ZA200603610B - Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of HCV replication - Google Patents
Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of HCV replication Download PDFInfo
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- ZA200603610B ZA200603610B ZA200603610A ZA200603610A ZA200603610B ZA 200603610 B ZA200603610 B ZA 200603610B ZA 200603610 A ZA200603610 A ZA 200603610A ZA 200603610 A ZA200603610 A ZA 200603610A ZA 200603610 B ZA200603610 B ZA 200603610B
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- alkyl
- optionally substituted
- hydroxy
- alkoxy
- cycloalkyl
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Description
MACROCYCLIC CARBOXYLIC ACIDS AND ACYLSULFONAMIDES
AS INHIBITORS OF HCV REPLICATION
[0001] The present invention relates to compounds, processes for their synthesis, compositions and methods for the treatment of hepatitis C virus (HCV) infection. In particular, the present invention provides novel peptides analogs, pharmaceutical compositions containing such analogs and methods for using these analogs in the treatment of HCV infection.
[0002] Hepatitis C virus (HCV) infection is the most common chronic. blood borne infection in the United States. Although the numbers of new infections have declined, the burden of chronic infection is substantial, with Centers for Disease Control estimates of 3.9 million (1.8%) infected persons in the United States. Chronic liver disease is the tenth leading cause of: death among adults in the United States, and accounts for approximately 25,000 deaths annually, or approximately 1% of all deaths. Studies indicate that 40% of chronic liver disease is HCV-related, resulting in an estimated 8,000-10,000 deaths each year. HCV-associated end- stage liver disease is the most frequent indication for liver transplantation among adults.
[0003] Antiviral therapy of chronic hepatitis C has evolved rapidly over the last decade, with significant improvements seen in the efficacy of treatment. Nevertheless, even with combination therapy using pegylated IFN-a plus ribavirin, 40% to 50% of patients fail therapy, i.e., are nonresponders or relapsers. These patients currently have no effective therapeutic alternative. In particular, patients who have advanced fibrosis or cirrhosis on liver biopsy are at significant risk of developing complications of advanced liver disease, including ascites, jaundice, variceal bleeding, encephalopathy, and progressive liver failure, as wellasa markedly increased risk of hepatocellular carcinoma.
[0004] The high prevalence of chronic HCV infection has important public health implications for the future burden of chronic liver disease in the United States. Data derived from the
National Health and Nutrition Examination Survey (NHANES III) indicate that a large increase in the rate of new HCV infections occurred from the late 1960s to the early 1980s, particularly among persons between 20 to 40 years of age. It is estimated that the number of persons with long-standing HCV infection of 20 years or longer could more than quadruple from 1990 to 2015, from 750,000 to over 3 million. The proportional increase in persons infected for 30 or 40 years would be even greater. Since the risk of HCV-related chronic liver - disease is related to the duration of infection, with the risk of cirrhosis progressively increasing for persons infected for longer than 20 years, this will result in a substantial increase in cirrhosis-related morbidity and mortality among patients infected between the years of 1965- 198s.
[0005] HCV is an enveloped positive strand RNA virus in the Flaviviridae family. The single strand HCV RNA genome is approximately 9500 nucleotides in lingth and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In : infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins of the virus. In the case of HCV, the generation of mature nonstructural proteins (NS2, NS3, NS4, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. The first viral protease cleaves at the NS2-NS3 junction of the polyprotein. The second viral protease is serine protease contained within the N-terminal region of NS3 (herein referred to as “NS3 protease”). NS3 protease mediates all of the subsequent cleavage events at sites downstream relative to the position of NS3 in the polyprotein (i.e., sites located between the C-terminus of NS3 and the C-terminus of the polyprotein). NS3 protease exhibits activity both in cis, at the NS3-NS4 cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NSSA, and NS5A-NSSB sites. The NS4A protein is believed to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components.
Apparently, the formation of the complex between NS3 and NS4A is necessary for NS3- : mediated processing events and enhances proteolytic efficiency at all sites recognized by NS3.
The NS3 protease also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B is an RNA-dependent RNA polymerase involved in the replication of HCV RNA.
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[0007] Included in the scope of the invention are compounds of the formula I:
Re jE «il
Re eK 2=(
X
RZ 1a 12! 1
CY
@) : wherein: (a) R! is each independently H, halo, cyano, nitro, hydroxy, C,.s alkyl, C37 cycloalkyl, C4.10 alkylcycloalkyl, Cy.6 alkenyl, Cy.¢ alkoxy, hydroxy-Ci.¢ alkyl, Ci. alkyl optionally substituted with up to 5 fluoro, C,.¢ alkoxy optionally substituted with up to 5 fluoro, Cg or aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy,
SO,NR°R®, NHC(O)R’, NHC(O)NR’R®, NHC(S)NR RS, NR°R®, C(O)R®, C(O)OR?,
C(O)NR®R?, SO,R®, NHSO,R?; said thienyl, pyrimidal, furanyl, thiazolyl and oxazolyl in the definition of R™ and R' are optionally substituted by up to two halo, cyano, nitro, hydroxy, Ci alkyl, C37 cycloalkyl, C410 alkylcycloalkyl, Ca. alkenyl, C,. alkoxy, hydroxy-C,.¢ alkyl, C;.s alkyl optionally substituted with up to 5 fluoro, C,4 alkoxy optionally substituted with up to 5 fluoro; said Cg « 10 aryl, pyridal, phenoxy and thiophenoxy in the definition of R* are optionally substituted by up to three halo, cyano, nitro, hydroxy, Cis alkyl, C;.7 cycloalkyl, Cs.19 alkylcycloalkyl, C;. alkenyl, C,.¢ alkoxy, hydroxy-Cj.¢ alkyl, C,.¢ alkyl optionally substituted with up to 5 fluoro, C;.¢ alkoxy optionally substituted with up to 5 fluoro; (b) R? is H, C6 alkyl, Cs.7 cycloalkyl, C4.19 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C, alkyl, Cs.7 cycloalkyl, Cs.10 alkylcycloalkyl, Cy. alkenyl, C1. alkoxy, hydroxy-C.¢ alkyl, Cy.¢ alkyl optionally substituted with up to 5 fluoro, C,.¢ alkoxy optionally substituted with up to 5 fluoro; BN (c) Ris H, Cy alkyl, -C(O)R®, C(O)OR®, C(O)NR’R’, C(S)NR’R?, S(0),R5,;
(d) R® and R® are each independently H, Ci. alkyl, Cs; cycloalkyl, C10 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Ci-s alkyl, Cs.; cycloalkyl, C419 alkylcycloalkyl, Ca. alkenyl, hydroxy-Ci. alkyl, Ci. alkyl optionally substituted with up to 5 fluoro, Cy. alkoxy optionally substituted with up to 5 fluoro; (e) Y is a sulfonimide of the formula ~C(O)NHS(O)R®, where R* is Cy.6 alkyl, C37 cycloalkyl, C410 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C.¢ alkoxy, amido or phenyl, or R* is Cg or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Cis alkyl, C37 cycloalkyl,
Ca.10 alkylcycloalkyl, C,.¢ alkenyl, Cy alkoxy, hydroxy-Ci.¢ alkyl, Ci.6 alkyl optionally substituted with up to 5 fluoro, C). alkoxy optionally substituted with up to 5 fluoro; or Y is a carboxylic acid or pharmaceutically acceptable salt or ester thereof; ~~ (® m=0,1,0r2; (g) X=0,NH or NR; and h)Z=0orS.
[0008] Included within the scope of the invention isa pharmaceutical composition comprising an NS3 inhibitor that is a compound of formula I (e.g., formulas I-VII), or a therapeutically acceptable salt or ester thereof, in admixture with pharmaceutically acceptable carrier. Also included is any pharmaceutically acceptable prodrug derivative of a compound of formula I (e.g., formulas I-VII), where the prodrug is capable of providing increased gastrointestinal or liver absorption.
[0009] Also provided is a method of treating a patient having a hepatitis C viral infection, comprising administering to the patient a therapeutically effective amount of a compound of formula I, or a therapeutically acceptable salt or ester thereof, or a phanmaceutical composition as described above.
[0010] Further provided is a method of treating a patient having a hepatitis C viral infection, comprising administering to the patient an amount of a compound of formula I, or a therapeutically acceptable salt or ester thereof, or a pharmaceutical composition comprising the compound of formula I, in combination with an amount of one or more additional antiviral agent(s), effective to achieve a sustained viral response in the patient.
[0011] As used herein, the term “hepatic fibrosis,” used interchangeably herein with “liver fibrosis,” refers to the growth of scar tissue in the liver that can occur in the context of a chronic hepatitis infection.
[0012] The terms “individual,” “host,” “subject,” and “patient” are used interchangeably herein, and refer to a mammal, including, but not limited to, primates, including simians and humans.
[0013] As used herein, the term “liver function” refers to a normal function of the liver, . including, but not limited to, a synthetic function, including, but not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5’-nucleosidase, y- glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.
[0014] The term “sustained viral response” (SVR; also referred to as a “sustained response” or a “durable response”), as used herein, refers to the response of an individual to a treatment regimen for HCV infection, in terms of serum HCV titer. Generally, a “sustained viral response” refers to no detectable HCV RNA (e.g., less than about 500, less than about 200, or less than about 100 genome copies per milliliter serum) found in the patient’s serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of treatment.
[0015] "Treatment failure patients" as used herein generally refers to HCV-infected patients who failed to respond to previous therapy for HCV (referred to as "non-responders") or who initially responded to previous therapy, but in whom the therapeutic response was not maintained (referred to as "relapsers"). The previous therapy generally can include treatment with IFN-a monotherapy or IFN-a combination therapy, where the combination therapy may include administration of IFN-o and an antiviral agent such as ribavirin.
[0016] As used herein, the terms “treatment,” “treating,” and the like, refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in : terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease. “Treatment,” as used herein, covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.€., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease.
[0017] The terms “individual,” “host,” “subject,” and “patient” are used interchangeably herein, and refer to a mammal, including, but not limited to, murines, simians, humans, mammalian farm animals, mammalian sport animals, and mammalian pets.
[0018] A “specific pirfenidone analog,” and all grammatical variants thereof, refers to, and is limited to, each and every pirfenidone analog shown in Table 1.
[0019] As used herein, the term “a Type I interferon receptor agonist” refers to any naturally occurring or non-naturally occurring ligand of human Type I interferon receptor, which binds : to and causes signal transduction via the receptor. Type I interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like.
[0020] As used herein, the term “Type II interferon receptor agonist” refers to any naturally occurring or non-naturally occurring ligand of human Type II interferon receptor that binds to and causes signal transduction via the receptor. Type II interferon receptor agonists include native human interferon-y, recombinant IFNy species, glycosylated IFN-y species, pegylated
IFN-y species, modified or variant IFN-y species, IFN-y fusion proteins, antibody agonists specific for the receptor, non-peptide agonists, and the like.
[0021] As used herein, the term “a Type III interferon receptor agonist” refers to any naturally occurring or non-naturally occurring ligand of humanlL-28 receptor a (“IL-28R”), the amino acid sequence of which is described by Sheppard, et al., infra., that binds to and causes signal - transduction via the receptor.
[0022] As used herein, the term “interferon receptor agonist” refers to any Type I interferon receptor agonist, Type II interferon receptor agonist, or Type Ill interferon receptor agonist.
[0023] The term "dosing event" as used herein refers to administration of an antiviral agent to a patient in need thereof, which event may encompass one or more releases of an antiviral agent from a drug dispensing device. Thus, the term “dosing event,” as used herein, includes, but is not limited to, installation of a continuous delivery device (e.g., a pump or other controlled release injectible system); and a single subcutaneous injection followed by installation of a continuous delivery system.
[0024] "Continuous delivery" as used herein (e.g., in the context of "continuous delivery ofa substance to a tissue") is meant to refer to movement of drug to a delivery site, e.g., into a tissue in a fashion that provides for delivery of a desired amount of substance into the tissue over a selected period of time, where about the same quantity of drug is received by the patient each minute during the selected period of time.
[0025] "Controlled release" as used herein (e.g., in the context of "controlled drug release") is meant to encompass release of substance (e.g., a Type I or Type III interferon receptor agonist, e.g., IFN-a) at a selected or otherwise controllable rate, interval, and/or amount, which is not substantially influenced by the environment of use. "Controlled release" thus encompasses, but is not necessarily limited to, substantially continuous delivery, and patterned delivery (e.g, intermittent delivery over a period of time that is interrupted by regular or irregular time intervals).
[0026] "Patterned" or "temporal" as used in the context of drug delivery is meant delivery of drug in a pattern, generally a substantially regular pattern, over a pre-selected period of time (e.g., other than a period associated with, for example a bolus injection). "Patterned" or "temporal" drug delivery is meant to encompass delivery of drug at an increasing, decreasing, substantially constant, or pulsatile, rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation for a unit time), and further encompasses delivery that is continuous or substantially continuous, or chronic."
[0027] The term "controlled drug delivery device" is meant to encompass any device wherein the release (e.g., rate, timing of release) of a drug or other desired substance contained therein is controlled by or determined by the device itself and not substantially influenced by the environment of use, or releasing at a rate that is reproducible within the environment of use.
[0028] By "substantially continuous" as used in, for example, the context of "substantially continuous infusion" or "substantially continuous delivery” is meant to refer to delivery of drug in a manner that is substantially uninterrupted for a pre-selected period of drug delivery, where the quantity of drug received by the patient during any 8 hour interval in the pre-selected : period never falls to zero. Furthermore, "substantially continuous” drug delivery can also encompass delivery of drug at a substantially constant, pre-selected rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation for a unit time) that is substantially uninterrupted for a pre-selected period of drug delivery.
[0029] By “substantially steady state” as used in the context of a biological parameter that may vary as a function of time, it is meant that the biological parameter exhibits a substantially constant value over a time course, such that the area under the curve defined by the value of the biological parameter as a function of time for any 8 hour period during the time course (AUCS8hr) is no more than about 20% above or about 20% below, and preferably no more than about 15% above or about 15% below, and more preferably no more than about 10% above or about 10% below, the average area under the curve of the biological parameter over an 8 hour period during the time course (AUC8hr average). The AUCS8hr average is defined as the quotient (q) of the area under the curve of the biological parameter over the entirety of the time course (AUCtotal) divided by the number of 8 hour intervals in the time course (ttotall/3days), i.e., q= (AUCtotal)/ (ttotall/3days). For example, in the context of a serum concentration of a drug, the serum concentration of the drug is maintained at a substantially steady state during a time course when the area under the curve of serum concentration of the drug over time for any 8 hour period during the time course (AUC8hr) is no more than about 20% above or about 20% below the average area under the curve of serum concentration of the drug over an 8 hour period in the time course (AUCS8hr average), i.e., the AUC8hr is no more than 20% above or 20% below the AUCShr average for the serum concentration of the drug over the time course.
[0030] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It : is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
[0031] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
[0032] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention : belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
[0033] It must be noted that as used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a method” includes a plurality of such methods and reference to “a dose” includes reference to one or more doses and equivalents thereof known to those skilled in the art, and so forth.
[0034] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.
Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
[0035] The present invention provides compounds of formula I, as well as pharmaceutical compositions and formulations comprising any compound of formula. I. A subject compound is useful for treating HCV infection and other disorders, as discussed below.
COMPOSITIONS
[0036] The present invention provides compounds having the general formula I: a
RY == = Re? w
Nagy
RR" “ge O al {oT 12 ! 13 . 1 wherein: (a) R! and R? are each independently H, halo, cyano, nitro, hydroxy, C;.¢ alkyl, C.7 cycloalkyl, Cs-10 alkyleycloalkyl, Ca alkenyl, C4 alkoxy, hydroxy-Cj alkyl, C, alkyl optionally substituted with up to 5 fluoro, C,.¢ alkoxy optionally substituted with up to 5 : fluoro, Ce or 10 aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S(O);NR’R’, NHC(O)NRR’, NHC(S)NRR’, C(O)NRR’, NR°R’, C(O)R’,
C(O)OR®, NHC(O)R®, NHC(O)OR?, SOR®, NHS(0),R?, OCH.NRR’, or OCH,R" where R'6 is imidazolyl or pyrazolyl; said thienyl, pyrimidal, furanyl, thiazolyl and oxazolyl in the definition of R! and R? are optionally substituted by up to two halo, cyano, nitro, hydroxy, Ci. alkyl, Cs.7 cycloalkyl, C419 alkylcycloalkyl, Cy.¢ alkenyl, Cy. alkoxy, hydroxy-Ci.s alkyl, C;.¢ alkyl optionally substituted with up to 5 fluoro, C;.¢ alkoxy optionally substituted with up to 5 fluoro; said Cg 10 aryl, pyridal, phenoxy and thiophenoxy in the definition of R! and R? are optionally substituted by up to three halo, cyano, nitro, hydroxy, Cy. alkyl, Cs.7 cycloalkyl, C419 alkylcycloalkyl, C,.¢ alkenyl, C16 alkoxy, hydroxy-C,. alkyl, C;.6 alkyl optionally substituted with up to 5 fluoro, C.¢ alkoxy optionally substituted with up to 5 fluoro; (b)m=0,1,0r2 (c) R*is H, C, alkyl, Cs.; cycloalkyl, Cs.10 alkylcycloalkyl phenyl or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Ci. alkyl, C3. cycloalkyl, Cs.10 alkylcycloalkyl, Ca alkenyl, Ci. alkoxy, hydroxy-Cj.¢ alkyl, C;.6 alkyl optionally substituted with up to 5 fluoro, Cs alkoxy optionally substituted with up to 5 fluoro; (d) R® is C6 alkyl, C(O)NRR’, C(S)NR’R’, C(O)R?, C(O)OR?, S(O),R?, or (CO)CHR”NH(CO)R?; (© R® and R7 are each independently H, C.¢ alkyl, C;.7 cycloalkyl, Cq4.;9 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Ci. alkyl, Cs.7 cycloalkyl, C4.19 alkylcycloalkyl, Cs.s alkenyl, hydroxy-Cj.¢ alkyl, Ci. alkyl optionally substituted with up to 5 fluoro, C,. alkoxy optionally substituted with up to 5 fluoro; or R® and R” are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyi; ® R? is C1 alkyl, C3. cycloalkyl, Cs-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Ci.¢ alkoxy, or phenyl; or R%is Cg or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Ci. alkyl, C3.7 cycloalkyl, Cs.19 alkylcycloalkyl, Cy.¢ alkenyl, C1.s alkoxy, hydroxy-Ci. alkyl,
C1. alkyl optionally substituted with up to 5 fluoro, C1. alkoxy optionally substituted with up to 5 fluoro; or R® is Cy. alkyl optionally substituted with up to 5 fluoro groups; or R3is
Claims (1)
1. A compound having the formula I, VIII, or IX: R! Ry Rr! a i” RM ” wo rR Y R12 -I= R R “R, /, ~ \ R20 ), \ TNR? TS oY N R13 N XX Le v=( R12 v=( Rr? v=( R12 w w w
1.Y J 1.Y J 1.Y RRSN : “ge O 2 RRSN ’ “8 O ue RR®N ’ “ge O a 9 H 14 ° } 14 s J 14 12 t 12 ’ 12 ' 13 13 13 11 10 11 10 1 I VII IX wherein: (a) R' and R? are each independently H, halo, cyano, nitro, hydroxy, Ci. alkyl, Cs; cycloalkyl, C410 alkylcycloalkyl, Cy alkenyl, Cy alkoxy, hydroxy-C, ¢ alkyl, Ci alkyl optionally substituted with up to 5 fluoro, C,. alkoxy optionally substituted with up to 5 fluoro, Cs or 10 aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S(O); NR®R’, NHC(O)NR®R’, NHC(S)NR®R’, C(O)NR®R’, NR°R’, C(O)R®, C(O)OR®, NHC(O)R?, NHC(O)OR?, SOR? NHS(0),R®, CH,NR®R’, OCH,NRR’, or OCH, R’ where R’is imidazolyl or pyrazolyl; said thienyl, pyrimidal, furanyl, thiazolyl and oxazolyl in the definition of R' and R? are optionally substituted by up to two halo, cyano, nitro, hydroxy, C,¢ alkyl, Cs.; cycloalkyl, C410 alkylcycloalkyl, C, alkenyl, C, alkoxy, hydroxy-C,. alkyl, C,.c alkyl optionally substituted with up to 5 fluoro, Cy.¢ alkoxy optionally substituted with up to 5 fluoro; said Cg or 10 aryl, pyridal, phenoxy and thiophenoxy in the definition of R' and R? are optionally substituted by up to three halo, cyano, nitro, hydroxy, Cs alkyl, C3; cycloalkyl, C4.10 alkylcycloalkyl, C,.6 alkenyl, C, alkoxy, hydroxy-C, ¢ alkyl, Ci alkyl optionally substituted with up to 5 fluoro, C, alkoxy optionally substituted with up to 5 fluoro; B (bym=20,1, or 2; 233 AMENDED SHEET
(c) R*is H, Cy. alkyl, Cs3.7 cycloalkyl, C410 alkylcycloalkyl phenyl or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy,
C1. alkyl, C37 cycloalkyl, Ca.10 alkylcycloalkyl, Cy. alkenyl, Ci alkoxy, hydroxy-C; alkyl, Cis alkyl optionally substituted with up to 5 fluoro, C;. alkoxy optionally substituted with up to 5 fluoro; (d) RS is Cy alkyl, C(O)NR’R’, C(S)NRR, C(O)R®, C(O)OR®, S(O),R®, or (CO)CHR*NH(CO)R; {e) R® and R are each independently H, C16 alkyl, Cs.7 cycloalkyl, Cq.10 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Ci. alkyl, Cs.; cycloalkyl, Cs.10 alkylcycloalkyl, Ca alkenyl, hydroxy-C,.¢ alkyl, Cy. alkyl optionally substituted with up to 5 fluoro, C, alkoxy optionally substituted with up to 5 fluoro; or RS and R’ are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; (fH) R® is Cy alkyl, C.7 cycloalkyl, Ca.10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Ci. alkoxy, or phenyl; or R8 is Cg or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Cy alkyl, Cs. cycloalkyl, Cs.19 alkylcycloalkyl, Cz. alkenyl, Cy alkoxy, hydroxy-Ci.s alkyl, C1. alkyl optionally substituted with up to 5 fluoro, Cy. alkoxy optionally substituted with up to 5 fluoro; or R®is Cre alkyl optionally substituted with up to 5 fluoro groups; or R38 is a tetrahydrofuran ring linked throught the Cs or C4 position of the tetrahydrofuran ring; or Risa tetrapyranyl ring linked through the C4 position of the tetrapyranyl ring; (8) Y is a sulfonimide of the formula —C(O)NHS(O)R’, where R® is Crs alkyl, Cs cycloalkyl, C410 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Ci. alkoxy, or phenyl, or R® is Cg or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Cis alkyl, C3.7 cycloalkyl, Cs.jo alkylcycloalkyl, Ca.6 alkenyl, Cy. alkoxy, hydroxy-Cy.¢ alkyl, Cy.¢ alkyl optionally substituted with up to 5 fluoro, Cy alkoxy optionally substituted with up to 5 fluoro; or R’ is a Cy alkyl optionally substituted with up to'5 fluoro groups, NR®R’, or (CO)OH, or Risa heteroaromatic ring optionally substituted up to two times with halo, cyano, nitro, hydroxyl, or C.¢ alkoxy; or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
(kb) R™? and R™ are each independently H, Cy. alkyl, C3.7 cycloalkyl, Cs10 alkylcycloalkyl, Cé or 10 aryl, hydroxy-Ci alkyl, Cy. alkyl optionally substituted with up to 5 fluoro, (CH2):NRR’, (CHy),C(O)OR™ where Ris H, Cy alkyl,
Cs. cycloalkyl, Cs.10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Ci. alkoxy, or phenyl; or Rr" is Cg or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Ci.¢ alkyl, Ca.7 cycloalkyl, Ca-10 alkylcycloalkyl, Cz.¢ alkenyl, C16 alkoxy, hydroxy-Ci. alkyl, Ci alkyl optionally substituted with up to 5 fluoro,
C1. alkoxy optionally substituted with up to 5 fluoro; said Cs or 10 aryl, in the definition of R!® and R!! is optionally substituted by up to three halo, cyano, nitro, hydroxy, Ci.s alkyl, Cs. cycloalkyl, Ca.10 alkylcycloalkyl, Ca. alkenyl, Ci.6 alkoxy, hydroxy-Ci.s alkyl, Ci.¢ alkyl optionally substituted with up to 5 fluoro,
C,.5 alkoxy optionally substituted with up to 5 fluoro; or R and R"! are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or RY and RM are combined as O; @Hp=0orl; @ R!? and R"3 are each independently H, C;.¢ alkyl, Cs. cycloalkyl, Cq10 alkylcycloalkyl, Cg or 10 aryl, hydroxy-Ci.¢ alkyl, Ci. alkyl optionally substituted with up to 5 fluoro, (CHz).NR’R’, (CH;)xC(O)OR™ where R™ is H, Cy.¢ alkyl,
Cs. cycloalkyl, C4.10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C;.¢ alkoxy, or phenyl; or RY is Cg or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1 alkyl, C3 cycloalkyl, C4.10 alkylcycloalkyl, Cy. alkenyl, Cy. alkoxy, hydroxy-C.¢ alkyl, Cy. alkyl optionally substituted with up to 5 fluoro,
C\.¢ alkoxy optionally substituted with up to 5 fluoro; said Cs or 10 aryl, in the definition of R™ and R"? is optionally substituted by up to three halo, cyano, nitro, hydroxy, C.¢ alkyl, Cs.7 cycloalkyl, Ca.10 alkylcycloalkyl, Ca alkenyl, Cg alkoxy, hydroxy-C,.s alkyl, Cy alkyl optionally substituted with up to 5 fluoro,
C1. alkoxy optionally substituted with up to 5 fluoro; or R'? and R" are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R' and RY are each independently C,_ ¢ alkyl optionally substituted with (CHz),OR®; (k) R? is H, C,.6 alkyl, Cs.7 cycloalkyl, Cs. alkylcycloalkyl, Cs or 10 aryl, hydroxy-
C1.6 alkyl, C1. alkyl optionally substituted with up to 5 fluoro, (CH) NRK’,
(CH2):C(O)OR™ where R" is H, C; alkyl, C3; cycloalkyl, Cao alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C; alkoxy, or phenyl; or R" is Ceor 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C,. alkyl, C37 cycloalkyl, C4 0 alkylcycloalkyl, C,¢ alkenyl, C, alkoxy, hydroxy-C, alkyl,
Ci. alkyl optionally substituted with up to 5 fluoro, C, alkoxy optionally substituted with up to 5 fluoro; said Cg or 10 aryl, in the definition of R'? and R"is optionally substituted by up to three halo, cyano, nitro, hydroxy, Cs alkyl, Cs.7 cycloalkyl, C410 alkylcycloalkyl, C4 alkenyl, C,. alkoxy, hydroxy-C, alkyl, Ci alkyl optionally substituted with up to 5 fluoro, C,. alkoxy optionally substituted with up to 5 fluoro; M)n=1-4; (m) V is selected from O, S, or NH; (n) when Vis O or S, W is selected from O, NR'®, or CRS; when V is NH, W is selected from NR or CR", where R'S is H, C, alkyl, C5; cycloalkyl, C410 alkylcycloalkyl or C, alkyl optionally substituted with up to 5 fluoro; (0) the dashed line represents an optional double bond; (p) R* is Cy alkyl, Cs; cycloalkyl, C419 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C;. alkoxy, C1 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R*' is Cer 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C,. 6 alkyl, C3.7 cycloalkyl, Ca. alkylcycloalkyl, Co alkenyl, C, alkoxy, hydroxy- Ci alkyl, C6 alkyl optionally substituted with up to 5 fluoro, C,¢ alkoxy optionally substituted with up to 5 fluoro; or or R* is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy; and (q) R*? is Cy. alkyl, C37 cycloalkyl, Cs.10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C,.s alkyl optionally substituted with up to 5 fluoro, or phenyl. (r) Z is a fused or appended aryl or heteroaryl ring system.
2. A compound having the formula II: 236 AMENDED SHEET
© RM iN : R =l= N o=( w 1a Pn 2. , oO 4 12 J 13 11 I wherein:
(a) R! and R? are each independently H, halo, cyano, hydroxy, C1 alkyl, C,.3 alkoxy
(b) R® is, C(O)NRR’, C(O)R?, C(O)OR?;
(9) R® and R’ are each independently H, Cy. alkyl, Cs.7 cycloalkyl, Ca-10 alkylcycloalkyl or phenyl; .
(d) R® is Cy. alkyl, C37 cycloalkyl, Cs.10 alkylcycloalkyl or 3-tetrahydofuryl.
(e) Y is a sulfonimide of the formula ~C(O)NHS(O)R’, where R’ is C13 alkyl, Cs cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, Ci; alkyl, C37 cycloalkyl, Cy; alkoxy, or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
() R™® and R" are each independently H, C3 alkyl, or R'® and R" are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
(2) W is selected from O or NH; and
(h) the dashed line represents an optional double bond.
3. A compound of the general formula III as claimed in claim 1: Rr!
JR SN N 0 v Os N 5 - “2, Id 12 / 13 1 I wherein:
(a) R" and R? are each independently H, halo, cyano, hydroxy, C,.3 alkyl, C3 alkoxy
(b) R® is, C(O)NRR’, C(O)R®, C(O)OR®;
(¢) R® is Cy alkyl, Cs; cycloalkyl, Cs.10 alkylcycloalkyl or 3-tetrahydofuryl.
(d) Y is a sulfonimide of the formula -C(O)NHS(O),R®, where R’ is C, alkyl, C3, cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, Ci; alkyl, C7 cycloalkyl, C,3 alkoxy, or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
(e) W is selected from O or NH; and
(f) the dashed line represents an optional double bond.
238 AMENDED SHEET
4. A compound having the general formula ¥V: Rr" i R10 - BD / N — w ON 1 ¥ J NH 1 NS
RS. I. < H N vg © 5 12 H
13 .
1 . Iv . wherein: (a) R! and R? are each independently H, halo, cyano, hydroxy, Ci.3 alkyl, C,.3 alkoxy (b) R® is C(0)OR® or C(O)NHR® (¢) R® is Cy. alkyl, Cs. cycloalkyl, or 3-tetrahydofuryl. (d) R’ is Cy; alkyl, C34 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, Ci.3 alkyl, C;.3 alkoxy (¢) R" and RY are each independently H, Cy alkyl, or R*® and R" are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (f) W is selected from O or NH (g) the dashed line represents an optional double bond.
5. A compound having the general formula V: Rr! y—R =x N = w O Oo a \ Ep : 9 R “w 2. , 0 J H 12 / 13 1" \Y wherein: (a) R' and R? are each independently H, halo, cyano, hydroxy, C, 3 alkyl, C,_; alkoxy (b) R® is C(O)OR® or C(O)NHR® (¢) R®is C16 alkyl, Cs cycloalkyl, or 3-tetrahydofuryl. (d) R? is C,.3 alkyl, C35 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C;.; alkyl, C;.; alkoxy (e) W is selected from O or NH (f) the dashed line represents an optional double bond.
6. A compound having the general formula VI: R! RM Ry RO —|= N o=( 2 O 00 \ A LE, 8) 9 "Sy 7 vy, 0 J H ne od ! 12 H 13 10 1" VI wherein: 240 AMENDED SHEET
(a) R! and R? are each independently H, chloro, fluoro, cyano, hydroxy, C.3 alkyl,
C;.3 alkoxy (b) R® is C(O)OR® or C(O)NHR® (©) R® is Cy.6 alkyl, Cs. cycloalkyl (d) BR? is C,.3 alkyl, C34 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C3 alkyl, C,.; alkoxy (¢) R™ and R" are each independently H, C,.; alkyl, or RY and R" are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl. (f) the dashed line represents an optional double bond.
7. A compound having the general formula VII: i» EN N = 0 aw AY oy J, 4 J NR ne \ yd ’ 12 / 0 ” 13 vi wherein: (a) R! and R? are each independently H, chloro, fluoro, cyano, hydroxy, Ci. alkyl, C3 alkoxy (b) R® is C(O)OR® or C(O)NHR® (¢) R® is Cy4 alkyl, Cs cycloalkyl (d) R’ is C13 alkyl, C34 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C,.3 alkyl, C;.3 alkoxy; and (e) the dashed line represents an optional double bond.
8. A pharmaceutical composition comprising: a) a composition of any one of claims 1-7; and N b) a pharmaceutically acceptable carrier.
9. Use of a compound of any one of claims 1 to 7 for the manufacture of a medicament for treating a hepatitis C virus infection in an individual.
10. Use of claim 9, wherein a sustained viral response is achieved.
11. Use ofa compound of any one of claims 1 to 7 for the manufacture of a medicament for treating liver fibrosis in an individual.
12. Use ofa compound of any one of claims 1 to 7 for the manufacture of a medicament for increasing liver function in an individual having a hepatitis C virus infection.
13. Use of claim 9, 11, or 12, wherein the use further comprises administering to the individual an effective amount of a nucleoside analog
14. Use of claim 13, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.
15. Use ofclaim 9, 11, or 12, wherein the use further comprises administering to the individual pirfenidone or a pirfenidone analog administered orally daily in an amount of from about 400 mg to about 3600 mg.
16. Use of claim 9, 11, or 12, wherein the use further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.
17. Use of claim 9, 11, or 12, wherein the use further comprises administering to the individual an effective amount of a tumor necrosis factor antagonist selected from the group consisting of etanercept, infliximab, and adalimumab.
18. Use of claim 9, 11, or 12, wherein the use further comprises administering to the individual an effective amount of thymosin-a. 242 AMENDED SHEET
19. Use of claim 18, wherein the thymosin-a is administered subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.
20. Useofclaim 9, 11, or 12, wherein the use further comprises administering to the individual an effective amount of interferon-gamma (IFN-y).
21. Use of claim 20, wherein the IFN-y is administered subcutaneously in an amount of trom about 10 pg to about 300 ug.
22. Use of claim 9, 11, or 12, wherein the use further comprises administering to the individual an effective amount of interferon-alpha (IFN-a),
23. Use of claim 22, wherein the IFN-q is monoPEG (30 kD, linear)-ylated consensus [FN-a administered at a dosing interval of every 8 days to every 14 days.
24. Use of claim 22, wherein the IFN-q is monoPEG (30 kD, linear)-ylated consensus [FN-a administered at a dosing interval of once every 7 days,
25. Use of claim 22, wherein the IFN-a INFERGEN consensus IFN-q.
26. Use of claim 9, 11, or 12, further comprising administering an effective amount of an agent selected from 3’-azidothymidine, 2’,3’-dideoxyinosine, 2.3’ dideoxycytidine, 2-,3-didehydro-2",3’-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.
27. The compound of Claim 1 having the formula: 7 0] \ “W 070 e , oO oi qo9o9 > oA TY a NT 0 H - Ho \ 243 AMENDED SHEET
> : ' -
28. The composition of Claim 8, comprising a compound having the formula: g oo QO N 00,9 yo dy /
29. The use of Claim 9, 11 or 12, comprising administering an effective amount of a compound having the formula: : N oo 0OsN 009 N+ © N y/
30. A compound of the formula [ to VII as claimed in any one of claims 1 to 7 and 27, substantially as hereinbefore described or exemplified.
31. A compound of the formula [ to VII including any new and inventive integer or combination of integers, substantially as herein described.
32. A pharmaceutical composition as claimed in claim 8 and 28, substantially as hereinbefore described or exemplified.
33. A pharmaceutical composition including any new and inventive integer or combination of integers, substantially as herein described.
34. Use of the compound as claimed in any one of claims 9 to 26 and 29, substantially as hereinbefore described or exemplified. 244 AMENDED SHEET
35. Use of the compound including any new and inventive integer or combination of integers, substantially as herein described. 245 AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US51154103P | 2003-10-14 | 2003-10-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200603610B true ZA200603610B (en) | 2007-04-25 |
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ID=37579094
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| Application Number | Title | Priority Date | Filing Date |
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| ZA200603610A ZA200603610B (en) | 2003-10-14 | 2006-05-08 | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of HCV replication |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN1889970B (en) |
| SI (1) | SI1680137T1 (en) |
| TN (1) | TNSN06103A1 (en) |
| ZA (1) | ZA200603610B (en) |
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| KR101868412B1 (en) * | 2009-02-27 | 2018-06-18 | 얀센 파마슈티칼스 인코포레이티드 | Amorphous salt of a macrocyclic inhibitor of hcv |
| CN102140100B (en) * | 2010-01-27 | 2014-06-11 | 爱博新药研发(上海)有限公司 | Polycyclic compound for inhibiting hepatitis C virus efficiently, preparation method thereof and application thereof |
| CN107043405B (en) * | 2016-02-05 | 2021-11-19 | 爱博新药研发(上海)有限公司 | Crystal form of polycyclic heterocyclic compound, preparation method, application and composition thereof |
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| US6608027B1 (en) * | 1999-04-06 | 2003-08-19 | Boehringer Ingelheim (Canada) Ltd | Macrocyclic peptides active against the hepatitis C virus |
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2004
- 2004-10-13 CN CN2004800354123A patent/CN1889970B/en active Active
- 2004-10-13 SI SI200431968T patent/SI1680137T1/en unknown
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| SI1680137T1 (en) | 2013-02-28 |
| CN1889970B (en) | 2012-06-13 |
| CN1889970A (en) | 2007-01-03 |
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