one or more active ingredients as pharmaceutical formulations. The formulations of the invention, both for nary and for human use, comprise at least one active ingredient, together with one or more acceptable carriers and ally other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
The formulations include those suitable for the administration routes set forth below.
The formulations may conveniently be ted in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally can be found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.), herein incorporated by reference in its entirety. Such methods include the step of bringing into association an active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations can be prepared by uniformly and intimately bringing into association one or more active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as es, cachets or tablets each containing a predetermined amount of an active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. An active ingredient may also be administered as a bolus, electuary or paste.
A tablet can made by compression or molding, ally with one or more accessory ients. Compressed s may be prepared by ssing in a suitable machine an active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a , lubricant, inert diluent, preservative, e active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the ed active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally can be formulated so as to e slow or controlled release of an active ingredient.
For administration to the eye or other external tissues e.g., mouth and skin, the formulations can be preferably applied as a topical nt or cream containing an active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, an active ingredient may be employed with either a paraffinic or a miscible ointment base. Alternatively, an active ingredient may be formulated in a cream with an oil-in- water cream base.
If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more yl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of an active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
The oily phase of the emulsions of ation Compounds and/or other active ients may be constituted from known ients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one fier with a fat or an oil or with both a fat and an oil. Preferably, a hilic emulsifier is included together with a lipophilic emulsifier which acts as a izer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
Emulgents and emulsion stabilizers suitable for use in the formulation of the invention e Tween® 60 (ICI Americas Inc.), Span 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
The choice of suitable oils or fats for the formulation is based on achieving the desired ic properties. The cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. ht or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, pyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination ing on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
Pharmaceutical formulations according to the present invention comprise one or more active together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing active ingredients may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be ed according to any method known to the art for the cture of pharmaceutical compositions and such itions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable ation. Tablets containing an active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are le for manufacture of tablets are acceptable. These excipients may be, for e, inert diluents, such as calcium or sodium ate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating , such as maize starch, or alginic acid; binding , such as cellulose, microcrystalline ose, starch, gelatin or acacia; and ating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl rate alone or with a wax may be employed.
Formulations for oral use may be also presented as hard gelatin capsules where an active ingredient(s) is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein an active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the cture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, nylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally ing phosphatide (e.g., lecithin), a condensation t of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
The aqueous suspension may also contain one or more vatives such as ethyl or n-propyl oxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
Oil suspensions may be formulated by suspending an active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a ning agent, such as x, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth herein, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. sible powders and granules of the invention suitable for preparation of an s sion by the addition of water provide an active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable sing or wetting agents and suspending agents are exemplified by those disclosed above.
Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally- occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The on may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening , such as glycerol, ol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated ing to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned herein. The e injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable t or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this e any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary ing upon the host d and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier al which may vary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution ed for intravenous infusion may contain from about 3 to 500 μg of an active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
Formulations suitable for administration to the eye include eye drops wherein an active ingredient is dissolved or suspended in a suitable r, especially an aqueous solvent for an active ingredient. An active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.
Formulations le for topical administration in the mouth include lozenges comprising an active ingredient in a ed basis, usually sucrose and acacia or tragacanth; pastilles comprising an active ient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes sing an active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
Formulations suitable for intrapulmonary or nasal administration have a particle size for e in the range of 0.1 to 500 μm (including particle sizes in a range between 0.1 and 500 μm in increments such as 0.5 μm, 1 μm, 30 μm, 35 μm, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of an active ingredient.
Formulations suitable for aerosol or dry powder administration may be prepared according to tional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of infections as bed herein.
Formulations suitable for vaginal administration may be presented as pessaries, s, creams, gels, pastes, foams or spray formulations containing in addition to an active ient such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the ation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
The formulations can be presented in unit-dose or dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid r, for example water for ion, immediately prior to use.
Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations can be those containing a daily dose or unit daily sub-dose, as herein above d, or an appropriate fraction f, of an active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above the formulations of ation Compounds and/or other active ingredients may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
Combination Compounds and other active ingredients can also be formulated to provide controlled release of an active ingredient to allow less frequent dosing or to improve the pharmacokinetic or toxicity e of an active ingredient. ingly, the invention also provides compositions comprising two or more of the Combination Compounds formulated for sustained or controlled release.
The effective dose of an active ient depends at least on the nature of the condition being treated, ty, r the compound is being used prophylactically (lower doses) or against an active disease or condition, the method of delivery, and the pharmaceutical formulation, and can be determined by the clinician using conventional dose escalation studies.
By way of example, compositions of the invention (e.g. s) can be formulated to provide effective doses. For example, with respect to Compound 1, or a pharmaceutically acceptable salt thereof, the composition may comprise from 1.0 mg to 100 mg, from 5 mg to 40 mg, from 30 mg to 50 mg, or 20 mg or 40 mg and can be adapted to be administered one or more times daily to a human being in need thereof in combination with any one or more of Compound 2, nd 3, Compound 6, Compound 4, Compound 5, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. With respect to Compound 2 or a pharmaceutically acceptable salt thereof, the composition may comprise from 25 mg to 800 mg, from 50 mg to 400 mg, or from 60 mg to 300 mg or from 70 mg to 200 mg or may be 150 mg and can be adapted to be administered one or more times daily to a human being in need thereof in combination with any one or more of Compound 1, Compound 3, Compound 6, Compound 4, Compound 5, nd 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. With respect to Compound 3, or a ceutically able salt thereof, the composition may comprise from 10 mg to 1000 mg, or 50 to 400 mg, or 100mg to 400mg or 200 mg to 400 mg and can be adapted to be administered one or more times daily to a human being in need thereof in combination with any one or more of Compound 1, Compound 2, Compound 6, Compound 4, Compound 5, Compound 7, Compound 9, Compound 10, Compound 11, nd 12, Compound 13, Compound 14, Compound 15 and Compound 16. With respect to Compound 4, or a pharmaceutically acceptable salt thereof, the ition may comprise from 25mg to 400mg or from 25mg to 200mg can be adapted to be administered one or more times daily to a human being in need thereof in combination with any one or more of Compound 1, Compound 2, nd 3, Compound 6, Compound 5 and Compound 7. With respect to Compound 5, or a pharmaceutically able salt thereof, the composition may comprise from 50mg to 1000mg or 100mg to 750mg can be adapted to be administered one or more times daily to a human being in need thereof in combination with any one or more of Compound 1, Compound 2, Compound 3, Compound 6, Compound 4, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, nd 13, Compound 14, Compound 15 and Compound 16. With respect to Compound 6, or a pharmaceutically able salt thereof, the composition may comprise from 1mg to 500mg or from 3 mg to 300 mg or from 3 mg to 200mg or from 3 mg to 100 mg or from 10 mg to 90 mg or from 30 mg to 90 mg can be adapted to be administered one or more times daily to a human being in need thereof in ation with any one or more of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 7, nd 9, Compound 10, Compound 11, Compound 12, nd 13, Compound 14, Compound 15 and Compound 16. With respect to Compound 7, or a pharmaceutically able salt thereof, the composition may comprise from 100 micrograms up to 3000mg, from 25mg up to , or from 50mg up to 1000mg and can be adapted to be administered one or more times daily (e.g. four times daily) to a human being in need thereof in combination with any one or more of nd 1, nd 2, nd 3, nd 4, Compound 5, Compound 6, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. With respect to Compounds 9 and 10, or pharmaceutically acceptable salts thereof, the composition may comprise 10 mg to 1000mg per day (according to US 2010/0298257). With respect to Compound 11, or pharmaceutically acceptable salts f, the composition may comprise 1mg to 1000mg per day ding to US 2010/0081628). Dosages for Compounds 1-7 that are co-administered may need to be adjusted to account for potential drug-drug interactions.
For example, although it does not appear that Compound 1 affects drug metabolizing systems, Compound 2 appears to have the effect of increasing the exposure of Compound 1 approximately 2-3X. Therefore, a dose reduction (e.g. 2x-3x) of Compound 1 would be anticipated when nd 1 is combined with Compound 2. In combination with Compound 16, Compound 2 appears to have the effect of increasing the exposure of Compound 6 approximately 5x, so dose reduction (e.g. 3x-5x) of Compound 16 would be anticipated when Compound 16 is dosed with Compound 2. ore, a 10 mg dose of Compound 6 when coadministered with Compound 2 approximate to a 30 mg dose.
The two or more Combination Compounds may be administered in conjunction with Ribavirin in amounts of about 800mg, 1000mg or 1200mg per day in single or multiple dosages (e.g. about 400mg, 500mg or 600mg twice daily).
Use of Combinations of the Invention In practice of this aspect of the invention, Combination Compounds may be used in the dosages set forth above.
One aspect of the present invention includes Compound 1 for use in a method of treating HCV infections, wherein compound 1 is used in combination with a second compound selected from the group consisting of Compound 2, Compound 3, Compound 4, nd 5, Compound 6, Compound 7, Compound 9, Compound 10, nd 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 3, Compound 4, Compound 5 or Compound 6.
Another aspect of the present invention includes Compound 2 for use in a method of treating HCV infections, wherein compound 2 is used in combination with a second compound selected from the group consisting of Compound 1, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be nd 4. r aspect of the present invention includes Compound 3 for use in a method of treating HCV infections, wherein compound 3 is used in combination with a second compound selected from the group consisting of Compound 1, Compound 2, Compound 4, Compound 5, nd 6, Compound 7, nd 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1 or Compound 6.
Another aspect of the present invention includes Compound 4 for use in a method of treating HCV infections, wherein Compound 4 is used in combination with a second nd selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7. The second compound may be nd 1 or Compound 2 or Compound 3 or Compound 6. r aspect of the present invention includes Compound 5 for use in a method of ng HCV infections, wherein Compound 5 is used in combination with a second compound selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1. r aspect of the present invention includes Compound 6 for use in a method of ng HCV ions, wherein Compound 6 is used in combination with a second compound selected from the group consisting of Compound 1, Compound 2, Compound 3, nd 4, Compound 5, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1, Compound 2, Compound 3 or Compound 4.
Another aspect of the present invention includes Compound 7 for use in a method of treating HCV infections, wherein Compound 7 is used in combination with a second compound selected from the group consisting of Compound 1, Compound 2, Compound 3, nd 4, Compound 5, Compound 6, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16.
Another aspect of the present invention es Compound 9 for use in a method of treating HCV infections, n Compound 9 is used in combination with a second compound ed from the group ting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6, and Compound 7. r aspect of the present invention includes Compound 10 for use in a method of treating HCV infections, wherein Compound 10 is used in combination with a second compound selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, nd 6, and Compound 7.
Another aspect of the t invention es Compound 11 for use in a method of treating HCV infections, wherein Compound 11 is used in combination with a second compound selected from the group consisting of Compound 1, nd 2, Compound 3, nd 5, Compound 6, and Compound 7.
Another aspect of the present invention es Compound 12 for use in a method of ng HCV infections, wherein Compound 12 is used in combination with a second compound ed from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6, and Compound 7. r aspect of the present invention includes Compound 13 for use in a method of treating HCV infections, n Compound 13 is used in combination with a second compound selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6, and Compound 7.
Another aspect of the present invention includes Compound 14 for use in a method of treating HCV infections, wherein nd 14 is used in ation with a second compound selected from the group consisting of Compound 1, Compound 2, nd 3, Compound 5, Compound 6, and Compound 7.
Another aspect of the present invention es Compound 15 for use in a method of treating HCV infections, wherein Compound 15 is used in combination with a second compound selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6, and Compound 7.
Another aspect of the present invention includes Compound 16 for use in a method of treating HCV infections, wherein Compound 16 is used in combination with a second compound selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6, and Compound 7.
Another aspect of the t invention includes Compound 1 for use in a method of treating HCV infections, wherein compound 1 is used in combination with a second compound and a third compound each selected from the group consisting of Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 3, or Compound 4, or Compound 5 or Compound 6. The second nd may be Compound 2 and the third compound may be Compound 4. The second compound may be Compound 3 and the third compound may be Compound 4. The second compound may be Compound 2 and the third compound may be Compound 6. The second compound may be nd 3 and the third compound may be Compound 6. The second compound may be Compound 4 and the third compound may be Compound 6.
Another aspect of the present invention includes Compound 2 for use in a method of treating HCV infections, wherein compound 2 is used in combination with a second compound and a third nd each selected from the group consisting of Compound 1, Compound 3, Compound 4, Compound 5, Compound 6, nd 7, Compound 9, Compound 10, nd 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 4. The second compound may be Compound 1 and the third compound may be Compound 4. The second compound may be Compound 1 and the third compound may be Compound 6. The second compound may be Compound 4 and the third compound may be Compound 6.
Another aspect of the present invention includes Compound 3 for use in a method of treating HCV infections, wherein compound 3 is used in combination with a second nd and a third compound each selected from the group consisting of Compound 1, Compound 2, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1 or Compound 6. The second nd may be Compound 1 and the third compound may be nd 4. The second compound may be Compound 1 and the third nd may be Compound 6. The second compound may be Compound 4 and the third compound may be Compound 6.
Another aspect of the t invention includes Compound 4 for use in a method of ng HCV infections, wherein Compound 4 is used in combination with a second nd and a third compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7. The second compound may be Compound 1, Compound 2, Compound 3 or Compound 6. The second compound may be Compound 1 and the third compound may be nd 2. The second compound may be Compound 1 and the third nd may be Compound 3. The second compound may be Compound 1 and the third compound may be Compound 6. The second compound may be Compound 2 and the third compound may be Compound 6. The second compound may be Compound 3 and the third compound may be nd 6.
Another aspect of the present invention includes Compound 5 for use in a method of treating HCV ions, wherein Compound 5 is used in ation with a second compound and a third compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, nd 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1.
Another aspect of the present invention includes Compound 6 for use in a method of treating HCV infections, wherein Compound 6 is used in combination with a second nd and a third compound each selected from the group consisting of Compound 1, Compound 2, nd 3, Compound 4, Compound 5, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, nd 15 and Compound 16. The second compound may be Compound 1, Compound 2, Compound 3 or Compound 4.
The second compound may be Compound 1 and the third compound may be nd 2.
The second compound may be nd 1 and the third compound may be Compound 3.
The second compound may be Compound 4 and the third compound may be Compound 6.
The second nd may be Compound 2 and the third compound may be Compound 4.
The second compound may be Compound 3 and the third compound may be Compound 4.
Another aspect of the present invention includes Compound 7 for use in a method of treating HCV infections, wherein Compound 7 is used in combination with a second compound and a third compound each selected from the group consisting of nd 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 9, Compound 10, Compound 11, Compound 12, nd 13, Compound 14, Compound 15 and Compound Another aspect of the present invention includes Compound 9 for use in a method of treating HCV infections, wherein Compound 9 is used in combination with a second nd and a third compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the present invention includes Compound 10 for use in a method of treating HCV infections, wherein Compound 10 is used in combination with a second compound and a third nd each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the present invention includes nd 11 for use in a method of treating HCV infections, wherein Compound 11 is used in ation with a second compound and a third compound each selected from the group consisting of Compound 1, Compound 2, nd 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the present invention includes Compound 1 for use in a method of ng HCV infections, wherein compound 1 is used in combination with a second nd, a third compound and a fourth compound each selected from the group consisting of Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 3, Compound 4, Compound 5, or Compound 6. The second compound may be nd 2 and the third compound may be Compound 4. The second compound may be Compound 3 and the third compound may be Compound 4. The second compound may be Compound 2 and the third compound may be Compound 6. The second compound may be Compound 3 and the third compound may be Compound 6. The second nd may be nd 4 and the third compound may be Compound 6.
Another aspect of the t invention includes Compound 2 for use in a method of treating HCV ions, wherein compound 2 is used in combination with a second compound, a third compound and a fourth compound each selected from the group consisting of nd 1, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 4. The second compound may be Compound 1 and the third nd may be Compound 4. The second compound may be nd 1 and the third compound may be Compound 6. The second compound may be Compound 4 and the third compound may be Compound 6.
Another aspect of the present invention includes Compound 3 for use in a method of treating HCV infections, wherein compound 3 is used in combination with a second nd, a third compound and a fourth compound each selected from the group consisting of Compound 1, Compound 2, Compound 4, Compound 5, Compound 6, nd 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1 or Compound 6. The second compound may be Compound 1 and the third compound may be Compound 4.
The second compound may be Compound 1 and the third compound may be Compound 6.
The second compound may be Compound 4 and the third nd may be Compound 6.
Another aspect of the present invention includes Compound 4 for use in a method of treating HCV infections, n Compound 4 is used in combination with a second compound, a third compound and a fourth compound each selected from the group ting of Compound 1, Compound 2, nd 3, Compound 5, Compound 6 and nd 7. The second compound may be Compound 1, Compound 2, Compound 3, or Compound 6. The second compound may be Compound 1 and the third compound may be Compound 2. The second compound may be Compound 1 and the third compound may be Compound 3. The second compound may be Compound 1 and the third compound may be Compound 6. The second compound may be Compound 2 and the third compound may be nd 6. The second compound may be Compound 3 and the third compound may be Compound 6.
Another aspect of the present invention includes nd 5 for use in a method of treating HCV infections, wherein Compound 5 is used in combination with a second compound, a third compound and a fourth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, nd 14, Compound 15 and Compound 16. The second nd may be Compound 1.
Another aspect of the present invention includes Compound 6 for use in a method of treating HCV infections, wherein nd 6 is used in combination with a second compound, a third compound and a fourth compound each selected from the group ting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, nd 14, Compound 15 and Compound 16. The second compound may be Compound 1, Compound 2, Compound 3, or Compound 4. The second compound may be Compound 1 and the third compound may be nd 2. The second compound may be Compound 1 and the third compound may be Compound 3. The second compound may be Compound 4 and the third compound may be Compound 6. The second compound may be nd 2 and the third compound may be Compound 4. The second compound may be Compound 3 and the third compound may be Compound 4.
Another aspect of the present ion includes Compound 7 for use in a method of treating HCV ions, wherein Compound 7 is used in combination with a second compound, a third compound and a fourth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16.
Another aspect of the present invention es Compound 9 for use in a method of ng HCV infections, wherein Compound 9 is used in combination with a second compound, a third compound and a fourth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, nd 5, Compound 6 and Compound 7.
Another aspect of the t invention includes Compound 10 for use in a method of treating HCV ions, wherein Compound 10 is used in combination with a second compound, a third compound and a fourth compound each ed from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the t invention includes Compound 11 for use in a method of treating HCV infections, wherein Compound 11 is used in combination with a second compound, a third compound and a fourth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the present invention includes Compound 1 for use in a method of treating HCV infections, n compound 1 is used in combination with a second compound, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, nd 7, Compound 9, Compound 10, nd 11, Compound 12, nd 13, Compound 14, nd 15 and Compound 16. The second compound may be Compound 3, Compound 4, Compound 5 or Compound 6. The second compound may be Compound 2 and the third compound may be Compound 4. The second compound may be Compound 3 and the third nd may be Compound 4. The second compound may be Compound 2 and the third compound may be Compound 6. The second compound may be Compound 3 and the third compound may be Compound 6. The second compound may be Compound 4 and the third compound may be Compound 6.
Another aspect of the present invention includes Compound 2 for use in a method of treating HCV infections, wherein compound 2 is used in combination with a second nd, a third compound, a fourth compound and a fifth compound each ed from the group consisting of Compound 1, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 4. The second compound may be Compound 1 and the third compound may be Compound 4. The second nd may be Compound 1 and the third compound may be Compound 6. The second compound may be Compound 4 and the third compound may be Compound 6.
Another aspect of the present invention includes Compound 3 for use in a method of treating HCV infections, n compound 3 is used in combination with a second compound, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 2, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, nd 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1 or Compound 6. The second compound may be Compound 1 and the third compound may be Compound 4.
The second compound may be Compound 1 and the third compound may be Compound 6.
The second nd may be Compound 4 and the third compound may be Compound 6. r aspect of the present invention includes Compound 4 for use in a method of ng HCV infections, wherein Compound 4 is used in combination with a second compound, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, nd 2, Compound 3, Compound 5, Compound 6 and Compound 7. The second compound may be Compound 1, Compound 2, Compound 3 or nd 6. The second compound may be Compound 1 and the third compound may be Compound 2. The second compound may be nd 1 and the third compound may be Compound 3. The second nd may be Compound 1 and the third compound may be Compound 6. The second compound may be nd 2 and the third compound may be Compound 6. The second compound may be Compound 3 and the third compound may be Compound 6.
Another aspect of the present invention includes nd 5 for use in a method of treating HCV infections, wherein Compound 5 is used in combination with a second compound, a third nd, a fourth nd and a fifth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 6, Compound 7, Compound 9, Compound 10, nd 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1.
Another aspect of the present invention includes Compound 6 for use in a method of treating HCV infections, wherein Compound 6 is used in ation with a second compound, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, nd 4, Compound 5, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1, Compound 2, nd 3, or Compound 4. The second compound may be Compound 1 and the third nd may be Compound 2. The second compound may be nd 1 and the third compound may be nd 3. The second compound may be Compound 4 and the third compound may be Compound 6. The second compound may be Compound 2 and the third compound may be Compound 4. The second compound may be Compound 3 and the third nd may be Compound 4.
Another aspect of the present ion includes Compound 7 for use in a method of treating HCV infections, wherein Compound 7 is used in ation with a second compound, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 9, Compound 10, Compound 11, Compound 12, nd 13, Compound 14, Compound 15 and Compound 16.
Another aspect of the present invention includes Compound 9 for use in a method of treating HCV infections, wherein Compound 9 is used in combination with a second compound, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 2, nd 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the present invention includes Compound 10 for use in a method of treating HCV infections, n Compound 10 is used in combination with a second compound, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the t invention includes Compound 11 for use in a method of treating HCV infections, wherein Compound 11 is used in combination with a second compound, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, nd 5, Compound 6 and Compound 7.
One aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV pecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 1 and further comprising administering a second nd selected from the group consisting of comprising Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be nd 3, Compound 4, Compound 5 or Compound 6.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 2 and further comprising administering a second compound selected from the group consisting of Compound 1, nd 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, nd 15 and nd 16. The second compound may be nd 4.
Another aspect of the present invention es a method for ameliorating one or more m of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of ng HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 3 and further comprising administering a second compound selected from the group consisting of Compound 1, nd 2, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, nd 15 and Compound 16. The second compound may be Compound 1 or Compound 6.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral , each method comprising administering Compound 4 and r comprising administering a second nd ed from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7. The second compound may be Compound 1 or Compound 2 or Compound 3 or nd 6.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral , each method comprising administering Compound 5 and further comprising administering a second compound selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, nd 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1. r aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for ng viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for ng emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 6 and further comprising administering a second compound ed from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be nd 1, Compound 2, Compound 3 or nd 4.
Another aspect of the present invention includes a method for ameliorating one or more m of HCV ion in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering nd 7 and further comprising administering a second compound selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for ng viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 9 and r comprising administering a second compound selected from the group consisting of nd 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human sed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 10 and further comprising administering a second compound selected from the group consisting of Compound 1, nd 2, Compound 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV ion in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for ng emergence of HCV pecies with ance to coadministered oral antiviral agents, each method comprising administering Compound 11 and further comprising administering a second compound selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human sed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with ance to coadministered oral antiviral , each method comprising stering Compound 1 and further comprising administering a second compound and a third compound each selected from the group ting of Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, nd 15 and Compound 16. The second compound may be Compound 3, or Compound 4, or Compound 5 or Compound 6. The second compound may be Compound 2 and the third compound may be Compound 4. The second compound may be Compound 3 and the third compound may be Compound 4. The second compound may be Compound 2 and the third compound may be Compound 6. The second compound may be Compound 3 and the third compound may be Compound 6. The second compound may be Compound 4 and the third compound may be Compound 6.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV ion in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral , each method comprising administering Compound 2 and further comprising administering a second compound and a third compound each selected from the group consisting of Compound 1, Compound 3, Compound 4, Compound 5, nd 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 4. The second compound may be Compound 1 and the third compound may be Compound 4. The second compound may be Compound 1 and the third nd may be Compound 6. The second compound may be Compound 4 and the third compound may be Compound 6.
Another aspect of the t invention includes a method for rating one or more m of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 3 and further comprising administering a second compound and a third compound each selected from the group ting of nd 1, Compound 2, nd 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1 or Compound 6. The second compound may be Compound 1 and the third compound may be Compound 4. The second compound may be Compound 1 and the third compound may be Compound 6. The second compound may be Compound 4 and the third compound may be Compound 6. r aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human sed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 4 and r sing administering a second compound and a third nd each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7. The second compound may be Compound 1, Compound 2, Compound 3 or Compound 6. The second compound may be Compound 1 and the third compound may be Compound 2. The second compound may be Compound 1 and the third compound may be Compound 3. The second compound may be Compound 1 and the third compound may be Compound 6. The second compound may be Compound 2 and the third compound may be Compound 6. The second compound may be Compound 3 and the third nd may be Compound 6.
Another aspect of the t invention includes a method for ameliorating one or more symptom of HCV ion in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method sing administering Compound 5 and further comprising administering a second compound and a third compound each selected from the group ting of Compound 1, Compound 2, nd 3, Compound 4, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1. r aspect of the present invention includes a method for ameliorating one or more m of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 6 and further comprising stering a second compound and a third compound each selected from the group consisting of Compound 1, Compound 2, nd 3, Compound 4, Compound 5, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1, nd 2, Compound 3 or Compound 4. The second compound may be Compound 1 and the third compound may be Compound 2. The second compound may be Compound 1 and the third compound may be Compound 3. The second compound may be Compound 4 and the third compound may be Compound 6. The second compound may be Compound 2 and the third compound may be Compound 4. The second compound may be Compound 3 and the third compound may be nd 4.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with ance to coadministered oral antiviral agents, each method comprising administering Compound 7 and further comprising administering a second compound and a third compound each selected from the group consisting of nd 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 9, Compound 10, Compound 11, Compound 12, nd 13, Compound 14, Compound 15 and Compound 16. r aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to nistered oral antiviral agents, each method comprising administering Compound 9 and further comprising administering a second compound and a third compound each ed from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method sing administering Compound 10 and further comprising administering a second compound and a third compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, nd 5, Compound 6 and Compound 7.
Another aspect of the t invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering nd 11 and further comprising administering a second compound and a third compound each ed from the group consisting of Compound 1, nd 2, Compound 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the t invention includes a method for ameliorating one or more m of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing nce of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 1 and further comprising administering a second compound, a third nd and a fourth compound each selected from the group consisting of nd 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 3, Compound 4, Compound 5, or Compound 6. The second compound may be Compound 2 and the third nd may be Compound 4. The second compound may be Compound 3 and the third compound may be Compound 4. The second compound may be Compound 2 and the third compound may be nd 6. The second compound may be Compound 3 and the third compound may be Compound 6. The second compound may be Compound 4 and the third compound may be Compound 6.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 2 and further comprising administering a second compound, a third nd and a fourth nd each selected from the group consisting of Compound 1, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, nd 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 4. The second compound may be Compound 1 and the third compound may be Compound 4. The second compound may be Compound 1 and the third compound may be Compound 6. The second nd may be Compound 4 and the third compound may be Compound 6.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with ance to coadministered oral antiviral agents, each method comprising administering nd 3 and further comprising administering a second compound, a third compound and a fourth compound each selected from the group consisting of Compound 1, Compound 2, Compound 4, Compound 5, Compound 6, nd 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1 or Compound 6. The second compound may be Compound 1 and the third compound may be nd 4.
The second compound may be Compound 1 and the third compound may be nd 6.
The second compound may be nd 4 and the third compound may be Compound 6. r aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human sed with HCV, a method of ng HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to nistered oral antiviral agents, each method comprising administering Compound 4 and further comprising administering a second nd, a third compound and a fourth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and nd 7.
The second compound may be Compound 1, nd 2, nd 3, or Compound 6. The second compound may be Compound 1 and the third compound may be Compound 2. The second compound may be Compound 1 and the third nd may be Compound 3. The second compound may be Compound 1 and the third compound may be Compound 6. The second compound may be Compound 2 and the third compound may be Compound 6. The second compound may be Compound 3 and the third compound may be Compound 6. r aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 5 and r comprising administering a second compound, a third compound and a fourth compound each selected from the group consisting of nd 1, Compound 2, Compound 3, Compound 4, Compound 6, Compound 7, nd 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 6 and r comprising administering a second compound, a third compound and a fourth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1, Compound 2, Compound 3, or Compound 4. The second nd may be Compound 1 and the third compound may be Compound 2. The second compound may be Compound 1 and the third compound may be Compound 3. The second compound may be Compound 4 and the third compound may be Compound 6. The second nd may be Compound 2 and the third compound may be Compound 4. The second compound may be Compound 3 and the third compound may be Compound 4.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for ng viral load in a human diagnosed with HCV, a method of ng HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to nistered oral antiviral agents, each method comprising administering Compound 7 and further comprising stering a second compound, a third compound and a fourth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 9, nd 10, Compound 11, Compound 12, Compound 13, Compound 14, nd 15 and Compound 16.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for ng viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 9 and further sing administering a second compound, a third nd and a fourth compound each selected from the group consisting of Compound 1, Compound 2, nd 3, nd 5, Compound 6 and Compound 7.
Another aspect of the present invention includes a method for rating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 10 and further sing administering a second compound, a third compound and a fourth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human sed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to nistered oral antiviral agents, each method comprising administering Compound 11 and further comprising administering a second compound, a third compound and a fourth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the t ion includes a method for ameliorating one or more m of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 1 and further sing administering a second nd, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 3, Compound 4, Compound 5 or Compound 6. The second compound may be Compound 2 and the third compound may be Compound 4. The second compound may be Compound 3 and the third compound may be Compound 4. The second compound may be nd 2 and the third compound may be Compound 6. The second compound may be Compound 3 and the third compound may be Compound 6. The second compound may be Compound 4 and the third compound may be Compound 6.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for ng emergence of HCV quasispecies with resistance to coadministered oral ral agents, each method comprising administering Compound 2 and further sing administering a second nd, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 4. The second compound may be nd 1 and the third compound may be Compound 4.
The second compound may be Compound 1 and the third compound may be Compound 6.
The second compound may be Compound 4 and the third compound may be nd 6.
Another aspect of the present invention includes a method for ameliorating one or more m of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to nistered oral ral agents, each method comprising administering Compound 3 and further comprising administering a second compound, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 2, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1 or Compound 6. The second compound may be Compound 1 and the third compound may be Compound 4. The second compound may be Compound 1 and the third compound may be Compound 6. The second nd may be Compound 4 and the third compound may be Compound 6.
Another aspect of the present invention includes a method for rating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV pecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 4 and further comprising administering a second nd, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7. The second compound may be Compound 1, Compound 2, Compound 3 or Compound 6. The second compound may be Compound 1 and the third nd may be Compound 2. The second compound may be Compound 1 and the third compound may be Compound 3. The second compound may be Compound 1 and the third compound may be Compound 6. The second compound may be Compound 2 and the third compound may be Compound 6. The second compound may be Compound 3 and the third compound may be Compound 6.
Another aspect of the t invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for ng emergence of HCV quasispecies with resistance to nistered oral antiviral agents, each method comprising administering nd 5 and further comprising administering a second compound, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound r aspect of the present invention es a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human t, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 6 and further sing administering a second compound, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, nd 4, Compound 5, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16. The second compound may be Compound 1, Compound 2, Compound 3, and Compound 4. The second compound may be Compound 1 and the third compound may be Compound 2. The second compound may be nd 1 and the third compound may be Compound 3. The second compound may be Compound 4 and the third compound may be Compound 6. The second compound may be Compound 2 and the third compound may be Compound 4. The second compound may be Compound 3 and the third compound may be Compound 4.
Another aspect of the present ion includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 7 and further comprising administering a second compound, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, nd 4, Compound 5, Compound 6, Compound 9, Compound 10, Compound 11, nd 12, Compound 13, Compound 14, nd 15 and Compound 16.
Another aspect of the present invention includes a method for ameliorating one or more m of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 9 and further comprising administering a second compound, a third compound, a fourth compound and a fifth compound each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human subject, and a method for reducing emergence of HCV pecies with resistance to coadministered oral antiviral agents, each method comprising administering Compound 10 and further comprising stering a second compound, a third compound, a fourth compound and a fifth nd each selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 5, Compound 6 and Compound 7.
Another aspect of the present invention includes a method for ameliorating one or more symptom of HCV infection in a human, a method for reducing viral load in a human diagnosed with HCV, a method of treating HCV in a human t, and a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents, each method comprising administering nd 11 and further comprising administering a second compound, a third compound, a fourth compound and a fifth compound each selected from the group ting of Compound 1, Compound 2, nd 3, Compound 5, nd 6 and nd 7.
Routes and Modes of Administration Two or more of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, nd 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and nd 16 and any other components of a combination therapy can be adapted to be administered by any route appropriate to the ion to be treated. Suitable routes include oral, rectal, nasal, l (including buccal and gual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. It will be appreciated that the preferred route may vary with, for e, the condition of the recipient.
A synergistic effect may be attained when the active ingredients are: (1) co-formulated (e.g. in a unitary dosage form) and administered or delivered simultaneously in a combined ation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., in separate tablets, pills or es, or by different ions in separate syringes. In general, during alternation therapy, an effective dosage of each active ient is administered sequentially, i.e. serially, s in combination therapy, effective dosages of two or more active ingredients are administered together.
Co-administration of a Combination Compound with one or more Combination Compounds generally refers to simultaneous or tial administration of one or more Combination Compounds, such that therapeutically effective amounts of two or more Combination Compounds are present in the body of the patient. In some cases, Combination Compounds (e.g. two, three or four Combinations Compounds) will be co-formulated to allow administration at the same time. In some cases, mulated Combination Compounds may be co-administered with one or more additional Combination Compounds.
Co-administration also includes administration of unit dosages of the ation Compounds before or after administration of unit dosages of one or more other active ients, for example, stration of two or more Combination Compounds within seconds, minutes, or hours of the administration of one or more other active ingredients. For example, a unit dose of a Combination Compound can be administered first, followed within seconds or minutes by administration of a unit dose of a second ation Compound, followed within seconds or minutes by administration of a unit dose of one or more other active ingredients. Alternatively, a unit dose of one or more other active ingredients can be administered first, followed within s or s by administration of a unit dose of a Combination Compound, followed within seconds or minutes by administration of a unit dose of a second Combination Compound. In some cases, it may be desirable to administer a unit dose of a Combination Compound first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a second Combination Compound, ed, after a period of hours (e.g., 1-12 , by administration of a unit dose of one or more other active ingredients. In other cases, it may be desirable to administer a unit dose of one or more other active ingredients first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a Combination Compound, followed, after a period of hours (e.g., 1-12 hours), by stration of a unit dose of a second Combination Compound. Where three or more Combinations Compounds are administered with one or more additional active ingredients, the Combination Compounds may be administered one after another within seconds, minutes, or hours (e.g. 1-12 hours) of each other and the one or more additional active ingredients may be administered before, during or after the administration of the Combination Compounds. Where Combination Compounds are co-formulated, they can be administered simultaneously, or before or after the administration of one or more additional active ingredients.
Unless otherwise ied, the combination therapy may be administered as te dosage forms with each active ingredient, administered together or separately, sequentially or concurrently, and close in time or remote in time to each other.
The course of treatment can extend, for example, from about 12 weeks to about 48 weeks, or longer, for example, from about 12 weeks to about 24 weeks.
The present invention es a combination of therapeutically ive components to ameliorate at least one symptom of HCV infection in a human being including, but not limited to, nausea, vomiting, loss of appetite, fatigue, ce, vomiting, diarrhea, dehydration, abdominal pain, cirrhosis of the liver. In addition, in some HCV infected individuals the use of combination therapy is ive to reduce the viral load of HCV viral particles present in the body of the infected person by a tically icant amount. Viral load can be measured, for example, by measuring plasma HCV RNA levels using, for example, the COBAS TaqMan HCV assay (Roche Molecular Systems). Typically, an HCV infected person who is treated with the Combination Compounds in accordance with the t invention experiences an improvement in one or all of the symptoms associated with the HCV infection.
Combinations of Two or more of the Combination Compounds with Ribavirin but not eron As discussed above, some current HCV treatments include the administration of interferon, but this treatment typically produces unwanted side effects. Therefore it would be desirable to find effective HCV treatments that do not require the administration interferon.
One aspect of the present invention es for itions, methods, uses and the like for the treatment of HCV comprising administering two or more of the Combination Compounds or pharmaceutically able salts thereof and ribavirin, without administering one or more interferons. This aspect of the invention may be particularly useful because it allows for the effective treatment of HCV without the side effects associated with the administration of one or more interferon.
In one embodiment of the present invention, the combined amount of ribavirin and Combination Compounds or ceutically acceptable salts thereof, optionally with one or more additional agents, is effective to treat HCV infection.
Another aspect of the present invention includes a method for ameliorating one or more symptoms of HCV infection in a human comprising: administering two or more of the ation Compounds or ceutically acceptable salts thereof and ribavirin, without concurrent administration of one or more interferon. In this regard, the t invention does not foreclose the potential for dosing one or more interferon. Rather, the present invention may be used in conjunction with another therapy that, in fact, includes one or more interferon. An aspect of the present invention includes efficacious treatment of HCV with ribavirin without the need for one or more interferon.
Another aspect of the present invention includes a method for ng viral load in a human diagnosed with HCV comprising: administering two or more of the Combination Compounds or pharmaceutically acceptable salts thereof and rin, but not one or more interferon. r aspect of the present invention includes a method for treating HCV in a human subject consisting essentially of administration of rin in conjunction with two or more of the Combination Compounds or pharmaceutically acceptable salts thereof. r aspect of the present invention includes a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents comprising: administering two or more of the Combination Compounds or pharmaceutically acceptable salts thereof and ribavirin, without concurrent stration of one or more eron.
Similarly, another aspect of the present invention includes a composition, e.g. a pharmaceutical composition for ameliorating one or more symptom of HCV infection in a human comprising two or more of the Combination Compounds or pharmaceutically acceptable salts thereof and ribavirin, without one or more eron. Another aspect of the present invention includes a composition for reducing viral load in a human diagnosed with HCV comprising two or more of the Combination Compounds or pharmaceutically acceptable salts thereof and ribavirin, but not one or more interferon. Another aspect of the present ion includes a ition for treating HCV in a human subject ting essentially of ribavirin in conjunction with two or more of the Combination Compounds or pharmaceutically able salts thereof. Another aspect of the present ion includes a composition for ribavirinbased HCV therapy comprising two or more of the Combination Compounds or pharmaceutically acceptable salts thereof, with the proviso that said composition does not include one or more interferon. Another aspect of the present invention includes a composition for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents sing two or more of the Combination Compounds or pharmaceutically acceptable salts thereof and ribavirin, without one or more interferon.
Similarly, another aspect of the present invention includes use of: two or more of the Combination Compounds or pharmaceutically acceptable salts f and rin, without one or more eron, in the manufacture of a medicament for ameliorating one or more symptoms of HCV infection in a human; as well as use of: two or more of the Combination Compounds or pharmaceutically acceptable salts f and ribavirin, but not one or more interferon, in the manufacture of medicament for reducing viral load in a human diagnosed with HCV; as well as use of ribavirin in conjunction with two or more of the Combination Compounds or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating HCV in a human subject, wherein said use does not include use of one or more interferon; as well as use of two or more of the Combination Compounds or ceutically acceptable salts thereof, in the manufacture of a medicament for ribavirin-based HCV therapy, wherein said use avoids stration of one or more interferon; as well as use of two or more of the Combination Compounds or pharmaceutically acceptable salts thereof and ribavirin, without one or more interferon in the cture of a medicament for reducing emergence of HCV pecies with resistance to nistered oral antiviral agents.
Another aspect of the present invention includes a combination comprising ribavirin and two or more of the Combination Compounds or pharmaceutically acceptable salts thereof, which combination is substantially free of one or more interferon. In one embodiment, the combination may occur as separate dosage forms with each active ingredient, administered together or separate, sequentially or concurrently, and close in time or remote in time to each other.
Another aspect of the present invention includes a kit comprising: ribavirin, two or more of the Combination Compounds and instruction regarding a treatment regimen to treat, reduce viral load, or delay onset or progression of HCV wherein the treatment regimen includes administration of the two or more of the Combination Compounds and ribavirin without administration of one or more interferon. In one embodiment, such a kit may also include packaging, such as a blister pack. Alternatively, such a kit may provide for individual prescription and dosing of each component as separately packaged pharmaceutics, but when combined with the instruction regarding a ent regimen to treat, reduce viral load, or delay onset or progression of HCV, such is intended to be within the scope of the present ion.
Another aspect of the present invention includes a pharmaceutical composition comprising: ribavirin; two or more of the Combination Compounds or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers. In one embodiment, the pharmaceutical composition may be a unitary dosage form.
Unless ise specified, the combination therapy with Ribavirin may be administered as te dosage forms with each active ient administered (including the Combination Compounds), may be administered together (e.g., in the form of a unit dosage, such as a tablet) or separately, sequentially or rently, and close in time or remote in time to each other. If stered separately, each compound may be administered with the other(s) at the same time, or either before or after such stration of the other(s). The active ingredients can be administered daily. In one embodiment, a daily dosage of the active ingredients is administered in separate sub-doses, such as one, two, three or four times per day.
Advantageously, the daily dosage of Combination nds or pharmaceutically acceptable salts thereof and ribavirin may be administered once per day.
Although the t invention includes itions, methods, uses and the like for the treatment of HCV comprising administering two or more Combination Compounds or a ceutically acceptable salt thereof; and ribavirin, but not one or more eron, the present invention does not foreclose the potential for dosing one or more interferon to the human. Rather, the present invention may be used in ction with another y for another indication that, in fact, includes one or more eron.
Combinations of Two or more of the Combination Compounds with Ribavirin and Interferon Another aspect of the present invention provides for compositions, methods, uses and the like sing administering two or more of the ation Compounds or pharmaceutically acceptable salts thereof and ribavirin, and one or more interferon for treatment of HCV. The administration of more interferon may be in temporal relation to the administration of the Combination Compounds and ribavirin.
Another aspect of the present invention includes a method for ameliorating one or more symptoms of HCV infection in a human comprising administering two or more of the Combination Compounds or pharmaceutically acceptable salts thereof, ribavirin, and one or more interferons. Another aspect of the present invention includes a method for reducing viral load in a human diagnosed with HCV comprising: administering two or more of the Combination Compounds or pharmaceutically acceptable salts thereof along with ribavirin and one or more interferons.
Another aspect of the present invention includes a method of ribavirin-based HCV therapy comprising administering two or more of the Combination Compounds or pharmaceutically acceptable salts thereof along with ribavirin, and one or more interferons.
Another aspect of the present invention es a method for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents comprising: administering two or more of the Combination Compounds or pharmaceutically acceptable salts thereof along with ribavirin and one or more interferons.
Another aspect of the present invention includes use of two or more of the Combination Compounds or pharmaceutically able salts thereof ribavirin, and one or more erons, in the manufacture of a medicament for ameliorating one or more symptoms of HCV infection in a human. Another aspect of the present invention es use of two or more of the Combination Compounds or pharmaceutically acceptable salts thereof along with ribavirin and one or more interferons, in the manufacture of medicament for reducing viral load in a human diagnosed with HCV. Another aspect of the present invention includes use of ribavirin in conjunction with two or more of the Combination Compounds or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating HCV in a human subject, n said use includes use of one or more interferons. Another aspect of the present ion includes use of two or more of the Combination nds or ceutically acceptable salts thereof, in the manufacture of a medicament for ribavirin-based HCV therapy, wherein said use es stration of one or more interferon. r aspect of the present invention includes use of two or more of the Combination Compounds or pharmaceutically acceptable salts thereof, ribavirin, and one or more interferons in the manufacture of a medicament for reducing emergence of HCV quasispecies with resistance to coadministered oral antiviral agents.
Another aspect of the present ion includes a combination comprising ribavirin and two or more of the Combination nds or pharmaceutically able salts thereof, which combination es one or more interferons.
Another aspect of the present invention includes a kit comprising: ribavirin, two or more of the Combination Compounds and one or more interferon; and instructions regarding a treatment regimen to treat, reduce viral load, or delay onset or ssion of HCV wherein the treatment regimen includes administration of the two or more of the Combination Compounds and ribavirin and administration of one or more interferon. In one embodiment, such a kit may also include packaging, such as a blister pack. atively, such a kit may provide for individual prescription and dosing of each component as separately packaged pharmaceutics, but when combined with the instruction regarding a treatment regimen to treat, reduce viral load, or delay onset or progression of HCV, such is intended to be within the scope of the present invention.
Another aspect of the present invention includes a pharmaceutical composition comprising: two or more of the ation Compounds or pharmaceutically acceptable salts thereof, ribavirin, and one or more interferon; and one or more pharmaceutically acceptable rs. In one ment, the pharmaceutical composition may be a unitary dosage form.
Unless otherwise specified, the combination therapy with Ribavirin and one or more interferons may be stered as separate dosage forms with the one or more erons administered to the patient and each of the remaining active ingredients to be employed in the combination therapy (including the Combination Compounds) are administered together (e.g., in the form of a unit dosage, such as a ) or separately, sequentially or concurrently, and close in time or remote in time to each other. If administered separately, each active ingredient may be administered with the other(s) at the same time, or either before or after such administration of the other(s). The active ingredients can be administered daily. In one embodiment, a daily dosage is administered in separate sub-doses, such as one, two, three or four times per day.
Combination Therapy, Including Additional Therapeutics In another ment, non-limiting examples of suitable combinations include the combinations of two or more of nd 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15 and Compound 16 with one or more onal active ingredients including HCV NS3 protease inhibitors, glucosidase 1 inhibitors, hepatoprotectants, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophilin inhibitors, HCV IRES inhibitors, HCV entry inhibitors, HCV maturation inhibitors, HCV assembly inhibitors, HCV infectivity inhibitors and pharmacokinetic enhancers, as well as other drugs for treating HCV. More specifically, one or more compounds of the t invention may be combined with one or more compounds selected from the group consisting of: (i) HCV NS3 protease inhibitors, e.g., boceprevir (SCH-503034, SCH-7), telaprevir (VX-950), TMC-435 (IUPAC N-[(2R,3aR,10Z,11aS,12aR,14aR) [2-(4-Isopropylthiazolyl)methoxymethylquinolinyloxy]methyl- ioxo-1,2,3,3a,4,5,6,7,8,9,11a,12,12a,13,14,14ahexadecahydrocyclopenta [c]cyclopropa[g][1,6]diazacyclotetradecin-12a- ylcarbonyl]cyclopropanesulfonamide], 0, ACH-1625, ACH-2684, BI- 201335, BI-1230, MK-5172, MK-7009, 0518, VBY-376, VX-500, GS- 9256, GS-9451, BMS-605339, PHX-1766, AS-101, YH-5258, YH-5530, YH- 5531, and 91 (R-7227); (ii) glucosidase 1 inhibitors, e.g., celgosivir (MX-3253), UT-231B, Miglitol; (iii) hepatoprotectants, e.g., emericasan (IDN-6556), ME-3738, lin, and MitoQ; (iv) nucleoside or nucleotide inhibitors of HCV NS5B polymerase, e.g., ., R1626, R7128 (R4048), IDX184, IDX-102, PSI-661, PSI-938, PSI-7851, PSI-7977, BCX-4678, valopicitabine (NM-283), MK-0608 and TMC649128; (v) non-nucleoside inhibitors of HCV NS5B polymerase, e.g., filibuvir (PF- 868554), ABT-333, 2, BI-207127, VCH-759, VCH-916, JTK-652, MK- 3281, VBY-708, VCH-222, A848837, ANA-598, GL60667, GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (nesbuvir), GSK625433, BILN-1941, and XTL-2125; (vi) HCV NS5A tors, e.g., ACH-2928, AZD-2836 (A-831), AZD-7295 (A-689), 6, 0052, BMS-824393, and PPI-461; (vii) TLR-7 agonists, e.g., imiquimod, 852A, ANA-773, ANA-975, AZD-8848 (DSP- 3025), PF-04878691, and SM-360320and Compound 8; (viii) cyclophilin tors, e.g., DEBIO-025, SCY-635, and NIM811; (ix) HCV IRES inhibitors, e.g., MCI-067; (x) pharmacokinetic enhancers, e.g. roxythromycin, BAS-100, 2, PF- 4194477, TMC-41629; (xi) HCV entry inhibitors (xii) HCV assembly inhibitors; (xiii) HCV maturation inhibitors; (xiv) HCV infectivity inhibitors; and (xv) other drugs for treating HCV, e.g., thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, NTZ), 01 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, 65, BIT225, PTX-111, ITX2865, TT-033i, ANA 971, NOV-205, tarvacin, , VGX-410C, EMZ- 702, AVI 4065, BMS-650032, BMS-791325, Bavituximab, MDX-1106 (ONO- 4538), Oglufanide, , and VX-497 (merimepodib)..
SYNTHETIC EXAMPLES Synthetic protocols for the preparation of Compounds 1, 2, 3, 6, 7, and 8 are known in the literature. Additionally, a synthetic protocol for preparing each of the Combination Compounds is provided in the Examples below.
Compound 1 can be prepared using tic s and intermediates like those described in US 7,754,720. Compound 1 can also be prepared as described in the following Example. e 1: 5-({6-[2,4-bis(trifluoromethyl)phenyl]pyridazinyl}methyl)(2-fluorophenyl)-5H- imidazo[4,5-c]pyridine 1.
N N Compound MW Amount Moles Equivalents 104 453.79 95mg 0.209 1 DME 500µL 2N aq. Na2CO3 313µL 0.626 3 105 257.93 80.9mg 0.313 1.5 Pd(PPh3)4 1155 12mg 0.0104 0.05 Compound 103 was dissolved in dimethoxyethane (DME). To this solution was added 2,4-bis(trifluromethyl)phenylboronic acid 105 and a 2N aq. Na2CO3 solution. To the resulting biphasic mixture was added Pd(PPh3)4 and the reaction was then heated at 80°C for 72 hrs.
The reaction was cooled to room ature and filtered through Celite and the Celite washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified on 6g SiO 2 using MeOH/CH2Cl2 to elute compound. The compound thus obtained was contaminated with PPh3(O). The product was repurified on a 1 mm Chromatotron plate with 0 to 5% MeOH/CH2Cl2 in 1% steps. The pure fractions were combined and concentrated in vacuo, then dried on high vacuum for 12 hrs. 11.8 mg of the free base of compound 1 was obtained with no PPh3 contamination. 1H NMR (300MHz,CD 3OD) δ 6.20 (s, 2), 7.32 (m, 3), 7.52 (m, 1), 7.78 (d, 1), 7.89 (d, 1), 7.95 (s, 2), 8.15 (m, 3), 8.35 (d, 1), 9.12 (s, 1); LC/MS M+H = 518.
The ediate compound 104 was prepared as follows. a. Preparation of Compound 102.
Error! s cannot be created from editing field codes. 101 102 Compound MW Amount mmoles Equivalents 101 128.56 5 g 38.9 1 TCCA 232.41 3.62 g 15.6 0.4 CHCl3 130 mL To a solution of the commercially available starting material 101 in CHCl3, trichloroisocyanuric acid (TCCA) was added at 60oC. Then the solution was stirred for 1.5 hrs, cooled, and filtered with HiFlo-Celite. The filtrate was concentrated and dried with . The yield was 5.037 g of compound 102. b. Preparation of Compound 104.
N N Cl N N N N H F 103 F N core N N NaOH, DMF N Cl Cl 102 104 Compound MW Amount mmoles Equivalents 102 163 5.073 g 31.12 1 103 213.2 6.635 g 31.12 1 NaOH (10%) 40 1.245 g 31.12 1 DMF 320 mL To a solution of compound 103 in DMF (dimethylformamide), NaOH was added.
Compound 102 was ved in DMF (20 mL) and added to the solution slowly. The reaction was stirred for 3 hrs, was diluted with water and extracted with EtOAc. The c layer was dried with Na2SO4. The solvent was removed and the product recrystallized with dichloromethane. The yield was 5.7 g of compound 103.
Compound 2 can be prepared using tic methods and intermediates like those described in USSN 12/202319 (US 20100051763 A1). Compound 2 can also be prepared as bed in the following Example.
Example 2: Preparation of Compound 2.
Cl S MeO N NH H OH O N N H O 206 N P O O Phosphinate ester 206 (23.7 g, 24.05 mmol) was dissolved in CH3CN (240 mL) and cooled to 0°C. Iodotrimethylsilane (17.4 mL, 122.3 mmol) was added at a fast drop-wise pace followed by, after 10 min, 2,6-lutidine (17.0 mL, 146.4 mmol). The reaction mixture was slowly warmed to room ature and stirred for 1 h then cooled back down to 0°C and 2,6-lutidine (11.1 mL, 95.6 mmol) followed by MeOH (24 mL) were added. The solution was concentrated in vacuo and the crude residue was purified by HPLC to afford 12.68 g of Compound 2 in 55% yield. 1H NMR (300 MHz, CDCl 3) δ 8.35 (d, J = 9.3 Hz, 1H), 8.28 (s, 1H), 7.85 (s, 1H), 7.64 (d, J = 9.6 Hz, 1H), 7.35-7.22 (m, 1H), 7.02-6.89 (m, 2H), 5.85 (bs, 1H), 4.82-4.71 (m, 2H), 4.33 (bs, 1H), 4.28-3.99 (m, 3H), 4.16 (s, 3H), 3.57-3.28 (m, 2H), .78m, 1H), 2.63-2.50 (m, 1H), 2.08-1.91 (m, 1H), 1.91-170 (m, 2H), 1.70-1.13 (m, 22H), 1.37 (d, J = 6.9 Hz, 6H); 31P NMR (121.4 MHz, CD3OD) δ 42.4; LCMS (M+1): 957.35. g.
Intermediate compound 206 was prepared as follows. a. Preparation of Compound 203.
Br OEt H H2N P O N N + O OH F O O H OEt O N N H O N P O O Compound 201 (17.42 g, 28.30 mmol) was dissolved in THF (136 mL) and cooled to 0°C. To the solution was added N-methylmorpholine (4.7 mL, 42.7 mmol). After 10 min at 0°C, i-butylchloroformate (4.05 mL, 30.96 mmol) was added dropwise. After an additional 1 h, (1- aminovinyl-cyclopropyl)-(2,6-difluoro-benzyl)-phosphinic acid ethyl ester 202 (8.94 g, 29.70 mmol) was slowly added as a solution in THF (20 mL). The suspension was warmed to room temperature and after 2 h it was ioned n H2O (400 mL) and ethylacetate (200 mL).
The aqueous layer was extracted with ethylacetate (200 mL x 2) and the combined organic layers were washed with HCl (1N, 225 mL) and H2O (200 mL). The acid wash and aqueous wash were combined and back-extracted with cetate (175 mL x 2, 100 mL x 2). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, and concentrated in vacuo providing 25.06 g of diene 203 in 98.5% crude yield. LCMS (M + 1): 898.06. b. Preparation of Compound 204.
H OEt O N N H O 203 N P O O Compound 203 (12.91 g, 14.36 mmol) was dissolved in CH2Cl2 (1440 mL) and the solution was ed for 30 minutes. The solution was heated to 40°C and s G1 catalyst (2.95 g, 3.59 mmol) was added. The reaction was refluxed for 17 h whereupon trishydroxymethylphosphine (22.3 g, 18.0 mmol), TEA (50 mL, 35.9 mmol), and H2O (400 mL) were added and the reaction mixture was heated to reflux for an additional 16 hours. The reaction mixture was cooled to room ature and the two layers were separated. The organic layer was washed with H2O (400 mL) and brine (300 mL), dried over MgSO4, and concentrated. The crude residue was purified by silica-gel chromatography to afford 8.30 g of macrocyclic olefin 204 in 66% yield. LCMS (M + 1): . c. Preparation of Compound 205.
H OEt O N N H O 204 N P O O The macrocyclic olefin 204 (7.34 g, 8.42 mmol) was dissolved in ethylacetate (105 mL) and rhodium on alumina (5% wt, 2.945 g, 0.40 wt %) was added. The system was evacuated and flushed with H2 (1 atm, 3x). To the system, after 3 h, was added more rhodium on a (5% wt, 842 mg, 0.10 wt %) and evacuated and flushed with H2 (1 atm, 3x). After an additional 1 h the suspension was filtered and concentrated in vacuo providing 6.49 g of reduced macrocycle 205 in 88% crude yield. LCMS (M + 1): 872.04. d. Preparation of nd 206.
Cl S MeO N NH H OEt O N N H O 205 N P O O The brosylate macrocycle 205 (6.49 g, 7.67 mmol) was ved in N- methylpyrrolidinone (25.0 mL) and 8-chloro(2-isopropylamino-thiazolyl)methoxyquinolinol 207 (2.564 g, 7.33 mmol) followed by Cs2CO3 (4.40 g, 13.50 mmol) were added.
The mixture was heated to 65°C for 6 h then diluted with ethylacetate (200 mL) and washed with LiCl (5%, 250 mL). The aqueous layer was extracted with ethylacetate (100 mL x 2) and the combined organic layers were washed with brine (150 mL), dried over Na2SO4/MgSO4, and concentrated in vacuo. The crude residue was purified via silica-gel chromatography (ethylacetate-methanol) affording 4.39 g of aminothiazole 206 in 58% yield. LCMS (M + 1): 985.28.
Intermediate Compound 201 can be ed as follows.
O2 O2 S S HO O O Br Br N N HN Boc OMe Boc OMe OMe O O O 208 209 H Br O N CO2H 210 + O O N N O OMe 211 O O S O N 212 N H O N OMe N O O OH O O O e. Preparation of compound 209. nd 208 (7.00 g, 28.55 mmol) and DABCO (5.13 g,45.94 mmol) were dissolved in toluene (30 mL). A toluene (11 mL) solution of brosylchloride (10.22 g, 40.01 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc (210 mL) and 0.5N HCl (200 mL) was added. The two layers were separated and the aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (200 mL), dried with Na2S04, filtered, and trated.
The crude t was purified by combi-flash to give 12.23 g of compound 209 in 92% yield. f. Preparation of compounds 210 and 212.
Compound 209 (12.2 g, 26.3 mmol) was treated with 4 N HCl / 1,4-dioxane (60 mL) and stirred for 1 hour. The on mixture was concentrated and dried under vacuum for minutes. The crude amine HCl salt of compound 210 was dissolved in DMF (150 mL) and acid 211 (14.2 g, 52.6 mmol) was added. HATU (20.0 g, 52.6 mmol) and NMM (13.5 g, 131.5 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc (300 mL), washed with 1 N HCl (200 mL), saturated NaHCO3, brine, dried with Na2SO4, and concentrated. The crude product was purified by flash to give 15.1 g of compound 212 in 93% yield. g. Preparation of compound 213.
To a solution of 212 (12.8 g, 20.7 mmol) in CH2Cl2 (50 mL) was added 4 N HCl in 1,4- dioxane (50 mL, 200 mmol). The reaction mixture was stirred at room temperature for 2 hours, trated, dried under vacuum for 20 minutes, and then dissolved in CH3CN (50 mL).
Saturated NaHCO3 in H20 (50 mL) was added and stirred for 5 minutes. Freshly prepared cyclopentylchloroformate in THF (50mL) was added. The reaction was complete within 1 h.
The solvent was removed under reduced pressure and the e was d with EtOAc.
The mixture was brought to pH = 2 with 1 N HCl and the two layers were separated. The organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated to give crude compound 213 (3.18 g). h. Preparation of compound 201.
The crude ester 213 (3.18 g, 5.07 mmol) was dissolved in THF (25 mL), H2O (25 mL), and then MeOH (6 mL) and LiOH (660 mg, 25.4 mmol) was added. The reaction mixture was stirred at room temperature for 1h and d with EtOAc. The on mixture was acidified to pH 2 with 1 N HCl and the two layers were separated. The aqueous layer was extracted with EtOAc (2 x). The combined organic layers were washed with brine, dried with Na2SO4 concentrated and dried under vacuum to give 3.09 g of acid 201.
Intermediate ro(2-isopropylamino-thiazolyl)methoxy-quinolinol 207 can be prepared as follows.
Cl Cl O O Cl O MeO N MeO N N2 MeO N OH OH O O 214 OH 215 216 Cl S MeO N NH i. Preparation of 8-chlorohydroxymethoxyquinolinecarboxylic acid 215.
To a on of methyl 8-chlorohydroxymethoxyquinolinecarboxylate 214 (36.5g, 0.145 mol) in a mixture of 1:1 of MeOH: THF (160 mL total) was added a solution of LiOH (30.5 g, 0.725 mol) in H20 (80 mL). The mixture was stirred at room temperature for an hour when LCMS analysis showed complete conversion to the carboxylic acid. The reaction was worked up by removal of the volatiles and adjusting the pH of the solution to 6 using aqueous 6N HCl. The resulted gummy residue was filtered and dried on the lyophilizer for 2 days to provide 34.4 g (99.6 %) of compound 215 as a white solid. EI MS (mlz) 253.9 [M+H]. j. Preparation of 2-(2-diazo-l-oxo)chloromethoxyquinolinyl isobutyl carbonate 216.
To a solution of 8-chlorohydroxymethoxyquinolinecarboxylic acid 215 (10.2 g, 0.04 mol) in THF (400 mL) was added triethyl amine (12.3 mL, 0.088 mol) and i-Butylchloroformate (11.6 mL, 0.088 mol) at 0°C under an argon atmosphere. The e was d at 0°C for 1 hour when LCMS analysis demonstrated tion of the reaction to e the desired mixed anhydride. EI MS (mlz) 454.0 [M+H]. To the reaction mixture of the anhydride was added a 1M solution of diazomethane (121 mL, 0.121 mol) in diethyl ether via a plastic funnel at 0°C. This mixture was allowed to stir while warming up to room temperature for additional 2 hours. Analysis of the mixture by LCMS demonstrated completion of the reaction. The septum was d and the reaction was stirred for onal 20 minutes before removal of the t. The residue was dried further under high vacuum to provide compound 216, which was carried on to the next step. EI MS (m/z) 377.9 [M+H]. k. Preparation of 8-chloro(2-(isopropylamino)thiazolyl)methoxyquinoiinol 207.
To a cooled solution of 2-(2-diazo-l-oxo)chloromethoxyquinolinyl isobutyl carbonate 216 (15.2 g, 0.040 mol) at 0°C in THF (268 mL) was added 48% HBr (23 mL, 0.201 mol) slowly over 15 minutes. The solution was stirred at 0°C for an additional 40 minutes when LCMS analysis demonstrated complete reaction. The reaction was worked up by addition of aqueous 1N NaOH (180 mL) at 0° C to adjust the pH of the aqueous layer to 9. The layers were separated and the aqueous layer was washed with EtOAc (2 x 200 mL). Combined organic extracts were washed with brine and dried over MgS04. The t was removed in vacuo to provide 17.7 g of a yellow solid. EI MS (m/z) 431.9 [M+H].
The solution of the bromoketone obtained from the us reaction was suspended in i-propanol (270 mL) and isopropylisourea (9.4 g, 0.080 mol). The reaction mixture was heated at 72 oC for 32 hours. LCMS analysis of the reaction demonstrated complete conversion to the d·product. The reaction was allowed to cool to room temperature to allow for the product to precipitate out of the solution. The reaction was further cooled to 0°C for 12 hours before filtration. The filtrate was washed with ether and dried on lyopholizer to provide 8.03 g of compound 207 as an orange solid. 1H NMR (500 MHz, CDCl 3): δ 8.21 (d, J= 9 Hz, 1H), 7.74 (s, 1H), 7.44 (d, J= 10Hz), 1H), 7.07 (s, 1H), 4.05 (s, 3H), 3.92 (pentet, J=6 Hz, 1H), 1.25 (d, J= 7 Hz, 6H): EI MS (m/z) 350.0 [M+H]. nd 3 can be prepared using synthetic methods and intermediates like those bed in USSN 12/215,605 (US 20090257978 A1). Compound 3 can also be prepared as described in the following Example.
Example 3: Preparation of Compound 3 Cl N O N S 315 O N OH O N O Compound 315 (12 g, 13 mmol) was dissolved in THF (200 ml), LiOH (11g, 260 mmol) in H2O (200 ml) was added, followed by MeOH (200 ml). The mixture was kept stirring at room temperature for 20 hours. Upon tion of the reaction, 4 N HCl in H2O was added to adjust pH to 7 at 0 oC. The mixture was extracted with EtOAc (2 x 400 ml). The combined organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give nd 3 as a yellow solid (11 g, 93%). LC/MS = 911.52(M++1). 1H NMR (300MHz, CD3OD) δ 7.95 (d, 1H), 7.90 (s, 1H), 7.48 (s, 1H), 7.31 (d, 1H), 5.42 (s, 1H), 4.37 (dd, 1H), 4.20 (m, 2H), 3.83-3.56 (m, 7H), 3.50 (m, 2H), 3.39 (m, 2H), 2.45 (m, 1H), 2.27(m, 1H), 1.62 (m, 2H), 1.50 (m, 1H), 1.33 (m, 2H), 1.18 (m, 1H), 1.05 (m, 8H), 0.90 (m, 3H), 0.76 (m, 11H), 0.14-0.04 (m, 2H) The intermediate compound 315 was prepared as follows.
O O N N O O O OH O O Et2Zn, CH2I2 OH Et3N O O N DCM, 0oC rt CH2Cl2 O 301 302 a. Preparation of compound 301.
To a dry, argon purged three-neck round bottom flask (1000 mL) were added anhydrous romethane (100 mL) and Et2Zn (28 mL, 273 mmol) at 0 oC. (CAUTION: Source of argon can not be from needle. Use appropriate glass adapter only. A second bubbler can also be attached to the flask to t excessive pressure build up.) Cyclopentenol (10.0 mL, 119 mmol) was then added dropwise (large quantity of ethane gas was produced) to the flask and the reaction mixture was allowed to stir until the evolution of gas had ceased. Diiodomethane (22 mL, 242 mmol) was then added dropwise over a period of 30 minutes. The reaction was allowed to warm to room temperature and continued to stir overnight under a positive flow of argon, at which point TLC analysis had indicated complete disappearance of the starting alcohol. The reaction was then diluted with CH2Cl2 and quenched with 2M HCl (white precipitate should be completely dissolved). The biphasic mixture was poured into a separatory funnel and the organic layer was collected. The solvent was removed under reduced pressure until 100 mL of material containing compound 301 remained. b. ation of nd 302.
Anhydrous dichloromethane (525 mL) was added to the flask followed by the dropwise addition of triethylamine (34 mL, 245 mmol). The reaction continued to stir at room ature under a positive flow of nitrogen at which point, disuccinimidylcarbonate (40.7 g, 159 mmol) was added to the flask portion wise. The reaction was allowed to stir until TLC analysis indicated complete disappearance of the starting al (2-3 days). Upon tion, the reaction mixture was quenched with 1M HCl (200 mL x 2) and washed with H20 (200 mL x 2).
The desired material was extracted using CH2Cl2 and the ed c layers were dried using anhydrous MgSO4 and passed through a silica plug. The solvent was removed under reduced pressure and the crude material was purified using flash chromatography (Rf = 0.33, 1:1 Hex/EtOAc) to provide compound 302 (22 g, 75%): 1H NMR (300 MHz, CDCl 3): δ 5. 24 (t, 1H), 3.82 (s, 4H), 2.24 (m, 2H), 2.03 (d, 2H), 1.38 (m, 2H), 0.48 (m, 1H), 0.40 (m, 1H).
Br O H O O N CO2H O O Boc O 304 N 303 O Br O Br O S O O O OMe N N H H O N O O N O O O 306 O 305 Br O Br O S S O O O O 302 O O H H N N N O N O H H O N O O N O O c. Preparation of compound 304.
N-t-Boc-cisHydroxy-L-Proline methyl ester 303 (100.0 g, 407.7 mmol) and DABCO (1.5eq, 68.6g, 611.6 mmol) were dissolved in anhydrous toluene (200 mL) in a 2 L three necked round bottom flask with a mechanical r and an addition . After cooling the solution to 0 °C under N2, A solution of 4-Bromo-benzenesulfonyl chloride , 135.6g, 530.0 mmol) in 300 mL of toluene was added through addition funnel over 60 minutes. The reaction mixture was stirred and warmed to room temperature overnight (16 hours). The mixture was slowly poured into 2L 1M Na2CO3 (aq.), and the product was extracted with EtOAc (2L). After the organic phase was washed by 0.5 N HCl (2L), H2O (1L), and brine (1L), it was dried ), concentrated to give 195.45 g of a yellow oily brosylate product.
To a solution of the above brosylate (407.7 mmol) in dichloromethane (300 mL) was slowly added 4.0 M HCl in dioxane (500 mL, 5eq) and the resulting solution was allowed to stir at room temperature for 2 hours. After ether ) was added to the reaction mixture, the mixture was stirred for 15 minutes and the white precipitate was collected by tion. The solid was washed with ether and hexane and then dried under vacuum overnight to obtain 153.0 g of the HCl amine salt of compound 304, 381.8 mmol, in 94% yield for two steps. d. Preparation of compound 305.
To a on of Boc-tert-butyl-glycine (97.0g, 420.0 mmol) in DMF (200mL) and methylene chloride ) were added HATU (217.76g, 572.7 mmol) and Hunig’s base (126 mL, 1145.4 mmol) at room temperature. After the mixture was stirred for 20 minutes at room temperature, a solution of the previous HCl salt (153.0 g, 381.8 mmol) and Hunig’s base (126 mL, 1145.4 mmol) in DMF (200mL) and dichloromethane ) was added to the above acid mixture in one portion. The reaction e was stirred at room temperature for 3h, with monitoring by LCMS. The reaction mixture was concentrated to remove dichloromethane under reduced pressure and the white solid that formed was filtered off. The remaining DMF solution was diluted with ethyl acetate (1L), washed successively with 3% LiCl (aq) (3x650mL), sat’d NH4Cl (2x500mL), 0.5N HCl (aq) (2x600mL), brine (500mL), sat’d NaHCO3 (3x500mL), and brine (500mL). The resulting organic fraction was dried (MgSO4) and trated to afford compound 305 (111g). e. Preparation of nd 306.
To a on of the methyl ester 305 (120 g, 207.8 mmol) in THF (300 mL), MeOH (75 mL) was added a on of LiOH (26.18 g, 623.4 mmol) in H2O (150 mL). The solution was allowed to stir at room temperature for 4 hours. The mixture was cooled in an ice-bath while acidifying with 3N HCl to pH about 5.5, stirred for 10minutes, and the resulting white solids were collected by filtration. The solids were washed with more water, ether and hexane. The solids were dried under vacuum at 40oC overnight to give 95.78g (82%) of the acid 306. f. Preparation of compound 307.
To a solution of the carboxylic acid 306 (81.4 g, 144.27 mmol) in DMF (200mL) and dichloromethane (200mL) was added HATU (82.3g, 216.4 mmol) and Hunig’s base (47.5 mL, 432.8 mmol) at room temperature. After the mixture was stirred for 20 minutes at room ature, a solution of amine (158.7 mmol) and s base (47.5 mL, 1145.4 mmol) in DMF (200mL) and romethane (200mL) was added to the above acid mixture in one portion. The on mixture was stirred at room temperature for 3 hours and red by LCMS. After the mixture was concentrated under reduced pressure to remove dichloromethane, the white solids that formed were filtered off. The remaining DMF solution was diluted with ethyl acetate (600mL) and successively washed with 3% LiCl (aq) (2x550mL), sat’d NH4Cl (500mL), 1N HCl (aq) (500mL), sat’d NaHCO3 (500mL), and brine (300mL). The resulting organic fraction was dried (Na2SO4) and trated to afford compound 307 (111g). g. Preparation of compound 308.
Compound 307 was dissolved in 4N HCl in dioxane (300 mL) at room temperature and stirred for 2 hours. It was then concentrated under vacuum, and co-evaporated with dichloromethane (2 x 200mL) to dryness. The residue was dissolved in EtOAc (600mL) and sat’d aq. NaHCO3 (1L). It was stirred vigorously. After 10 minutes, carbonic acid bicyclo[3.1.0]hexyl ester 2,5-dioxo-pyrrolidinyl ester 302 (41.4 g, 173.1 mmol) was added in one portion. After the resulting mixture was stirred for another 30 minutes, the organic layer was collected and washed with brine (500mL), dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography on silica gel with ethyl e/hexane to afford 94.44 g (92%) of compound 308.
Cl OMe Cl OMe Cl O NH2 HO NH2 MeO O NH2 309 310 O O O S H N OMe Cl N HOOC N H H O N S 311 MeO OMe Cl N O N S H N N Cl N OMe Cl N O N S O N S N 303 + 313 O O H H N N N O N O H H O N O O N O O 314 315 h. Preparation of compound 310. 1-(2-Aminochlorohydroxy-phenyl)-ethanone 309 (70.7 g, 354 mmol) was stirred in 48% aq. HBr (500 mL) at 110 oC for 72 hours. After the e was cooled to 0 oC with stirring, the solids were filtered and washed with water. The resulting solids were triturated with a saturated NaHCO3 solution (~350 mL), filtered, washed with water, and dried under vacuum to give ~ 40 g (61%) of crude 310 as a dark brown solid. LC/MS = 186 (M++1). i. Preparation of compound 311. 1-(2-Aminochlorohydroxy-phenyl)-ethanone 310 (40 g, 215 mmol) was dissolved in DMF (360 ml). Cesium carbonate (140 g, 430 mmol) was added, followed by bromoacetaldehyde dimethyl acetal (54.5 g, 323 mmol). The mixture was then vigorously d at 65 oC for 24 hours. Upon cooling to room temperature, EtOAc (1 L) and H2O (1 L) were added to the mixture. The organic layer was extracted with EtOAc (1 x 400 ml). The combined c layer was washed with aqueous 3% LiCl solution (2 x 1L), brine, dried 4) and concentrated in vacuo. The residue was purified by silica gel chromatography to give compound 311 as a white solid (39 g, 67%). j. Preparation of compound 312.
To a e of 1-[2-Aminochloro(2,2-dimethoxy-ethoxy)-phenyl]-ethanone 311 ( 13 g, 47.5 mmol) and isopropylaminothiazolecarboxylic acid romide (12.64 g, 47.5 mmol) in pyridine (150 ml) was slowly added phosphorus oxychloride (9.47 g, 61.8 mmol) at -40 oC. The mixture was then stirred at 0 oC for 4 hours. Upon completion of the on, H2O (30 ml) was added dropwise to the mixture. The mixture was then stirred at 0 oC for another 15 minutes. The mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with a sat. NaHCO3 aqueous solution. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in CH 2Cl2, hexanes were added slowly to the solution, and a yellow solid started to crash out. More hexanes were added until not much product was left in the mother liquid to provide compound 312 (18 g, 85%). k. Preparation of compound 313. ropylamino-thiazolecarboxylic acid [6-acetylchloro(2,2-dimethoxy-ethoxy)- phenyl]-amide 312 (18 g, 40.7 mmol) was suspended in toluene (400 ml). NaH (2.4 g, 61 mmol) was added to the vigorously stirred mixture while ring H2 evolution. The mixture became a clear solution during heating to reflux. The reaction was complete after refluxing for 3 hours. The mixture was cooled to room temperature. A solution of AcOH (69.2 mmol) in H2O (3 vol) was added to the mixture. After vigorous agitation for 1 hour at 0 oC, the solids were ted by filtration, rinsed forward with H2O. The wet cake was dried under high vacuum to a constant weight to provide compound 313 (15 g, 86%). l. ation of compound 314.
To a mixture of brosylate intermediate 303 (15 g, 35 mmol) and compound 313 (27.5 g, 38.5 mmol) in NMP (200 ml) was added cesium carbonate (25.1 g, 77 mmol). The mixture was stirred at 65 oC for 5 hours. The on was cooled to room temperature and EtOAc (600 ml) and an aqueous solution of 3% LiCl (600 ml) were added to the mixture. The organic layer was washed with aqueous 3% LiCl (1 x 600 ml), brine, dried (Na2SO4) and concentrated in vacuo.
The residue was purified by silica gel chromatography to give the desired methyl ester as a yellow solid (23.6 g, 75%). LC/MS = 900.13(M++1). m. Preparation of compound 315.
Methyl ester 314 (23.6 g, 26 mmol) was dissolved in glacial acetic acid (200 ml), 1.4 N HCl in H2O (75 ml) was added to the solution. The mixture was stirred at 60 oC for 1 hour.
Upon completion of the reaction, the mixture was concentrated to remove the solvents, coevaporated with toluene (x 2) to remove residual acetic acid. The e was then dissolved in EtOAc (500 ml) and sat. NaHCO3 aqueous solution h to neutralize the e) while monitoring CO2 evolution. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was further dried under high vacuum for 1 h and used as is for the next step. The crude was dissolved in CH2Cl2 (360 ml), line (3.4 g, 39 mmol) and sodium triacetoxyborohydride (7.2 g, 34 mmol) were added to the mixture at 0 oC. Then l acetic acid (0.47 g, 7.8 mmol) was added dropwise to the mixture. The reaction was complete in 10 s at 0 oC. Sat. NaHCO3 aqueous solution was added to quench the reaction. After stirring for another 20 minutes, the organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography to give the desired amine product 315 as a yellow solid (12 g, 50%). LC/MS = 924.63(M++1). nd 4 can be prepared as described in the following Example.
Example 4: Preparation of Compound 4.
O O N N P O NH2 N O H O N O O N CN N P O N O OH O H N O O CN O Chralcel OD-H O OH 4 column separation O NH2 O O N N P O N O H O N O OH Diastereomeric mixture 414 was dissolved in heptane and isopropanol (70%:30%, 230 mg in 4.5 mL of the mixed solvents) and subjected to chiral column separation under the following conditions: Column: Chiralcel OD-H, 2 x 25 cm Solvent system: 70% heptane and 30% isopropanol Flow rate: 6 mL/min.
Loading volume per run: 2.5 mL Compound 4 had a ion time of 20 minutes. 1H NMR (300 MHz, CDCl 3): δ 8.00 (s, 1H), 7.1-7.3 (m, 5H), 6.83 (d, 1H), 6.71 (d, 1H), 6.09 (brs, 2H), 5.95 (s, 1H), 5.04 (m, 2H), 4.67 (q, 1H), 4.35-4.52 (m, 2H), 4.00 (m, 2H), 2.74 (m, 1H), 1.40 (d, 3H), 1.2-1.3 (12H), 0.98 (s, 3H). 31P NMR (121.4 MHz, CDCl 3): δ 2.72 (s). Compound 4 was subsequently recrystallized from MTBE for x-ray quality crystals.
Compound 4a had a retention time 50 min. 1H NMR (300 MHz, CDCl 3): δ 7.98 (s, 1H), 7.1-7.3 (m, 5H), 6.83 (d, 1H), 6.73 (d, 1H), 6.02 (brs, 2H), 5.95 (s, 1H), 5.08 (d, 1H), 5.00 (m, 1H), 4.68 (q, 1H), 4.38-4.56 (m, 2H), 3.98 (m, 2H), 2.74 (m, 1H), 1.40 (d, 3H), 1.2-1.3 (12H), 0.99 (s, 3H). 31P NMR (121.4 MHz, CDCl 3): δ 2.61 (s).
The intermediate diastereomeric e 414 was prepared as follows. a. Preparation of Compound 402.
O O O O O OH AcCl O O CH3OH O OH O OH O O 401 402 To a solution of nd 401 (22.0 g, 54.9 mmol, ed according to the procedures described in J.O.C., 2004, 6257) in methanol (300 mL) was dropwise added acetyl chloride (22 mL) at 0 oC using a dropping funnel over a period of 30 minutes and then stirred at room temperature for 16 hours. The mixture was concentrated, re-dissolved in ethyl acetate (400 mL), washed with ice-cold 2 N NaOH, and trated to dryness, affording the crude methyl ether 402 as an oil. MS = 437.2 (M + Na+). b. ation of Compound 403.
O O O O NaOCH3 O OH CH3OH HO OH To a solution of compound 402 in methanol (300 mL) was added 0.5 M sodium methoxide solution in ol (20 mL, 10 mmol), and stirred for 16 hours at room temperature. The reaction was quenched with 4.0 N HCl solution in dioxane (2.5 mL, 10 mmol). The mixture was then concentrated, affording the crude compound 403. MS = 201.0 (M + Na+). c. Preparation of Compound 404.
HO O O O BnCl, KOH O O HO OH n X-405 O O toluene 403 404 A mixture of compound 403, Tritron X-405 (70% in water, 6.0 g), 50% KOH (in water, 85 g) in toluene (500 mL) was heated to reflux with a Dean-Stark trap attached. After 1 hour collecting 25 mL of water, benzyl de (33 g, 260 mmol) was added and continued to reflux with stirring for 16 hours. The mixture was then cooled and partitioned between ethyl acetate (400 mL) and water (300mL). The organic layer was washed with water (300 mL), and concentrated. The residue was purified by silica gel column chromatography (20% EtOAc / hexanes), affording the methyl ether 404 as an oil (22.0 g, 89% in three steps). 1H NMR (300 MHz, CDCl3): δ 7.3 (m, 15H), 4.5 - 4.9 (m, 7H), 4.37 (m, 1H), 3.87 (d, 1H), 3.56 (m, 2H), 3.52 (s, 3H), 1.40 (s, 3H). d. Preparation of Compound 405.
O O O 3M H2SO4 O O OH acetic acid O O O O 404 405 To a solution of 404 (22.0 g, 49.0 mmol) in acetic acid (110 mL) was added 3 M sulfuric acid (prepared by mixing 4.8 g of trated sulfuric acid with 24 mL of water) and stirred at 70 oC for 8 hours. The mixture was concentrated to a volume of 20 mL, and partitioned between ethyl acetate and ice-cold 2N NaOH. The ethyl acetate layer was concentrated, and purified by silica gel column chromatography (~35% EtOAc / hexanes), affording compound 405 as an oil (17.0 g, 80%). MS = 457.2 (M + Na+). e. Preparation of Compound 406.
O O O O O OH DMSO, Ac2O O O O O 405 406 To a solution of compound 405 (45 g, 104 mmol) in DMSO (135 mL) was dropwise added acetic ide (90 mL, 815 mmol) at room temperature under argon. The e was stirred for 16 hours at room temperature, and then poured into ice-water (1 L) while stirring.
After ice was completely melted (30 minutes), ethyl e (500 mL) was added. The organic layer was ted. This extraction process was repeated three times (3x500 mL). The organic extracts were combined and concentrated. The residue was purified by silica gel column chromatography (20% EtOAc / hexanes), affording compound 406 as an oil (39 g, 88%). 1H NMR (300 MHz, DMSO-d 6): δ 7.3 (m, 15H), 4.4 - 4.8 (m, 7H), 4.08 (d, J = 7.5 Hz, 1H), 3.75 (dd, J = 2,4, 11.4 Hz, 1H), 3.64 (dd, J = 5.4, 11.4 Hz, 1H), 1.51 (s, 3H). f. Preparation of Compound 407.
N N O O O O N Bn Br N O Bn N BuLi, TMSCl O O O O Bn Bn THF Bn Bn 406 407 To a dry, argon purged round bottom flask (100 mL) were added o-pyrrolo[2,1- f][1,2,4]triazinylamine (234 mg, 1.10 mmol) (prepared according to WO2007056170) and anhydrous THF (1.5 mL). TMSCl (276 µL, 2.2 mmol) was then added and the reaction mixture stirred for 2 hours. The flask was placed into a dry ice/acetone bath (-78 oC) and BuLi (2.5 mL, 4.0 mmol, 1.6M in hexanes) was added dropwise. After 1 hour, a solution of compound 406 (432.5 mg, 1.0 mmol) in THF was cooled to 0 oC and then added to the reaction flask dropwise.
After 1 hour of stirring at -78 oC, the flask was warmed to 0 oC and sat. NH 4Cl (5 mL) was added to quench the on. The organics were extracted using EtOAc (3 x 10 mL) and the combined organic layers were dried using MgSO4. The solvent was removed under reduced pressure and the crude al was purified using flash chromatography (hexanes / EtOAc). 560 mg (90 %) of compound 407 was isolated as a mixture of two anomers. LC/MS = 567.2 (M + H+). 1H NMR (300 MHz, CDCl 3): δ 7.85 (m, 1H), 7.27 (m, 15H), 7.01 (m, 1H), 6.51 (m, 1H), 4.66 (m, 8H), 4.40 (m, 2H), 3.79 (m, 3H), 1.62 (s, 2’-CH3 from the one anomer), 1.18 (s, 2’-CH3 from the other anomer). g. Preparation of Compound 408.
NH2 NH2 N N O O N O O N Bn N TMSCN, BF3-Et2O Bn N OH CN O O O O Bn Bn Bn Bn 407 408 To a solution of Compound 407 (1 g, 1.77 mmol) in CH2Cl2 (20 mL) at 0o C was added TMSCN (1.4 mL, 10.5 mmol) and BF3-Et2O (1 mL, 8.1 mmol). The on mixture was stirred at 0 oC for 0.5 hours, then at room temperature for additional 0.5 hour. The reaction was quenched with NaHCO3 at 0 oC, and diluted with CH 3CO2Et. The organic phase was ted, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel, eluted with CH3CO2Et-hexanes (1:1 to 2:1), to give compound 408 (620 mg, 61%) as an isomeric mixture. MS = 576.1 (M + H+). h. Preparation of Compound 409.
NH2 NH2 O N O N HO BCl3 O N Bn N N CN CN O O HO OH Bn Bn 408 409 To a solution of compound 408 (150 mg, 0.26 mmol) in CH2Cl2 (4 mL) at -78 oC was added BCl3 (2 mL, 1M in ). The reaction mixture was stirred at -78 oC for 1 hour. The reaction was quenched at -78 oC by dropwise on of TEA (2 mL) and MeOH (5 mL). The mixture was allowed to warm up to room temperature, evaporated, and co-evaporated with MeOH several times. The residue was treated with NaHCO3 (1 g in 10 mL H2O), trated and purified by HPLC to give the desired product compound 409 (48 mg, 60%). 1H NMR (300 MHz, D2O): δ 7.74 (s 1H), 6.76 (d, J = 5 Hz, 1H), 6.73 (d, J = 5 Hz, 1H), 4.1 (m, 1H), 3.9 (m, 1H), 3.8 (m, 2H), 0.84 (s, 3H). MS = 305.9 (M + H+). The other alpha-anomer was also obtained (9 mg, 11%): 1H NMR (300 MHz, D 2O): δ 7.70 (s 1H), 6.8 (d, J = 5 Hz, 1H), 6.7 (d, J = Hz, 1H), 4.25 (d, J = 9 Hz, 1H), 4.07 (m, 1H), 3.85 (m, 1H), 3.7 (m, 1H), 1.6 (s, 3H). MS = 306.1 (M + H+). i. ation of Compound 412.
O O .HCl Cl P Cl NH2 O O O O N P Cl 411 O H TEA / CH2Cl2 410 412 Compound 410 (commercially available, 4.99 g, 23.8 mmol) was dissolved in dichloromethane (100 mL) and alanine isopropyl ester hydrochloride 411 (3.98 g, 23.8 mmol) was added. The resulting clear solution was cooled -78 oC for 30 min. Triethylamine (6.63 mL, 47.5 mmol) was added dropwise over 15 minutes. The e was then allowed to warm to room temperature. After 16 hours, the solvent was removed by argon stream. The residue was re-dissolved in MTBE (25 mL) and the insoluble was removed by filtration under argon.
The filtrate was sed by argon stream and the crude product 412 was used for the next reaction without further purification. 1H NMR (300 MHz, CDCl 3): 7.1-7.4 (m, 5H), 5.1 (m, 1H), 4.35 (m, 1H), 4.15 (m, 1H), 1.5 (d, 3H), 1.2 (m, 6H). 31P NMR (121.4 MHz, CDCl 3): δ 7.8 and 8.4 (2s). j. Preparation of Compound 413.
NH2 NH2 N O O N HO N Compound 412 N P O N O N O H N O O CN NMI / )3 CN HO OH THF HO OH 409 413 To a solution of compound 409 (1.03 g, 3.37 mmol) in trimethyl phosphate (2.0 mL) and THF (20 mL) was added N-methyl imidazole (1.5 g, 18.3 mmol) at 0 oC. A solution of compound 412 (2.5 g, 8.18 mmol) in THF (3 mL) was dropwise added. The resulting mixture was allowed to warm to room temperature over 1.5 hours. The e was partitioned between ethyl acetate and water. The ethyl acetate layer was trated and the e was purified by silica gel chromatography (ethyl acetate to 10% ethanol / ethyl acetate), affording 1.15 g (59%) of compound 413 as 1:1 reomeric mixture at orous. 1H NMR (300 MHz, CDCl3): δ 8.02 (s, 1H), 7.1-7.4 (m, 5H), 6.8 (2d, 1H), 6.7 (2d, 1H), 6.08 (brs, 2H), 5.03 (m, 1H), 4.6 (m, 1H), 4.4 (m, 2H), 3.9-4.1 (m, 3H), 1.31 (d, 3H), 1.2 (m, 6H), 0.83 (s, 3H). 31P NMR (121.4 MHz, CDCl 3): δ 2.78 (s). MS = 575.1 (M + H+). k. Preparation of Compound 414.
O O N O O N N P O N N P O O H N N O O O H O N O CN O OH HO OH 413 414 To a solution of compound 413 (175 mg, 0.305 mmol) in acetonitrile (2 mL) was added N,N-dimethylformamide dimethyl acetal (41 µL, 0.34 mmol, 1.1 eq.) and stirred at room temperature for 1 hour. The reaction was complete (by LCMS). The mixture was then concentrated to dryness. To the residue were added DCC (250 mg, 1.21 mmol, 4 eq.), acetonitrile (5 mL) and isobutyric acid (55 mg, 58 µL, 2 eq.). The mixture was stirred at room temperature for 48 hours. Water (0.2 mL) and trifluoroacetic acid (0.1 mL) were added at 0 oC and stirred at room temperature for 64 hours. Sodium bicarbonate (500 mg) was added at 0 oC. The mixture was stirred at room temperature for 0.5 hour and ed. The filtrate was concentrated and the residue was purified by silica gel column chromatography (5% methanol / dichloromethane), affording 144 mg (73%) of compound 414 as 1:1 diastereomeric mixture at phosphorus. 1H NMR (300 MHz, CDCl 3): δ 8.00 (s, 1H), 4 (m, 5H), 6.83 (d, 1H), 6.71 (2d, 1H), 5.97 (brs, 2H), 5.94 (d, 1H), 5.07 (2d, 1H), 5.01 (m, 1H), 4.68 (m, 1H), 4.4 (m, 2H), 4.0 (m, 2H), 2.74 (m, 1H), 1.4 (2d, 3H), 1.2-1.3 (12H), 0.98 and 0.99 (2s, 3H). 31P NMR (121.4 MHz, CDCl3): δ 2.56 and 2.65 (2s). MS = 645.1 (M + H+).
Compound 5 can be prepared as bed in the following Example.
Example 5: Preparation of 5: 5-(3,3-dimethylbutynyl)[(cishydroxy{[(3S)- ydrofuranyloxy]methyl}cyclohexyl){[(1R)methylcyclohexen yl]carbonyl}amino]thiophenecarboxylic acid 5.
O S S HO OMe O 509 OH O N O N O 508 5 5-(3,3-dimethyl-butynyl)[((1R)methyl-cyclohexenecarbonyl)-(1-oxaspiro [2.5]octyl)-amino]-thiophenecarboxylic acid methyl ester 508 (132 mg, 0.28 mmol) and (S)-tetrahydro-furanol 509 (247 mg, 2.8 mmol) in 1-methyl-pyrrolidinone (3 mL) were treated with potassium tert-butoxide (251 mg, 2.24 mmol) , sealed at heated to 40 °C for 16 hours. After g the mixture was treated with 2 M HCl until pH 3, partitioned between ethyl acetate and water and separated. The organic layer was washed with 5% lithium chloride solution, water, brine, and dried over sodium sulfate. After tion and concentration the residue was purified by HPLC with CH3CN (0.1% TFA)/H2O(0.1% TFA) to afford 107 mg (70% yield) of compound 5 as a white powder: MS (m/z): 544.0 [M+H]+; HPLC retention time 4.22 min (2-98% acetonitrile: water with 0.05% trifluoroacetic acid).
The intermediate compound 508 was prepared as follows. a. Preparation of Compound 502.
(S)hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (2.60 g, 20 mmol) and diisopropylethylamine (5.2 mL, 30 mmol) in romethane (25 mL) was cooled to -10 °C and treated dropwise with acryloyl chloride (2.03 mL, 25 mmol) and stirred for 2 h. 1M HCl (20 mL) was added and the organic layer was washed with sodium bicarbonate and water. The organic layer was dried over sodium sulfate, filtered and concentrated. Flash chromatography (10-40% EtOAc, hexanes) ed 2.09 g (57% yield) of the desired (S)-4,4-dimethyl oxotetrahydrofuranyl acrylate 501 as a clear oil.
(S)-4,4-dimethyloxotetrahydrofuranyl acrylate 501 (2.05 g, 11.1 mmol) in dichloromethane (17.5 mL) and hexanes (2.5 mL) was cooled to -10 °C and treated with titanium tetrachloride (2.2 mL, 1 M in dichloromethane, 2.2 mmol). The yellow solution was d for 15 minutes and treated with isoprene (1.67 mL, 16.7 mmol) dropwise over 5 minutes.
After stirring for 2 hours, an additional portion of isoprene (1.67 mL, 16.7 mmol) was added and the reaction mixture was stirred at -10 to 0 °C for 3.5 hours. The reaction mixture was quenched with um chloride (sat. aq.). Water and ethyl acetate: hexanes (1:1) were added. The organic layer was ted and the aqueous layer was extracted again with ethyl acetate:hexanes (1:1). The ed organic layers were dried over sodium sulfate, filtered and concentrated. The e was purified by flash chromatography (10-50% EtOAc:Hex, 80 g column) to afford 1.30 g (46% yield) of (R)-((S)-4,4-dimethyloxotetrahydrofuranyl) 4- methylcyclohexenecarboxylate 502 as a clear oil. b. Preparation of Compound 503.
(R)-((S)-4,4-dimethyloxotetrahydrofuranyl) 4-methylcyclohexenecarboxylate 502 (1.30 g, 5.15 mmol) in THF (10 mL), water (1 mL) and methanol (1 mL) was treated with lithium hydroxide monohydrate (2.16 g, 51.5 mmol) and warmed to 50 °C with stirring. After 1hour, the reaction e treated with 1M HCl. The mixture was extracted with hexanes:THF (10:1), dried over sodium sulfate, filtered and concentrated to 0.738 g (quantitative yield) of (R) methylcyclohexenecarboxylic acid 503 as a white powder. c. Preparation of Compound 504.
(R)methylcyclohexenecarboxylic acid 503 (371 mg, 2.65 mmol), opically dried by evaporation from toluene, was treated with potassium phosphate tribasic (1.13 g, 7.94 mmol), suspended in dichloromethane (7.6 mL) and treated with dimethylformamide (4 drops).
The reaction mixture was cooled to 0 °C and treated dropwise with oxalyl chloride (0.75 mL, 7.9 mmol). The reaction mixture was allowed to warm to ambient temperature while stirring for 2 hours. After filtering the solids, the solution was concentrated, treated with hexanes and concentrated again to afford (R)methylcyclohexenecarbonyl chloride 504 as a light yellow oil which was used immediately in the next step. d. Preparation of Compound 506.
(R)methylcyclohexenecarbonyl chloride 504 (2.65 mmol), 5-(3,3-dimethyl-but ynyl)(1,4-dioxa-spiro[4.5]decylamino)-thiophenecarboxylic acid methyl ester 505 (250 mg, 0.66 mmol) and potassium ate tribasic (562 mg, 2.65 mmol) were suspended in dichloroethane (1.7 mL), sealed with a cap and heated to 90 °C. After 16 hours, the reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous extracted again with ethyl e. The combined organic layers were dried over sodium e, filtered and concentrated. Flash chromatography (10-40% Hexanes) afforded 220 mg (67% yield) of the desired 5-(3,3-dimethyl-butynyl)[(1,4- dioxa-spiro[4.5]decyl)-((1R)methyl-cyclohexenecarbonyl)-amino]-thiophene carboxylic acid methyl ester 506 as a beige foam. e. Preparation of Compound 507.
-Dimethyl-butynyl)[(1,4-dioxa-spiro[4.5]decyl)-((1R)methyl-cyclohex enecarbonyl)-amino]-thiophenecarboxylic acid methyl ester 506 (219 mg, 0.438 mmol) was dissolved in THF (3.5 mL) and d with 4M HCl (1.75 mL, 7.01 mmol). The reaction mixture was heated to 45 °C and stirred 2 h. Ethyl acetate was added and the organic layer was separated then washed with water, sodium bicarbonate (sat aq), water, and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to 0.190 g (95% yield) of the desired 5-(3,3-dimethyl-butynyl)[((1R)methyl-cyclohexenecarbonyl)-(4-oxocyclohexyl )-amino]-thiophenecarboxylic acid methyl ester 507 as a white foam. f. ation of Compound 508.
Trimethylsulfoxonium chloride (79 mg, 0.62 mmol) in DMSO (1.5 mL) was treated with sodium e (21 mg, 60% oil dispersion, 0.53 mmol) and stirred at ambient temperature for min. -Dimethyl-butynyl)[((1R)methyl-cyclohexenecarbonyl)-(4-oxo- cyclohexyl)-amino]-thiophenecarboxylic acid methyl ester 507 in THF (1 mL + 0.5 mL) was added se and the reaction mixture was stirred for 45 min. The orange solution was treated with 5% citric acid until pH 3 and partitioned between water and ethyl acetate. The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organics were washed with 5% LiCl, water and brine, and dried over sodium sulfate.
After filtration and concentration, the residue was purified by flash chromatography (20-75% EtOAc:hexanes) to afford 0.134 g (70% yield) of 5-(3,3-dimethyl-butynyl)[((1R)methylcyclohexenecarbonyl )-(1-oxa-spiro[2.5]octyl)-amino]-thiophenecarboxylic acid methyl ester 508 as a white powder.
Compound 6, Can be prepared using synthetic s and intermediates like those described in USSN 12/779,023 (US 20100310512 A1). Compound 6, Can also be prepared as described in the following Example.
Example 6: Preparation of (1-{3-[6-(9,9-Difluoro{2-[5-(2-methoxycarbonylaminomethylbutyryl a-spiro[2.4]heptyl]-3H-imidazolyl}-9H-fluorenyl)-1H- benzoimidazolyl]aza-bicyclo[2.2.1]heptanecarbonyl}methyl-propyl)- carbamic acid methyl ester 6. 1. HCl Dioxane / DCM 2. HATU, DIEA, DMF N O F F H H O NH N OH N O N N H 611 O 614 O HN O O 3-[6-(9,9-Difluoro{2-[5-(2-methoxycarbonylaminomethyl-butyryl)azaspiro [2.4]heptyl]-3H-imidazolyl}-9H-fluorenyl)-1H-benzoimidazolyl]azabicyclo [2.2.1]heptanecarboxylic acid tert-butyl ester 614 (115 mg, 0.138 mmol) was dissolved in methylene chloride (2 mL) and HCl in dioxane (4M, 2 mL) was added and stirring at room temperature was continued. After 20 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.5 mL) and DIEA (53.4 mg, 0.414 mmol) was added. A solution of 2- (L) Methoxycarbonylaminomethyl-butyric acid 611 (24.2 mg, 0.138 mmol), HATU (52.4 mg, 0.138 mmol) and DIEA (17.8 mg, 0.138 mmol) in DMF (1 mL) was added. The reaction was d at room ature. After 20 s, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, s LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by RP-HPLC (eluent: water / MeCN w/ 0.1% TFA) to yield nd 6 (76 mg).
LCMS-ESI+: calc’d for C49H54F2N8O6: 888.9 (M +); Found: 890.0 (M+H+). 1H-NMR: 300 MHz, (dmso-d6) δ: 8.20-7.99 (m, 8H), 7.73 (s, 2H), 7.37 – 7.27 (m, 2H), 5.25 (dd, J = 7.2 Hz, 1H), 4.78 (s, 1H) 4.54 (s, 1H), 4.16 (m, 1H), 4.02 (m, 1H), 3.87 (m,1H), 3.74 (m, 1H), 3.55 (s, 3H), 3.53 (s, 3H), 2.75 (m, 1H), 2.25 (m, 2H), 2.09 – 2.04 (m, 2H), 1.88 – 1.79 (m, 2H), 1.54 (m, 1H), 0.94 - 0.77 (m, 15H) 0.63 (m, 4H) ppm. 19F-NMR: 282 MHz, (dmso-d 6) δ: -109.1 ppm [- 74.8 ppm TFA].
The intermediate compound 614 was prepared as follows.
Bo c Cbz Cbz Cbz N 1. HCl, MeOH Et2Zn, TFA, 2. Cbz-Cl, NMM N CH2I2 N N CO2Me CO2Me CO2Me CO2H DCM + 604 601 602 NMO, OsO4 THF/H2O/acetone Cbz LiOH, Cbz THF, MeOH, H2O N N N CO2Me CO2H CO2Me + 606 603 OH a. Preparation of compound 4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester 602. 4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 601 (10.0 g, 44 mmol) was dissolved in MeOH (75 mL) at room temperature and HCl (4M in dioxane, 75 mL) was added. ng at room temperature was continued for 4 hours. All volatiles were removed in vacuo and a beige solid was obtained. The crude material was suspended in methylene chloride (100 mL) and N-Methyl morpholine (13.3 g, 132 mmol) was added. The mixture was cooled to 0 °C and benzyl chloroformate (8.26 g, 48.4 mmol) was added while stirring. After 30 minutes, the on was warmed to room temperature and the solution was washed with water and aqueous HCl (1M). The solution was dried over sodium sulfate. Filtration and ation of solvents gave crude product, which was purified by silica gel chromatography (eluent: EtOAc / hexanes) to yield compound 602 (10.2 g). LCMS-ESI+: calc’d for C15H17NO4: 275.3 (M +); Found: 276.4 (M+H+). b. ation of a mixture of Compounds 603 and 604.
An oven-dried 3-neck round bottom flask was equipped with a nitrogen inlet r and a 250 mL on funnel. The third neck was sealed with a septum. The flask was charged with a stir bar, dichlorormethane (120 mL) and diethyl zinc (1.0 M in hexane, 118 mL, 118 mmol) then cooled to 0 ˚C in an ice bath. The addition funned was charged with dichloromethane (40 mL) and trifluoroacetic acid (9.1 mL, 118 mmol). After the diethyl zinc solution had cooled to 0 ˚C (about 25 minutes), the trifluoroacetic acid on was added dropwise over 20 min to the stirred reaction mixture. After ng for another 20 min at 0 ˚C, diiodomethane (9.5 mL, 118 mmol) was added slowly over 4 minutes. After another 20 min, 4- methylene-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester 602 (8.10 g, 29.4 mmol) was added in 30 mL dichloromethane by cannula. The flask containing 4-methylenepyrrolidine-1 ,2-dicarboxylic acid 1-benzyl ester 2-methyl ester was then rinsed with r 10 mL dichloromethane and this solution was also transferred to the reaction mixture by cannula.
The reaction mixture was allowed to warm to RT and stirred for 110 h (about 5 days) after which the reagents were quenched with saturated aqueous ammonium chloride (~150 mL).
The contents of the flask were slowly poured into a 2 L sep funnel containing saturated aqueous sodium onate (800 mL). The aqueous phase was extracted three times with 300 mL ethyl acetate. The combined organics were dried over magnesium sulfate and concentrated to provide a e of Compounds 603 and 604. c. Preparation of a Compound 603.
The crude material from sub-part b was dissolved in 3:1:1 ter/acetone (165 mL) then treated with N-methylmorpholine-N-oxide (3.45 g, 29.4 mmol) and osmium tetroxide (4 wt% in water, 5 mL, 0.818 mmol). After stirring at RT for 7 h, the reagents were quenched with 1 M aqueous sodium thiosulfate (~100 mL). The contents of the flask were then poured into a 1 L sep funnel containing water (~300 mL). The aqueous phase was extracted three times with 300 mL dichloromethane. The combined cs were dried over magnesium sulfate and concentrated. The crude residue was ed by silica column tography (5% to 45% EtOAc/hexane) to provide 5-aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester 6- methyl ester 603 as a clear oil (5.54g, 19.15 mmol, 65%) as a clear oil. 1H NMR (CDCl 3) δ 7.36-7.29 (m, 5H), 5.21-5.04 (m, 2H), 4.56-4.47 (m, 1H), 3.75 (s, 1.5H), 3.60 (m, 1.5H), 03.51- 3.37 (m, 2H), 2.32-2.25 (m, 1H), 1.87-1.80 (m, 1H), 0.64-0.51 (m, 4H). d. Preparation of 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester 606.
-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester 6-methyl ester 603 (244 mg, 0.840 mmol) was dissolved in THF (2.0 mL) / MeOH (1.5 mL). An aqueous solution of LiOH (35.5 mg, 0.84 mmol) was added and stirring at room temperature was continued. After 3 hours, the on was neutralized with aqueous HCl (1M) and the organic solvents were removed in vacuo. The crude mixture was diluted with water and EtOAc and the organic layer was collected. All volatiles were removed in vacuo and the crude acid 606 was used without further purification. SI+: calc’d for C15H17NO4: 275.3 (M +); Found: 276.3 (M+H+).
O F F 1. 3)4 (2.5%), SnBu3 OEt PdCl2(PPh3)2 (2.5%) deoxofluor Dioxane 80 oC 3h Br Br Br Br 2. NBS (1x) H2O 607 608 3. N-Cbzcyclopropyl (L) Proline 606, DIEA, DMF, MeCN, rt Cbz Cbz N F F N F F O O NH4OAc, m-Xyl, N Br Br O N 609 610 1. HBr / HOAc O 2. HATU, DIEA, DMF N F F OH N O F F O N H 611 H N O NH Br Br N N 610 612 O N B N N O F F H H O O O N 613 NH N N Boc Pd(PPh3)4 (10%), 614 K2CO3 (3x) DME / H2O e. Preparation of a 2,7-Dibromo-9,9-difluoro-9H-fluorene 608. 2,7-Dibromo-fluorenone 607 (4.0 g, 11.8 mmol) was ded in deoxofluor (12 mL) at room temperature and EtOH (4 drops) was added. The stirred sion was heated at T = 90° C for 24 hours (CAUTION: Use of deoxofluor at elevated temperatures, as described above, is cautioned as rapid and violent exotherms may occur). The reaction was cooled to room temperature and poured onto ice containing sodium bicarbonate. A solid formed and was collected via filtration. The crude material was taken into EtOAc and was washed with aqueous HCl (1M) and brine. The solution was dried over sodium e. Filtration and evaporation of solvents gave crude product, which was purified by silica gel chromatography (eluent: EtOAc / hexanes) to yield 608 (3.2 g). 19F-NMR: 282 MHz, (dmso-d δ: -111.6 ppm. Before using the al in the next step, it was exposed as a on in EtOAc to al. f. Preparation of 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester 6-[2-(7- bromo-9,9-difluoro-9H-fluorenyl)oxo-ethyl] ester 609. 2,7-Dibromo-9,9-difluoro-9H-fluorene 608 (372 mg, 1.04 mmol), Pd(PPh3)4 (30.0 mg, 0.026 mmol), PdCl2(PPh3)2 (18.2 mg, 0.026 mmol), As(PPh3)3 (5.0 mg) were dissolved in dioxane (10 mL) under an argon atmosphere. Ethoxyvinyl-tributyl tin (376.4 mg, 1.04 mmol) was added. The mixture was heated for 140 minutes at 85 °C (oil bath). The reaction was cooled to room temperature. N-bromo succinimide (177 mg, 1.0 mmol) was added followed by water (2 mL). The reaction was d at room temperature for 3 hours, after which the majority of the dioxane was removed in vacuo. The crude reaction mixture was d with EtOAc and was washed with water. All volatiles were removed in vacuo. Toluene was added and all volatiles were removed in vacuo for a second time. The crude material was dissolved in DMF / MeCN (2 mL, 1:1) at room temperature. A solution of N-Cbzcyclopropyl (L) proline 606 (0.84 mmol) and DIEA (268 mg, 2.08 mmol) in MeCN (2 mL) was added and stirring at room temperature was continued. After 14 hours, most of the MeCN was removed in vacuo and the crude reaction mixture was diluted with EtOAc. The mixture was washed with aqueous HCl (1M), aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and evaporation of ts gave the crude on product, which was purified via silica gel chromatography t: EtOAc / hexanes) to yield compound 609 (176 mg). LCMS-ESI+: calc’d for C30H24BrF2NO5: 596.4 (M +); Found: 595.
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