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WO2010118367A2 - Pyrimidines antivirales - Google Patents

Pyrimidines antivirales Download PDF

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Publication number
WO2010118367A2
WO2010118367A2 PCT/US2010/030598 US2010030598W WO2010118367A2 WO 2010118367 A2 WO2010118367 A2 WO 2010118367A2 US 2010030598 W US2010030598 W US 2010030598W WO 2010118367 A2 WO2010118367 A2 WO 2010118367A2
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Prior art keywords
compound
hcv
aryl
amine
composition
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PCT/US2010/030598
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English (en)
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WO2010118367A3 (fr
Inventor
Amy Qi Han
Eric Wang
Carla Gauss
Walter Xie
Glen Coburn
Jean-Marc Demuys
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Progenics Pharmaceuticals, Inc.
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Publication of WO2010118367A3 publication Critical patent/WO2010118367A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure generally pertains to derivatives of nitrogen-containing heterocyclic compounds, pyrimidines, pyrazolopyrimidines and imidazoiopyrimidines, their stereoisomers, polymorphs, salts, solvates, metabolites, synthetic methods for their preparation, pharmaceutical compositions of the same, and methods for their therapeutic utilization.
  • Such compounds may be useful in general embodiment for the treatment of viral diseases of the flavivirus family, and in one embodiment, for therapy for acute and chronic infections by hepatotrophic virions of the Hepatitis C class (NANB, Non-A, Non-B virus).
  • NANB Hepatitis C class
  • All references cited in this specification, including copending PCT application PCT/US2008/013964, and their references, are incorporated by reference herein where appropriate for teachings of additional alternative details, features, and/or technical background.
  • HCV Hepatitis C virus
  • Flaviviridae and genus Hepacivirus is responsible for chronically infecting approximately 200 million persons worldwide, roughly 3% of the current population of 6.6 billion (1 ). Infection predominantly occurs via the percutaneous exchange of infected blood. The initial infection fails to clear in most instances, and chronic hepatitis, resulting in decompensated liver disease or hepatocellular carcinoma occurs in many cases. Other morbidities associated with chronic HCV infection are mixed cryoglobulinemia, overt B-cell non-Hodgkin's lymphoma, and idiopathic pulmonary fibrosis (2).
  • HCV is structurally related to hepatitis G (HGV-C), GBV-A and GBV-B viruses that infect Tamarin monkeys, West-Nile virus, dengue fever, and yellow fever viruses (3).
  • HCV shows considerable intra-genomic diversity, existing in at least 6 major genotypes, with at least 50 subtypes having been identified.
  • the most effective, proven therapeutic regimen for HCV infection is a combination therapy incorporating alpha-interferon (IFN- ⁇ ) or pegylated IFN- ⁇ and ribavirin, 1-( ⁇ -D-Ribofuranosyi)-1 H-1 ,2,4-triazole-3-carboxamide.
  • This regimen is substantially more efficacious against infections of HCV genotypes 2 and 3, compared to genotype 1 , as measured by sustained viral response.
  • Genotype 1 comprised of subtypes 1a and 1 b, is the major infective agent in the United States, constituting roughly 80% of reported cases (4),
  • IFN- ⁇ probably functions as a genera! inhibitor of viral replication as weli as favorably modulating the host's antiviral immune response (4).
  • HCV is an enveloped, positive sense RNA virus possessing a ⁇ 9.6 kb genome with a single open reading frame.
  • the virus is approximateiy spherical in shape with a diameter of about 60 nm. in the intact virus the genome resides in an icosahedral core.
  • the genome is translated into a single ⁇ 3,000 amino acid polyprotein directed from an internal ribosome entry site (!RES) located within the 5' non-translated region.
  • !RES internal ribosome entry site located within the 5' non-translated region.
  • the structural proteins are released from the poiyprotein by cellular peptidases, whereas non-structural proteins are cleaved by viraily encoded proteases.
  • the envelope protein E2 possesses a binding site for CD81 , a tetraspannin receptor expressed on the cell surface of hepatocytes that acts as a receptor or co-receptor of the HCV viral particle (6).
  • CD81 is necessary but not sufficient for HCV entry. The expression of CD81 alone cannot explain the ce ⁇ ular tropism exhibited by HCV, because this receptor is ubiquitously expressed by a large number of tissue types (6). VanCampemoile et a/.
  • Fusion of the viral capsule with the lipid membrane of a potential host cell is important for viral entry into the cell and is thought to occur by a iow-pH endocytotic process mediated by CD81 (7).
  • HCV research has been hampered by the lack of suitable infectivity models, but recent advances have demonstrated that unmodified HCV envelope proteins can pseudotype retroviral particles and thereby mediate cell entry. Details of HCV tropism and cell entry can now be studied, because such HCV pseudovirus particles (HCVpp) seem to accurately replicate early stages of the viral life cycle (6-10). It has been demonstrated that human immunodeficiency virus (HIV) readily forms pseudotypes, bearing native HCV E1 and E2 glycoproteins, that are infectious for human hepatoma cell lines in vitro (7).
  • HCV human immunodeficiency virus
  • HCVpp accurately reproduce the essential biology of HCV entry into cells susceptible to infection by HCV, (See, e.g., reference 7) and serve as an authentic source of native, fusogenic forms of HCV envelope glycoproteins.
  • HCVpp also provide a means by which to assess HCV entry into cells and to screen small molecule compounds for inhibitory activity. The findings obtained using HCVpp have been substantiated using authentic HCV (12-15).
  • HCVpp entry into liver cells requires co-expression of both the E1 and E2 HCV envelope glycoproteins; neither individual protein is sufficient for entry. Similar to authentic HCV and related viruses, HCVpp fusion does not occur at the cell surface but rather requires endocytosis of virus into mildly acidic endosomes, where fusion is triggered by exposure to low pH (7,16). HCVpp have been shown to be specifically inhibited by monoclonal antibodies directed against £2, as well as by HCV patient sera (7-8,17-18). Studies with HCVpp have identified the presence of naturally-occurring, broad and cross-genotype neutralizing antibodies in sera from HCV-infected individuals (16-18).
  • HCVpp infect CD81 -positive primary hepatocytes and liver cell lines, and monoclonal antibodies directed against CD81 inhibit HCVpp infection (6-8,19-20).
  • CD81 -negative human hepatoma cells are resistant to HCVpp entry, but such ceils become permissive when modified to express CD81.
  • non-hepatic cells are resistant to infection regardless of CD81 expression.
  • CD81 expression is necessary but not sufficient for HCVpp to enter target cells. It has been demonstrated that CD81 functions as a post-attachment co-receptor for HCV as shown by the potent inhibitory activity of CD81 monoclonal antibodies added to HCVpp that was pre-bound to target cells (6). In addition, certain mutations in E2 abolish binding to CD81 but not to target cells (5, 21 ).
  • L 2 , L 4 , and L ⁇ are independently none, H, O, S, NRR', (CH 2 V 5 , CN, CRR', SO 2 , CO, CONHR or CONR'R, NHCONR R, halide, cycloalkyl, heterocycle, aryl, alkyne, alkene;
  • R 2 , R 4 , and R 6 are independently none, R, OR, amine, alkoxy, (CH 2 )o- 3 CF 3 , (CH 2 ) 0 - 3 W, alky!, aryl, cycloalkyl, heterocycle, fused alkyiaryl or heteroaikylaryl, substituted with 0-2 W;
  • W is H, halide, OR, CF 3 , NO 2 , CN, amine, aniline, ester, amide, sulfonamide, sulfone, amino acid, ether, urea acid, heterocycfe, alkyl, aryl, arylalkyl, alkyiaryl; and
  • R or R' is independently H, alkyl, aryl.
  • R 1 H, (u ⁇ )substit ⁇ ted alkyl, (un)substituted aryl, (un)substituted heterocycle;
  • R 3 H, (un)substit ⁇ ted alkyl, (un)substituted aryl, (un)substituted heterocycte;
  • R 4 , and R 6 are independently none, R, OR 1 amine, (CH 2 ) n CF 3 , CF 3 , CH 2 CF 3 , ⁇ CH 2 ) n W, alkyl, aryl, phenyl, cycfoaiky ⁇ ,
  • W is H, halide, OR, CF 3 , NO 2 , CN, SO 2 NRR', SO 2 R, amine, aniline, ester, amide, sulfarn ⁇ yl, amino acid, ether, urea, acid, heterocycle, heteroaromatic, alky), aryl, arylaikyt, afkylaryl, sulfone, sulfonamide substituted with alkyi, aryl, heterocycle, amino, aniline; and R or R 1 is independently H 1 alky!, aryl.
  • Ri H, (un)substituted alky!, (un)substituted aryl, (un)substituted heterocycle;
  • R 3 H, (un)substituted alkyl, (un)substituted aryl, (un)substituted heterocycle;
  • L 5 and L 7 are independently H, O, S, NRR', (CH 2 ),,, CN, CRR', SO 2 , CO, CONR'R,
  • R 5 , and R 7 are independently none, R, OR, amine, ⁇ CH 2 ) n CF 3 , (CH z ) n W, alky!, aryl, phenyl, cycloalkyl, piperidinyl, heterocycle, fused aryl, alkylaryl, or heteroaikylaryl, all of which are optionally substituted with 0-5 W, wherein n is chosen independently to be 0-5; W is H, halide, OR, CF 3 , NO 2 , CN, SO 2 NRR', SO 2 R, sulfamoyl, sulfone, amino acid, ether, urea, heterocycie, heteroaromatic, alkyl, aryi, arylalkyi, alkyiary!, suifone, sulf
  • R 1 H, (un)substituted alkyl, (un)substituted aryl, (un)substituted heterocycie;
  • R 2 H, (un)substituted alkyl, (un)substituted aryi, (un)substituted heterocycie;
  • L 4 and L 6 are independently H, O, S, NRR', (CH 2 J n , CN, CRR', SO 2 , CO, CONR'R,
  • R 4 , and R 6 are independently none, R, OR, amine, (CH 2 J n CF 3 , (CH 2 J n W, alkyl, aryl, phenyl, cycloalkyl, piperidinyl, heterocycie, fused aryl, alkylaryl, or heteroalkylaryl, all of which are optionally substituted with 0-5 W, wherein n is chosen independently to be 0-5;
  • W is H 1 haiide, OR, CF 3 , NO 2 , CN, SO 2 NRR', SO 2 R, amine, aniline, ester, amide, sulfamoyl, amino acid, ether, urea, heterocycie, heteroaromatic, alkyl, aryl, arylalkyi, alkylaryl, sulfone, sulfonamide substituted with alkyl, aryl, heterocycie, amino, aniline; and
  • R or R' is independently H, alkyl, aryl.
  • R 1 H, (un)substituted alkyl, (un)substituted ary!, (un)substituted heterocycie;
  • R 2 H, (un)substituted alkyl, (un)substituted aryl, (unjsubstituted heterocycie;
  • L 5 and L 7 are independently H, O, S, NRR', ⁇ CH 2 ) ni CN, CRR 1 , SO 2 , CO, CONR'R,
  • R 5 , and R 7 are independently none, R, OR, amino, amine, (CH 2 J n CF 3 , (CHa) n W, alkyl, aryl, phenyl, cycioalkyl, piperidinyl, heterocycle, fused aryl, alkylaryl, or heteroalkylaryl, all of which are optionally substituted with 0-5 W, wherein n is chosen independently to be 0-5;
  • W is H, halide, OR, CF 3 , NO 2 , CN, SO 2 NRR', SO 2 R, amino, amine, ani ⁇ ne, ester, amide, sulfonamide, sulfamoyl, sulf ⁇ ne, amino acid, ether, urea, acid, heterocycle, heteroaromatic, alkyl, aryl, arylalkyl, alkylaryl, suifone, sulfonamide substituted with alkyl, aryl, heterocycle, amino, aniline; and R or R' are independently H, alkyl, aryl.
  • composition comprising at least one of a compound, stereoisomer, hydrate, polymorph, or a salt thereof, of a compound of the invention, as exemplified in Tables 1-35, below.
  • compositions of a compound of the invention comprising a pharmaceutically acceptable carrier, the composition further comprising a solid formulation, a semisolid formulation, a solution formulation, an aqueous formulation, an immediate release formulation, a sustained release formulation, an enteric coating formulation or a lyophilized formulation, such formulation optionally being a packaged unit dosage.
  • a pharmaceutical dosage unit composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the invention suitable for treating viral infections of the family Flaviviridae, and, in one aspect, infections by HCV.
  • a further embodiment of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier or excipient.
  • the composition of the invention may further comprise at least one additional antiviral active ingredient such as an interferon, an anti-HCV monoclonal antibody, an anti-HCV polyclonal antibody, a HCV RNA polymerase inhibitor, a HCV protease inhibitor, an IRES inhibitor, a helicase inhibitor, an antisense compound, an anti-viral small molecule, or a ribozyme.
  • additional antiviral active ingredient such as an interferon, an anti-HCV monoclonal antibody, an anti-HCV polyclonal antibody, a HCV RNA polymerase inhibitor, a HCV protease inhibitor, an IRES inhibitor, a helicase inhibitor, an antisense compound, an anti-viral small molecule, or a ribozyme.
  • antiviral active ingredients may be provided in
  • an antiviral active ingredient may be selected from one or more of the following in any combination: ribavirin, interferon- ⁇ , interferon- ⁇ -2 ⁇ , or a combination thereof.
  • ribavirin interferon- ⁇ , interferon- ⁇ -2 ⁇ , or a combination thereof.
  • Different doses of a compound of the invention may be needed depending on the status of the viral infection, such that different dosages may be needed prior to potential infection, or for early, post infection. Other, different dosages may be needed for obtaining a sustained viral response in the case of a long-term, chronic infection.
  • a compound of the invention may be co-adrninistered with one or more chemotherapeutic drugs or therapeutic or antiviral agents, in one example, with antiviral agents such as ribavirin and/or interferon-alpha (IFN- ⁇ ), and in other examples, with microbial anti- infective agents or with anti-cancer agents.
  • chemotherapeutic drugs or therapeutic or antiviral agents in one example, with antiviral agents such as ribavirin and/or interferon-alpha (IFN- ⁇ ), and in other examples, with microbial anti- infective agents or with anti-cancer agents.
  • IFN- ⁇ interferon-alpha
  • compounds and/or compositions of the invention are administered via an entry portal of the subject body, for example, via oral, enteral, parenteral, subcutaneous, topical and/or intravenous routes,
  • a compound of the invention when a viral infection is being treated, or prophylaxis is desired, a compound of the invention may be administered by any route of administration, including, intravenously, parenteraily, subcutaneously, intramuscularly, or orally.
  • a compound of the invention may be formulated to provide an immediate release dosage form that predominantly releases compound in the stomach.
  • a compound of the invention may be coated to provide an enteric dosage form designed to preferentially release in the intestine, with little or no release in the stomach, [0028] Also provided in one embodiment of the invention is provided a method for treating or preventing infection by a virus of the family Flavivi ⁇ dae, comprising administering to a patient in need thereof a compound and/or composition in an amount effective to treat or prevent the infection.
  • an effective amount of a compound of the invention and/or composition of the invention inhibits or blocks entry of HCV into a susceptible cell.
  • the HCV is of genotype 1 , and more preferably of genotype 1a, genotype 1b, or combinations thereof.
  • the susceptible cell is in a patient, and the compound and/or composition is administered to the patient.
  • [0030] in an embodiment of the invention is a method comprising contacting an HCV-infected cell with a compound and/or composition of the invention, in an amount effective to inhibit or block exit of newly formed HCV particles from an HCV-infected cell.
  • a method of inhibiting HCV infection of a cell susceptible to HCV infection comprising contacting the cell with the compound and/or composition of the invention, in an amount effective to inhibit HCV infection of the cell
  • a method of preventing or diminishing HCV infection in a subject comprising administering to the subject a compound and/or composition of the invention in an amount effective to prevent or diminish the HCV infection.
  • the compound and/or composition of the invention may be administered to the subject before, after, or during exposure of the subject to HCV.
  • an embodiment of the invention is a method of reducing exposure of a subject to HCV infection outside or on the external body surface of the subject, comprising contacting the outside or external body surface of the subject with a compound and/or composition of the invention, in an amount effective to inactivate or inhibit the virus so as to reduce exposure of the subject to HCV infection.
  • In one embodiment of the invention is a method of reducing the occurrence of HCV infection in a population of individuals, comprising administering to the population of individuals in need thereof a compound of the invention in an amount effective to reduce the occurrence of HCV infection in the population.
  • In one embodiment of the invention is a method of treating or preventing a liver disease in a subject, which comprises administering to the subject compound and/or composition of the invention in an amount effective to inhibit infection of the subject's HCV susceptible cells, thereby treating or preventing the liver disease in the subject.
  • a method of treating or preventing an HCV associated disorder in a subject which comprises administering to the subject a compound and/or composition of the invention in an amount effective to inhibit infection of the subject's HCV susceptible cells, thereby treating or preventing an HCV associated disorder in the subject
  • methods for prophylactically preventing or diminishing HCV infections in a warm-blooded animal which comprises administering before, after or during the exposure of said animal to the infective viral agent, a prophylactically effective amount of a compound of the invention.
  • kits for reducing the occurrence of HCV infection in a population of individuals comprising administering to the population of individuals in need thereof a compound and/or composition of the invention in an amount effective to reduce the occurrence of HCV infection in the population.
  • kits for reducing exposure of a subject to HCV infection outside or on the external body surface of the subject comprising contacting the outside or external body surface of the subject with a compound of the invention in an amount effective to inactivate or inhibit the virus so as to reduce exposure of the subject to HCV infection.
  • a liver disease in a subject comprises administering to the subject a compound and/or composition of the invention, in an amount effective to inhibit infection of the subject's HCV susceptible cells, thereby treating or preventing the liver disease in the subject.
  • a method for inhibiting infection of a susceptible cell wherein the cell is contacted with a compound or composition of the invention, in an amount effective to inhibit HCV infection of the cell; further, wherein the cell is in a patient and a compound of the invention is administered to the patient.
  • a method of reducing or diminishing the severity of HCV infection in a subject infected or exposed to HCV comprising administering a compound of the invention to the patient in effective amount.
  • a method of inactivating, inhibiting, decontaminating, or rendering inactive or weakly infective objects, spaces, surfaces, or substances that have been contaminated with HCV which comprises contacting the objects, spaces, surfaces, or substances with a compound of the invention, in an amount effective to inactivate, inhibit, decontaminate, or render inactive or weakiy infective the HCV.
  • compounds of the invention inhibit HCV entry by blocking the interaction of HCV E2 envelope glycoprotein with the scavenger receptor B1 (SR- B1 ) integral membrane, cell surface receptor.
  • [0045] in an embodiment of the invention is a method of inhibiting HCV entry via the SR-B1 receptor into a ceil susceptible to HCV infection, comprising contacting the ceil with a compound of Tables 1-35 S infra.
  • Compounds of the invention may also be used solely or in combination with other antiviral, inactivating or decontaminating agents or drugs to render inactive or weakly infective surfaces or substances that have been contaminated with Flaviviridae such as HCV or other viruses.
  • prodrugs may enhance a number of desirable pharmaceutical qualities (e.g., solubility, bioavailability, manufacturing, efc.).
  • Prodrugs of the compounds of the invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Metabolites of the disclosed compounds may possess pharmacological activity.
  • the compounds are also useful as research or diagnostic reagents, as radioisomers or otherwise, whereby such compounds can be used, for example, to establish competitive binding constants for other compounds, or, for example, as quantitative reagents to assess viral titer.
  • Fig. 1 depicts a schematic representation of various HlV- 1 based pseudoviral particles utilized in assays to evaluate the compounds of the invention.
  • Test and control pseudoparticles include HCVpp, VSVpp (Vesicular Stomatitis Virus pp), MLVpp (Murine Leukemia Virus pp), HiV-i pp, and human patient specific HCVpp, The pseudoviruses are capable of only a single round of infection in target cells. Of the pseudoparticles, HCVpp only recapitulate the process of HCV entry.
  • Fig. 2 illustrates the inhibition of viral pseudoparticle entry into target cells by pyrimidine compounds of the invention and a control (antibody JS-81) as a function of concentration of the inhibitors.
  • Fig. 3 shows the inhibition of viral pseudoparticle entry into target cells by pyrazolopyrimidine and imidazolopyrimidines compounds of the invention and a control (antibody JS-81 ) as a function of concentration of the inhibitors.
  • Fig. 4 shows that a representative pyrazolopyrimidine compound of Table 35 potently neutralizes binding of sE2-6xHis to surface expressed SR-BI on Huh7.5.1 cells.
  • Fig. 5 shows that a compound of the invention, Compound B, maintains its ability to potently neutralize binding of sE2-6xHis to surface expressed SR-BI on Huh7.5.1 cells following pre-treatment and a washout.
  • the present invention provides in one embodiment the selective inhibition or blockade of HCV entry into hepatocytes and other permissive cell types.
  • heterocyclic compounds of the pyrimidine type surprisingly were discovered to be highly active in preventing the entry of HCV genotype 1 pseudoviruses into potential eukaryotic hosts, activity that may include other virions of the Flaviviridae family. This property of the inventive compounds, as described herein, is advantageous because current therapies are poorly efficacious against HCV genotype 1 , the predominant genotype in the United States of America.
  • the blocking mechanism of the compounds may involve direct interaction of HCV with the ectopic domain of the CD81 receptor, or alternatively a direct binding of the compounds with the viral structural proteins E1/E2 such that virion docking is impeded.
  • the compounds may also potentially block the assembly and/or facile release of viral particles from infected cells via intracellular binding to newly formed E1/E2 structural proteins. In this therapeutic modality, the compounds would function as virion assembly or exit inhibitors.
  • the invention further provides the stereoisomers of the compounds disclosed herein, as well as to prodrugs, polymorphs, solvates, ail salts thereof, particularly pharmaceutically acceptable salts, synthetic methods for the preparation of compounds of the invention, pharmaceutical compositions of the same, and methods for therapeutic and/or prophylactic utilization, preparation, and pharmaceutical compositions.
  • the invention also provides methods for utilizing these compounds in anti-viral treatment, therapy, or prophylaxis, either as monotherapy or in combination with other antiviral or chemotherapeutic and/or prophylactic agents. Further, the invention provides for any human and/or animal subject or patient that may be treated with compounds according to the invention.
  • therapeutic and “therapy” are used to describe the administration of medicaments to a patient to correct, treat, ameliorate, or eradicate a condition or infection that has already initiated.
  • prophylactics I Iy and “prophylaxis” describe protective medications or preventive treatments that are administered to a subject and/or applied to an object before contact with HCV, for example, to prevent or diminish the intensity of a subsequent infection of the patient by the virus, or to prevent or diminish contamination of the object by the virus.
  • acyl denotes a radical provided by the residue after removal of hydroxy) from an organic acid.
  • acylamino embraces an amine radical substituted with an acyi group.
  • aryloxy denotes a radical provided by the residue after removal of hydrido from a hydroxy-substituted aryl moiety (e.g., phenol).
  • alkanoyl groups include acetyl (ethanoyi), n-propanoyl, n-butanoyl, 2- methylpropanoyi, n-pentanoyl, 2-methylbutanoyi, 3-methylbutanoyi, 2,2- dimethylpropanoyl, heptanoyl, decanoyl, and palmitoyl.
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyfs described below, but that contain at least one double bond and must contain at least two carbon atoms.
  • alkenyl includes straight- chain alkenyl groups (e.g., ethylenyi, propeny!, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycioalkenyi (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cyclo heptenyl, cyclooctenyl), afkyl or alkenyl substituted cycioalkenyi groups, and cycloaikyl or cycioalkenyi substitute
  • lower aikylene herein refers to those alkyiene groups having from about 1 to about 6 carbon atoms.
  • alkenyj includes both "unsubstituted alkenyls” and “substituted alkenyis”, the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, aikyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyioxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyi, arninocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, aSkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, diaikylamino, arylamino, diarylamino, and alkylaryfamino), acyiamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthi
  • alkenylene in general, refers to an alkyiene group containing at least one carbon- carbon double bond.
  • Preferred alkenylene groups have from 2 to about 4 carbons.
  • alkoxy and alkoxyalkyl embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical.
  • alkoxyalkyl also embraces alkyl radicals having two or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyaikyl and dialkoxyalkyl radicals.
  • alkoxy or alkoxyalkyl radicals may be further substituted with one or more halo atoms, such as fluoro chloro or bromo to provide "haloalkoxy” or "haloalkoxyalkyl” radicals.
  • halo atoms such as fluoro chloro or bromo to provide "haloalkoxy" or "haloalkoxyalkyl” radicals.
  • alkoxy radicals include methoxy butoxy and trifluoromethoxy.
  • Alkyl in general, refers to an aliphatic hydrocarbon group which may be straight, branched or cyclic having from 1 to about 10 carbon atoms in the chain, and all combinations and subcombinations of ranges therein, e.g., a cycioalkyl, branched cycloalkyialky!, a branched alkylcycloalky having 4-10 carbon atoms.
  • alkyl includes both "unsubstituted alkyls" and “substituted alkyls,” the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the backbone.
  • “Lower alkyl” refers to an alkyl group having 1 to about 6 carbon atoms.
  • Alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyi, t-butyl, n-pentyl, cyclopentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyciohexyl, cyclooctyl, adamantyi, 3-methyipentyl, 2-dimethylbutyl, and 2,3- d ⁇ methyibutyi, cyclopropylmethyl and cyclobutyimethyl,
  • Alkyl substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy
  • araikyl embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyi, phenethyl, phenylpropyl, and diphenethyl.
  • benzyl and phenylmethyl are interchangeabie.
  • n-alkyl means a straight chain (i.e. unbranched) unsubstituted alkyl group.
  • Branched refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain.
  • alkynyi includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond and two carbon atoms.
  • alkynyl includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyi, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloaikyl or cycSoalkenyl substituted alkynyl groups.
  • amido when used by itself or with other terms such as “amidoalkyi", “N- monoalkylamido”, “N-monoarylamido”, “N,N-dtalkylarnido", “N-aikyl-N-arylamido", “N-alkyl-N- hydroxyamido” and “N-alkyl-N-hydroxyamidoalkyl”, embraces a carbonyl radical substituted with an amino radical.
  • N-alkyiamido and “N,N-dialkyiamido M denote amido groups which have been substituted with one alkyl radical and with two aikyt radicals, respectively.
  • N-monoarylamido and “N-a!kyI-N-aryiamido” denote amido radicals substituted, respectively, with one aryl radical, and one alkyl and one aryl radical.
  • N-alkyl-N-hydroxyamido embraces amido radicals substituted with a hydroxyl radical and with an alkyl radical.
  • N-alkyl-N-hydroxyamidoalkyl embraces aikyl radicals substituted with an N-alkyi-N- bydroxyamido radical.
  • amidoalkyl embraces alkyl radicals substituted with amido radicals.
  • amine or "amino” have their common, ordinary meaning.
  • the amines useful in the invention have the general formula:
  • R 3 wherein R 1 , R 2 , and R 3 are identical or a combination of different hydrido, straight or branched chain alkyl groups, alkenyl groups, alkylene groups, alkenylene groups, cycloalkyl groups, cycloalkyl-substituted alkyl groups, cycloafkenyl groups, alkoxy groups, alkoxy-aikyl groups, acyl groups, aryl groups, aryl-substituted alkyl groups, and heterocyclic groups, such as morpholine. If none of R r3 are hydrido, the compound is a tertiary amine.
  • Exemplary tertiary amines useful according to the invention also are cycloalkyl tertiary amines (e.g., N-methylmorphoiine, N- methylpyrrolidine, N-methylpiperidine), pyridine and Proton Sponge® (N 1 N, N', N'-tetramethyl- 1 ,8- naphthalene).
  • aminoalkyl embraces alkyl radicals substituted with amine radicals.
  • alkylaminoalkyi embraces aminoalkyl radicals having the nitrogen atom substituted with an alkyl radical.
  • anti-HCV compound refers to any compound showing the effect of inactivating the virus or diminishing its' infectivity or replication in any way.
  • anti-HCV activity for example, is a compound that interferes with the entry of HCV into an animal cell; such a compound is an "entry inhibitor”. If such a compound interferes with the exit of vira! replicons from the cell, after infection by the virus, the compound is an "exit inhibitor”.
  • a third possibility is a compound that enhances the effectiveness of the subject's immune system in attacking and neutralizing the virus.
  • Yet another possibility for example, is a compound that interferes with the viral life cycle once the virus has gained cellular entry.
  • ⁇ CV-metalloprotease a viral enzyme that is thought to cleave the vira! polypeptide at its NS2-NS3 junction.
  • NS5b HCV encoded RNA dependent RNA polymerase
  • the viral HCV-polymerase, NS5b is essential for viral replication.
  • an "HCV-serine protease” inhibitor Such a compound interferes with the virally encoded serine protease known as NS3-4A that is essential for viral polypeptide cleavage.
  • HCV-he ⁇ case an "HCV-he ⁇ case” inhibitor which prevents the unwinding of the virat genome by interfering with the enzyme HCV-helicase encoded by the virus.
  • Anti-HCV monoclonal antibodies are antibodies that are reactive toward HCV.
  • the antibodies are identical, having been produced by cells that are all genetically identical clones of a single parent cell.
  • Anti-HCV polyclonal antibodies are antibodies that are reactive against HCV. Such antibodies are derived from different cell lines, and are a mixture of immunoglobulin molecules secreted against the virus, each reconizing a specific antigenic site or epitope on the virus.
  • anti-infective agent refers to a compound, composition, substance, reagent, drug, and the like, which acts therapeutically or prophylactically against infectious virat ⁇ e.g. HCV), bacterial, protozoal, or other agents by inhibiting their growth, replication, and survival.
  • Anti-infective agents may comprise preparations that contain natural or synthetic antibiotic agents.
  • anti-cancer agent or “cancer chemotherapeutic agent” refers to a compound, composition, substance, reagent, drug, and the like, which acts therapeutically or prophylactically by inhibiting the growth, replication, spread, and survival of cancer cells.
  • Anticancer agents may comprise preparations that contain natural or synthetic materials that act therapeutically singly or in combination to achieve their effect,
  • antisense molecule refers to a nucleic acid molecule (DNA, RNA, or a chemical analogue) that will complementarily bind to viral RNA, thus preventing the translation of viral proteins, thereby interfering with the viral life cycle. More generally, an antisense molecule binds to or pairs with messenger RNA (mRNA), e.g., an mRNA transcript, to block the expression of a gene, thus effectively turning off that gene and inhibiting its function.
  • mRNA messenger RNA
  • the interfering molecule typically an oligonucleotide, is termed “antisense” because its base sequence is complementary to the RNA, i.e., the "sense” sequence. (Thus, for instance, a sense segment of RNA “ 5'-AAGGUC-3' " would be blocked by the complementary antisense oligonucleotide " 3'-UUCCAG-S' ").
  • aryl alone or in combination, means a carbocyciic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronapthyl, indane and biphenyl.
  • Aryl-substituted aikyl in general, refers to an linear alkyl group, preferably a lower alky! group, substituted at a carbon with an optionally substituted aryl group, preferably an optionally substituted phenyl ring.
  • exemplary aryi-substitutedl aikyt groups include, for example, phenylmethyl, phenylethyl and 3- ⁇ 4-methylphenyl)propyl,
  • associated liver disorder refers to any liver dysfunction or malady associated with infection by a virus of the Flaviviridae family, in one example HCV.
  • cycloalkyl embraces radicals having three to ten carbon atoms, such as cyclopropyi cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,
  • carbocycle is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicydic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic.
  • carbocycles include, but are not limited to, cyclopropyi, cyclobutyl, cyclopentyl, cydohexyl, cycloheptyl, adamantyl, cyclooctyl,
  • Carbocycle are cyclopropyi, cyclobutyl, cyclopentyi, and cyclohexyl.
  • Cydoalkyl-substituted alkyl in general, refers to a linear alky! group, preferably a lower alkyl group, substituted at a terminal carbon with a cycioalkyl group, preferably a C 3 -C 8 cycioalkyl group.
  • Typical cydoalkyl-substituted alkyl groups include cyclohexylmethyl, cyclohexylethyl, cyclopentylethyl, cyclopentylpropyl, cyclopropylmethyl and the like.
  • Cycloalkenyl in general, refers to an olefinicaily unsaturated cycioalkyl group having from about 4 to about 10 carbons, and all combinations and subcombinations of ranges therein.
  • the cycloaikenyl group is a C 5 -C 8 cycloalkenyl group, i.e., a cycloalkenyl group having from about 5 to about 8 carbons.
  • halo means halogens such as fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical for one example, may have either a bromo, chloro or a fluoro atom within the radical.
  • Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may hav ⁇ more than two of the same halo atoms or a combination of different halo radicals.
  • HCV associated disorder is a illness or disorder that is caused or happens as a result of HCV infection.
  • heterocycle or “heterocyclic ring” is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated (aromatic), and which consists of carbon atoms and 1 , 2, 3 or 4 heteroatoms independently selected from the group consisting of
  • hydroxyalkyi embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxy! radicals.
  • hydro denotes a single hydrogen atom (H)
  • This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (-CH 2 - ⁇ radical.
  • interferon denotes a natural protein produced by the cells of the immune response of most vertebrates when challenged by foreign agents such as viruses, bacteria, parasites and tumor cells.
  • interferons e.g., interferon-alpha, interferon-beta, interferon-garnma
  • cytokines cytokines
  • interferons are biological defense modifiers, which inhibit viral replication within cells of the body and thereby assist immune response, e.g., the eradication of virus and viral infection
  • interferons are antiviral and anti-oncogenic, assist macrophage and natural killer lymphocyte activation, and enhance major histocompatibility complex glycoprotein classes I and II, and thereby the presentation of foreign (microbial) peptides to T ceils, which have immune effector function to combat infection.
  • liver disease refers to any pathology, dysfunction, illness, inflammation, cancer or malady of the liver.
  • Non-limiting examp ⁇ es are amebic liver abscess, autoimmune hepatitis, biliary atresia, cirrhosis, dessiminated coccidioido-mycosis, delta agent (hepatitis D), drug-induced cholestasis, hemochromatosis, hepatitis A, hepatitis B, hepatitis C, hepatocellular carcinoma, liver disease due to alcohol, primary biliary cirrhosis, pyogenic liver abscess, Reye's syndrome, sclerosing cholangitis, and Wilson's disease.
  • N-alkylamino and “N,N-dialkyIamino” denote amino groups which have been substituted with one alkyl radical and with two alkyl radicals, respectively.
  • Organic solvent has its common ordinary meaning to those of skill in the art.
  • organic solvents useful in the invention include, but are not limited to, tetrahydrofuran, acetone, hexane, ether, chloroform, acetic acid, acetonitrtle, chloroform, cyclohexane, methanol, and toluene.
  • Anhydrous organic solvents are included.
  • patient refers to animals, including mammals, e.g., rodents (mice, rats) dogs, rabbits, sheep, goats, and non-human primates.
  • rodents mice, rats
  • rabbits sheep, goats
  • non-human primates e.g., monkey, rats
  • patient refers preferably to humans.
  • prodrug refers to compounds specifically designed to maximize the amount of active species that reaches the desired site of reaction that are of themselves typically inactive or minimally active for the activity desired, but through biotransformation or chemical reaction are converted into biologically active molecules.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • s ⁇ ch conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, giycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfontc, methanesulf ⁇ nic, ethane disulfonic, oxalic, ethylenediaminetetraacet ⁇ c , and the like.
  • physiologically acceptable salts are prepared by methods known in the art, e.g., by dissolving the free amine bases with an excess of the acid in aqueous alcohol, or neutralizing a free carboxylic acid with an alkali metal base such as a hydroxide, or with an amine.
  • Certain acidic or basic compounds of the present invention may exist as zwitterions. All forms of the compounds, including free acid, free base and zwitterions, are contemplated to be within the scope of the present invention. It is well known in the art that compounds containing both amino and carboxyl groups often exist in equilibrium with their zwitterionic forms.
  • ribozyme derived from a contraction of ribonucleic acid enzyme, refers to a RNA molecule that catalyzes a chemical reaction, typically either the hydrolysis of one of its' own phosphodiester bonds, or the hydrolysis of bonds in other RNAs. Ribozymes are naturally occuring or synthetic.
  • Non-limiting examples of naturally occuring ribozymes are Peptidyl transferase 23S rRNA, Rnase P, G1R1 branching ribozyme, Hairpin ribozyme, Hammerhead ribozyme, HDV ribozyme, Mammalian CPEB3 ribozyme, VS ribozyme, glmS ribozyme and CoTC ribozyme.
  • a "susceptible cell” is a cell which is subject to infection by a virus, in one example, HCV.
  • virion refers to a matured viral particle, either existing outside a cell, or nascent within a cell prior to release.
  • the subjects or patients to which the compounds of the present invention may be administered are vertebrates, in particular mammals.
  • the mammal is a human, nonhuman primate, dog, cat, sheep, goat, horse, cow, pig or rodent, In one embodiment, the mammal is a human.
  • compositions of the invention when used alone or in cocktails, are administered in therapeutically effective amounts.
  • a effective amount will be determined by the parameters discussed below; but typically is that amount which establishes a level of the drug(s) effective for treating a subject, such as a human subject, having one of the conditions described herein.
  • An effective amount means that amount alone, as a single dose, or multiple doses, necessary to delay or prevent the onset of, lessen the severity of, inhibit completely, lessen or reduce the progression of, eradicate or halt altogether the onset or progression of the condition being treated or a symptom associated therewith.
  • an effective therapeutic amount for example, is that amount which relieves a symptom of infection, which induces a decrease in viral load, which increases the time before relapse, or which decreases circulating viral RNA
  • an effective amount for example, would be an amount that prevents active infection, lowers the frequency of active infection, slows the time before an active infection occurs, or diminishes the intensity of the infection.
  • a variety of administration routes are available. The particular mode selected will depend, of course, upon the particular combination of drugs selected, the severity of the condition being treated, or prevented, the condition of the patient, and the dosage required for therapy and/or efficacy.
  • the methods of this invention may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects.
  • Such modes of administration include, without limitation, oral, rectal, topical, transdermal, subungual, intravenous infusion, pulmonary, intra-arterial, intra-adipose tissue, intra-lymphatic, intramuscular, intracavity, intraperitoneal (IP), intrathecal, subcutaneous (SC), aerosol, aural (e.g., via eardrops), intranasal, inhalation, intra-articular, needleless injection, subcutaneous or intradermal (e.g., transdermal) delivery.
  • a patient- controlled device or an implantable drug delivery device may be employed.
  • the administration may be by the patient, using an injection device for SC self-administration.
  • Oral, rectal, or topical administration may be important for long-term treatment.
  • Preferred rectal modes of delivery include administration as a suppository or enema wash.
  • the pharmaceutical preparations may conveniently be provided in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. In such form, the entire unit is intended to be administered to the patient as a separate dose. All methods include the step of bringing the compounds of the invention into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the compounds of the invention into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product. [00101] When administered, the pharmaceutical preparations of the invention are applied in pharmaceutically acceptable compositions.
  • Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, lubricants, and optionally other therapeutic substances and/or ingredients.
  • the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof and are not excluded from the scope of the invention.
  • Such pharmacologically and pharmaceutically acceptable saits include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluenesulfonic, tartaric, citric, methanesulfonic, formic, succinic, naphthalene-2-sulfonic, pamoic, 3-hydroxy-2-naphthalenecarboxylic, and benzene sulfonic.
  • acids hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluenesulfonic, tartaric, citric, methanesulfonic, formic, succinic, naphthalene-2-sulfonic, pamoic, 3-hydroxy-2-naphthalenecarboxylic, and benzene sulfonic.
  • the salts When used in pharmaceutical preparations, the salts preferably are pharmaceutically- acceptable for use in humans.
  • a bromide salt is an example of one such salt in the case that the parent compound is basic.
  • a sodium salt is an example of one such salt in the case that the parent compound is acidic.
  • radioisomers of the same are encompassed.
  • Such isomers obtained by replacing one or more component atoms of the compound by a radioactive atom, are of a variety well known to those or ordinary skill in the art.
  • such radioisomers can be used therapeutically to deliver localized radiation to a tissue, in one embodiment, a tissue infected with HCV; or in another example, a radioisomer may be used as a tracer to measure metabolic pathways in an animal, or to measure competitive binding in a laboratory sample of tissue.
  • Non-radioactively labeled compounds, produced by replacing one or more of the component atoms with an atomic isotope thereof, are also encompassed.
  • Hydrates are formed when water binds to the crystal structure of a compound in a fixed stoichiometric ratio, although generally this ratio will change depending on the surrounding humidity with which the hydrate is in equilibrium. Hydration is a more specific form of solvation.
  • Solvates are crystalline solid adducts containing either stoichiometric or nonstoichiometric amounts of a solvent incorporated within the crystal structure. If the incorporated solvent is water, the solvates are also commonly known as hydrates. Hydrates and solvates are welt known to those or ordinary skill in the art.
  • Polymorphism is characterized as the ability of a compound or drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice.
  • Amorphous solids consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice.
  • Polymorphism refers to the occurrence of different crystalline forms of the same drug substance. Polymorphs are well know to those of ordinary skill in the art.
  • Polymorphs or solvates of a solid can have different chemical and physical properties such as melting point, chemical reactivity, apparent solubility, dissolution rate, optical and electrical properties, vapor pressure, and density, for example. These properties can have a direct impact on the processing of drug substances and the quality or performance of drug products. Chemical and physical stability, dissolution, and bioavailability are some of these qualities.
  • a metastable solid form may change crystalline structure or solvate or desolvate in response to changes in environmental conditions, processing, or over time. New polymorphs can develop spontaneously over time.
  • Infection by Hepatitis C virus predominantly occurs via the percutaneous exchange of infected blood from an outside source, such as a contaminated syringe needle.
  • a compound of the disclosure is capable of reducing exposure of a patient to HCV infection.
  • a compound of the invention produces inactivation or inhibition, or diminishment of infectivity of the virus outside or on the body of a subject by bringing the virus in contact with a compound of the invention in effective amount.
  • An effective amount would be the amount of a compound of the invention that diminishes the infectivity of a virally contaminated outside source, upon the contact of the source with the subject.
  • Compounds of the invention may also be used solely or in combination with other antiviral, inactivating or decontaminating agents or drugs to render inactive or weakly infective spaces, sources, surfaces or substances that have been contaminated with Ftavivi ⁇ dae such as HCV or other viruses.
  • Ftavivi ⁇ dae such as HCV or other viruses.
  • allograft or xenograft tissues, blood, surgical instrument surfaces, syringes, garments, and transfusion apparatuses that pose a viral infective risk to others may be rendered virally inactive or weakly infective by use of the compounds.
  • airborne virally-contarninated blood particles pose an infective risk.
  • a compound of the invention may be dispersed as an aerosol in the contaminated space in an effective amount to inactivate or diminish the infectivity of the airborne virus by contact with the virus.
  • the pharmaceutical preparations of the present invention may include, or be diluted into, a pharmaceutica ⁇ y-acceptable carrier.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration to a human or other mammal such as non- human primate, for example, a dog, cat, horse, cow, sheep, pig, or goat.
  • carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
  • the carriers are capable of being commingled with the preparations of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy or stability.
  • Carrier formulations suitable for oral administration, for suppositories, and for parenteral administration, etc. can be found in Remington: The Science and Practice , of Pharmacy, 20th Edition. (Aifanso R. Gennaro): Uppincott Williams & Wilkins, Baltimore, MD, 2000.
  • Aqueous formulations may include one or more chelating agents, buffering agents, antioxidants and, optionally, isotonicity agents, preferably pH adjusted, for example, to between 3.0 and 3.5.
  • Chelating agents include, for example and without limitation, ethylenediaminetetraacetic acid (EDTA) and derivatives thereof, citric acid and derivatives thereof, niacinamide and derivatives thereof, sodium desoxycholate and derivatives thereof, and L-glutamic acid, N, N ⁇ diacetic acid and derivatives thereof.
  • EDTA ethylenediaminetetraacetic acid
  • citric acid and derivatives thereof citric acid and derivatives thereof
  • niacinamide and derivatives thereof sodium desoxycholate and derivatives thereof
  • L-glutamic acid N, N ⁇ diacetic acid and derivatives thereof.
  • Buffering agents include, without limitation, those selected from the group consisting of citric acid, sodium citrate, sodium acetate, acetic acid, sodium phosphate and phosphoric acid, sodium ascorbate, tartaric acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic acid, imidazole, sodium bicarbonate and carbonic acid, sodium succinate and succinic acid, histidine, and sodium benzoate and benzoic acid, and combinations thereof.
  • Antioxidants include, without limitation, those selected from the group consisting of an ascorbic acid derivative, butylated hydroxy anisole, butylated hydroxy toluene, alkyl gallate, sodium meta-bisulfite, sodium bisulfite, sodium dithionite, sodium thioglycollate acid, sodium formaldehyde sulfoxylate, tocopherol and derivatives thereof, monothiogiycerol, sodium sulfite, and combinations thereof.
  • an ascorbic acid derivative butylated hydroxy anisole, butylated hydroxy toluene, alkyl gallate, sodium meta-bisulfite, sodium bisulfite, sodium dithionite, sodium thioglycollate acid, sodium formaldehyde sulfoxylate, tocopherol and derivatives thereof, monothiogiycerol, sodium sulfite, and combinations thereof.
  • Isotonicity agents include, without limitation, those selected from the group consisting of sodium chloride, mannitol, lactose, dextrose, glycerol, and sorbitol and combinations thereof.
  • Preservatives that can be used with the present compositions include, without limitation, benzyl alcohol, parabens, thimerosal, chlorobutanol and preferably benzalkonium chloride and combinations thereof.
  • the preservative is present in a composition in a concentration of up to about 2% by weight. The exact concentration of the preservative, however, will vary depending upon the intended use and can be easily ascertained by one skilled in the art.
  • the compounds of the invention can be prepared in lyophilized compositions, preferably in the presence of one or more cryoprotecting agents such as trehalose, mannitol, lactose, sucrose, polyethylene glycol, and polyvinyl pyrrolidines, Cryoprotecting agents which result in a reconstitution pH of 6.0 or less are preferred.
  • the invention therefore provides a lyophilized preparation of compounds and/or compositions of the invention.
  • the preparation can contain a cryoprotecting agent, such as mannitol or lactose, which is preferably neutral or acidic in water.
  • Oral, parenteral and suppository formulations of agents are well known and commercially available.
  • the therapeutic compounds and/or compositions of the invention can be added to such well known formulations, which can be mixed together in solution or semisolid solution in such formulations, can be provided in a suspension within such formulations, or can be contained in particles within such formulations.
  • a product containing one or more therapeutic compounds of the invention and, optionally, one or more other active agents can be configured as an oral dosage.
  • the oral dosage may be a liquid, a semisolid or a solid.
  • the oral dosage may be configured to release the therapeutic compound of the invention before, after, or simultaneously with the other agent.
  • the oral dosage may be configured to have the therapeutic compound of the invention and the other agents release completely in the stomach, release partially in the stomach and partially in the intestine, in the intestine, in the colon, partially in the stomach, or wholly in the colon.
  • the oral dosage also may be configured whereby the release of the therapeutic compound of the invention is confined to the stomach or intestine while the release of the other active agent is not so confined or is confined differently from the therapeutic compound of the invention.
  • the therapeutic compound of the invention may comprise an enterically coated core or pellets contained within a pill or capsule that releases the other agent first and releases the therapeutic compound of the invention only after the therapeutic compound of the invention passes through the stomach and into the intestine
  • a therapeutic compound of the invention also can be in a sustained release material, whereby the therapeutic compound of the invention is released throughout the gastrointestinal tract and the other agent is released on the same or a different schedule.
  • the same objective for a therapeutic compound of the invention can be achieved with an immediate release of the therapeutic compound of the invention, combined with an enteric coated therapeutic compound of the invention. In this instance, the therapeutic compound could be released immediately in the stomach, throughout the gastrointestinal tract, or only in the intestine.
  • a therapeutic compound of the invention could be coated on the surface of the controlled release formulation in any pharmaceutically acceptable carrier suitable for such coatings and for permitting the release of the therapeutic agent of the invention, such as in a temperature sensitive pharmaceutically acceptable carrier used for controlled release routinely.
  • any pharmaceutically acceptable carrier suitable for such coatings and for permitting the release of the therapeutic agent of the invention such as in a temperature sensitive pharmaceutically acceptable carrier used for controlled release routinely.
  • Other coatings which dissolve when placed in the body are well known to those of ordinary skii! in the art.
  • a therapeutic compound of the invention also may be mixed throughout a controlled release formulation, whereby it is released before, after or simultaneously with another agent.
  • the therapeutic compound of the invention may be free, that is, solubilized within the material of the formulation.
  • the therapeutic compound of the invention also may be in the form of vesicles, such as wax coated micropellets dispersed throughout the material of the formulation.
  • the coated pellets can be fashioned to immediately release the therapeutic compound of the invention based on temperature, pH, or the like.
  • the pellets also can be configured so as to delay the release of the therapeutic compound of the invention, allowing the other agent a period of time to act before the therapeutic compound of the invention exerts its effects.
  • the therapeutic compound of the invention pellets also can be configured to release the therapeutic compound of the invention in virtually any sustained release pattern, including patterns exhibiting first order release kinetics or sigmoidal order release kinetics using materials of the prior art and well known to those of ordinary skill in the art.
  • a therapeutic compound of the invention also can be contained within a core within the controlled release formulation.
  • the core may have any one or any combination of the properties described above in connection with the pellets.
  • the therapeutic agent of the invention may be, for example, in a core coated with a material, dispersed throughout a material, coated onto a material or adsorbed into or throughout a material. It should be understood that the pellets or core may be of virtually any type. They may be drug coated with a release material, drug interspersed throughout material, drug adsorbed into a material, and so on. The material may be erodible or nonerodible.
  • a therapeutic compound of the invention may be provided in particles.
  • Particles as used herein means nano- or microparticles (or in some instances larger) which can consist in whole or in part of a compound of the invention or other agents as described herein.
  • the particles may contain the therapeutic compounds in a core surrounded by a coating, including, but not limited to, an enteric coating. Such compounds also may be dispersed throughout the particles. These compounds also may be adsorbed into the particles.
  • the particles may be of any order release kinetics, including zero order release, first order release, second order release, delayed release, sustained release, immediate release, and any combination thereof, etc.
  • the particle may include, in addition to the therapeutic compound, any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable materia! or combinations thereof.
  • the particles may be microcapsules which contain the antiviral compound in a solution or in a semisolid state.
  • the particles may be of virtually any shape.
  • Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic compounds of the invention.
  • Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired.
  • Btoadhesive polymers of particular interest include bioerodible hydrogels described by H. S.
  • the therapeutic compounds of the invention may be contained in controlled release systems.
  • controlled release is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controiled. This refers to immediate as well as nonimmediate release formulations, with nonimmediate release formulations including but not limited to sustained release and delayed release formulations.
  • sustained release ⁇ also referred to as "extended release” is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period.
  • delayed release is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug therefrom. "Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.” These formulations may be for any mode of administration.
  • Delivery systems specific for the gastrointestinal tract are roughly divided into three types: the first is a delayed release system designed to release a drug in response to, for example, a change in pH; the second is a timed-release system designed to release a drug after a predetermined time; and the third is a microflora enzyme system making use of the abundant enterobacteria in the lower part of the gastrointestinal tract (e.g., in a colonic site-directed release formulation).
  • An example of a delayed release system is one that uses, for example, an acrylic or cellulosic coating material and dissolves on pH change. Because of ease of preparation, many reports on such "enteric coatings" have been made, In general, an enteric coating is one which passes through the stomach without releasing substantial amounts of drug in the stomach (i.e., less than 10% release, 5% release and even 1 % release in the stomach) and sufficiently disintegrating in the intestinal tract (by contact with approximately neutral or alkaline intestine juices) to allow the transport (active or passive) of the active agent through the walls of the intestinal tract. [0125] Various in vitro tests for determining whether or not a coating is classified as an enteric coating have been published in the pharmacopoeia of various countries.
  • a coating which remains intact for at least 2 hours, in contact with artificial gastric juices such as HCI of pH 1 at 36 to 38 0 C and thereafter disintegrates within 30 minutes in artificial intestinal juices such as a KH 2 PO 4 buffered solution of pH 6,8 is one example.
  • artificial gastric juices such as HCI of pH 1 at 36 to 38 0 C and thereafter disintegrates within 30 minutes in artificial intestinal juices such as a KH 2 PO 4 buffered solution of pH 6,8
  • EUDRAGIT® material commercially available and reported on by Behringer, Manchester University, Saaie Co., and the like.
  • Enteric coatings are discussed further, below.
  • the enteric coating is typically, although not necessarily, a polymeric material.
  • Preferred enteric coating materials comprise bioerodible, gradually hydrolyzable and/or gradually water-soluble polymers.
  • the "coating weight,” or relative amount of coating material per capsule, generally dictates the time interval between ingestion and drug release.
  • any coating should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5 and above. It is expected that any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the practice of the present invention.
  • the selection of the specific enteric coating material will depend on the following properties: resistance to dissolution and disintegration in the stomach; impermeability to gastric fluids and drug/carrier/enzyme while in the stomach; ability to dissolve or disintegrate rapidly at the target intestine site; physical and chemical stability during storage; non-toxicity; ease of application as a coating (substrate friendly); and economical practicality.
  • Suitable enteric coating materials include, but are not limited to: cellulosic polymers such as cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethy! cellulose phthalate, hydroxypropyhmethyl cellulose succinate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ammonium methylacrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate ⁇ e.g., those copolymers sold under the trade name EUDRAGIT®); vinyl polymers and copolymers such as polyvinyl acetate, polyvinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate copolymers; and shellac (purified lac).
  • cellulosic polymers such as cellulose acetate phthalate, cellulose acetate trimellitate,
  • enteric coating material for use herein are those acrylic acid polymers and copolymers available under the trade name EUDRAGIT® from Rohm Pharma (Germany).
  • EUDRAGIT® series E, L, S, RL, RS and NE copolymers are available as solubilized in organic solvent, as an aqueous dispersion, or as a dry powder.
  • the EUDRAGIT® series RL, NE, and RS copolymers are insoluble in the gastrointestinal tract but are permeable and are used primarily for extended release.
  • the EUDRAGIT® series E copolymers dissolve in the stomach.
  • the EUDRAGIT® series L, L-30D and S copolymers are insoluble in stomach and dissolve in the intestine, and are thus most preferred herein.
  • a particular methacrylic copolymer is EUDRAGIT® L, particularly L-30D and EUDRAGIT® L 100-55.
  • EUDRAGIT® L-30D the ratio of free carboxyl groups to ester groups is approximatefy 1 :1.
  • the copolymer is known to be insoluble in gastrointestinal fluids having pH below 5.5, generally 1.5-5.5, i.e., the pH generally present in the fluid of the upper gastrointestinal tract, but readily soluble or partially soluble at pH above 5.5, i.e., the pH generally present in the fluid of lower gastrointestinal tract.
  • EUDRAGiT® S Another particular methacrylic acid polymer is EUDRAGiT® S, which differs from EUDRAGIT® L-30D in that the ratio of free carboxyl groups to ester groups is approximately 1 :2.
  • EUDRAGIT® S is insoluble at pH below 5.5, but unlike EUDRAGIT® L-30D, is poorly soluble in gastrointestinal fluids having a pH in the range of 5.5 to 7.0, such as in the small intestine.
  • This copolymer is soluble at pH 7.0 and above, i.e., the pH generally found in the colon.
  • EUDRAGIT® S can be used alone as a coating to provide drug delivery in the large intestine.
  • EUDRAGIT® S being poorly soluble in intestinal fluids beiow pH 7, can be used in combination with EUDRAGIT® L-3QD, soluble in intestinal fluids above pH 5.5, in order to provide a delayed release composition which can be formulated to deliver the active agent to various segments of the intestinal tract.
  • EUDRAGIT L-30D used, the more proximal release and delivery begins, and the more EUDRAGIT® S used, the more distal release and delivery begins.
  • both EUDRAGIT® L-30D and EUDRAGIT® S can be replaced with other pharmaceutically acceptable polymers having similar pH solubility characteristics.
  • the preferred enteric coating is ACRYL-EZE TM (methacrylic acid co-polymer type C; Coiorcon, West Point, PA).
  • the enteric coating provides for controlled release of the active agent, such that drug release can be accomplished at some generally predictable location.
  • the enteric coating also prevents exposure of the therapeutic and/or agent and carrier to the epithelial and mucosal tissue of the buccal cavity, pharynx, esophagus, and stomach, and to the enzymes associated with these tissues.
  • the enteric coating therefore helps to protect the active agent, carrier and a patient's internal tissue from any adverse event prior to drug release at the desired site of delivery.
  • the coated material of the present invention allows optimization of drug absorption, active agent protection, and safety.
  • the coating can, and usually does, contain a plasticizer to prevent the formation of pores and cracks that would permit the penetration of the gastric fluids.
  • Suitable plasticizers include, but are not limited to, triethyl citrate (Citroflex® 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec® A2), CarbowaxTM 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate.
  • Triethyl citrate Citroflex® 2
  • triacetin glyceryl triacetate
  • acetyl triethyl citrate Citroflec® A2
  • CarbowaxTM 400 polyethylene glycol 400
  • diethyl phthalate diethyl phthalate
  • tributyl citrate acetylated monoglycerides
  • glycerol glycerol
  • a coating comprised of an anionic carboxylic acrylic polymer will usually contain approximately 10% to 25% by weight of a plasticizer, particularly dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin.
  • the coating can also contain other coating excipients such as detackifiers, antifoaming agents, lubricants (e.g., magnesium stearate), and stabilizers (e.g., hydroxypropyiceliulose, acids and bases) to soiubilize or disperse the coating material, and to improve coating performance and the coated product.
  • the coating can be applied to particles of the therapeutic and/or agent(s), tablets of the therapeutic and/or agent(s), capsules containing the therapeutic agent(s)and the like, using conventional coating methods and equipment.
  • an enteric coating can be applied to a capsule using a coating pan, an airless spray technique, fluidized bed coating equipment, or the like.
  • Detailed information concerning materials, equipment and processes for preparing coated dosage forms may be found in Pharmaceutical Dosage Forms: Tablets, eds. Lieberman et al, (New York; Marcel Dekker, Inc., 1989), and in Ansei et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th Ed. (Media, PA: Williams & Wiikins, 1995).
  • drug dosage forms comprise an enterically coated, osmotically activated device housing a formulation of the invention.
  • the drug-containing formulation is encapsulated in a semipermeable membrane or barrier containing a small orifice.
  • the semipermeable membrane allows passage of water, but not drug, in either direction. Therefore, when the device is exposed to aqueous fluids, water will flow into the device due to the osmotic pressure differential between the interior and exterior of the device.
  • the drug-containing formulation in the interior will be "pumped” out through the orifice.
  • the rate of drug release will be equivalent to the inflow rate of water times the drug concentration.
  • the rate of water influx and drug efflux can be controlled by the composition and size of the orifice of the device.
  • Suitable materials for the semipermeable membrane include, but are not limited to, polyvinyl alcohol, polyvinyl chloride, semipermeable polyethylene glycols, semipermeable poiyurethanes, semipermeable poiyamides, semipermeable sulfonated polystyrenes and polystyrene derivatives; semipermeable poly(sodium styrenesulfonate), semipermeable poly(vinylbenzyltrimethylammonium chloride), and cellulosic polymers such as cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose trivalerate, cellulose trilmate, cellulose tripalmitate, cellulose trioctanoate, cellulose tripropionate, cellulose disuccinate, cellulose dipalm ⁇ tate, cellulose dicylate, cellulose acetate succinate, cellulose propionate succinate
  • drug dosage forms are provided that comprise a sustained release coated device housing a formulation of the invention.
  • the drug- containing formulation is encapsulated in a sustained release membrane or film.
  • the membrane may be semipermeable, as described above.
  • a semipermeable membrane allows for the passage of water inside the coated device to dissolve the drug.
  • the dissolved drug solution diffuses out through the semipermeable membrane.
  • the rate of drug release depends upon the thickness of the coated film and the release of drug can begin in any part of the GI tract. Suitable membrane materials for such a membrane include ethylcellulose.
  • drug dosage forms are provided that comprise a sustained release device housing a formulation of the invention.
  • the drug-containing formulation is uniformly mixed with a sustained release polymer.
  • sustained release polymers are high molecular weight water-soluble polymers, which when in contact with water, swell and create channels for water to diffuse inside and dissolve the drug. As the polymers swell and dissolve in water, more of drug is exposed to water for dissolution.
  • sustained release matrix Such a system is generally referred to as sustained release matrix.
  • Suitable materials for such a device include hydropropyl m ethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and methyl cellulose.
  • drug dosage forms comprise an enteric coated device housing a sustained release formulation of the invention.
  • the drug containing product described above is coated with an enteric polymer.
  • Such a device would not release any drug in the stomach and when the device reaches the intestine, the enteric polymer is first dissolved and only then would the drug release begin. The drug release would take place in a sustained release fashion.
  • osmotically activated devices can be manufactured using conventional materials, methods and equipment.
  • osmotically activated devices may be made by first encapsulating, in a pharmaceutically acceptable soft capsule, a liquid or semi-solid formulation of the compounds of the invention as described previously, This interior capsule is then coated with a semipermeable membrane composition (comprising, for example, cellulose acetate and polyethylene glycol 4000 in a suitable solvent such as a methylene chloride-methanol admixture), for example using an air suspension machine, until a sufficiently thick laminate is formed, e.g., around 0.05 mm. The semipermeable laminated capsule is then dried using conventional techniques.
  • a semipermeable membrane composition comprising, for example, cellulose acetate and polyethylene glycol 4000 in a suitable solvent such as a methylene chloride-methanol admixture
  • an orifice having a desired diameter e.g., about 0.99 mm
  • a desired diameter e.g., about 0.99 mm
  • the osmotically activated device may then be enterically coated as previously described.
  • the interior capsule is optional; that is, the semipermeable membrane may be formed directly around the carrier-drug composition.
  • preferred carriers for use in the drug-containing formulation of the osmotically activated device are solutions, suspensions, liquids, immiscible liquids, emulsions, sols, colloids, and oils.
  • Particularly preferred carriers include, but are not limited to, those used for enterically coated capsules containing liquid or semisolid drug formulations.
  • Cellulose coatings include those of cellulose acetate phthalate and trimeiiitate; methacrylic acid copolymers, e.g. copolymers derived from methylacrylic acid and esters thereof, containing at least 40% methylacrylic acid; and especially hydroxypropyl methylceliulose phthalate.
  • Methylacrylates include those of molecuiar weight above 100,000 daltons based on, e.g. methylacrylate and methyl or ethyl methyiacrylate in a ratio of about 1 :1.
  • Typical products include Endragit L, e.g. L 100-55, marketed by Rohm GmbH, Darmstadt, Germany.
  • Typical cellulose acetate phthalates have an acetyl content of 17-26% and a phthalate content of from 30-40% with a viscosity of ca. 45-90 cP.
  • Typical cellulose acetate trimeiiitates have an acetyl content of 17-26%, a trimellityi content from 25-35% with a viscosity of ca. 15-20 cS.
  • An example of a cellulose acetate trimeiiitate is the marketed product CAT (Eastman Kodak Company, USA).
  • Hydroxypropyl methylceliulose phthalates typically have a molecuiar weight of from 20,000 to 130,000 daltons, a hydroxypropyl content of from 5 to 10%, a methoxy content of from 18 to 24% and a phthalyl content from 21 to 35%,
  • An example of a cellulose acetate phthalate is the marketed product CAP (Eastman Kodak, Rochester N.Y., USA).
  • hydroxypropyl methylceliulose phthalates are the marketed products having a hydroxypropyl content of from 6-10%, a methoxy content of from 20-24%, a phthalyl content of from 21-27%, a molecular weight of about 84,000 daltons, sold under the trademark HP50 and available from Shin-Etsu Chemical Co. Ltd., Tokyo, Japan, and having a hydroxypropyl content, a methoxyl content, and a phthalyl content of 5-9%, 18-22% and 27-35%, respectively, and a molecular weight of 78,000 daltons, known under the trademark HP55 and available from the same supplier.
  • a timed release system is represented by Time Erosion System (TES) by Fujisawa Pharmaceutical Co., Ltd. and Pulsincap by R. P. Scherer. According to these systems, the site of drug release is decided by the time of transit of a preparation in the gastrointestinal tract. Since the transit of a preparation in the gastrointestinal tract is largely influenced by the gastric emptying time, some time release systems are also enterically coated. [0139] Systems making use of the enterobacteria can be classified into those utilizing degradation of azoaromatic polymers by an azo reductase produced from enterobacteria as reported by the group of Ohio University (M. Saffran, e ⁇ a/., Science, Vol.
  • the therapeutic compounds may be provided in capsules, coated or not.
  • the capsule material may be either hard or soft, and as will be appreciated by those skilled in the art, typically comprises a tasteless, easily administered and water soluble compound such as gelatin, starch or a ceilulosic material.
  • the capsules are preferably sealed, such as with gelatin bands or the like. See, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Co., 1995), which describes materials and methods for preparing encapsulated pharmaceuticals.
  • a product containing one or more therapeutic compounds of the invention can be configured as a suppository.
  • the therapeutic compound of the invention can be placed anywhere within or on the suppository to favorably affect the relative release of the therapeutic compound.
  • the nature of the release can be zero order, first order, or sigmoidal, as desired.
  • Suppositories are solid dosage forms of medicine intended for administration via the rectum. Suppositories are compounded so as to melt, soften, or dissolve in the body cavity (around 98.6 0 F) thereby releasing the medication contained therein.
  • Suppository bases should be stable, no n irritating, chemically inert, and physiologically inert.
  • suppositories contain oily or fatty base materials, such as cocoa butter, coconut oil, palm kernel oil, and palm oil, which often melt or deform at room temperature necessitating cool storage or other storage limitations.
  • U.S. Patent No. 4,837,214 to Tanaka et al. describes a suppository base comprised of 80 to 99 percent by weight of a lauric-type fat having a hydroxyl value of 20 or smaller and containing glycerides of fatty acids having 8 to 18 carbon atoms combined with 1 to 20 percent by weight diglycerides of fatty acids (which erucic acid is an example of). The shelf life of these type of suppositories is limited due to degradation.
  • suppository bases contain alcohols, surfactants, and the like which raise the melting temperature but also can lead to poor absorption of the medicine and side effects due to irritation of the local mucous membranes (see for example, U.S. Patent No. 6,099,853 to Hartelendy ef a/., U.S. Patent No. 4,999,342 to Ahmad ef at., and U.S. Patent No. 4,765,978 to Abidi ef a/.).
  • the base used in the pharmaceutical suppository composition of this invention includes, in general, oils and fats comprising triglycerides as main components such as cacao butter, palm fat, palm kernel oil, coconut oil, fractionated coconut oil, lard and WITEPSOL®, waxes such as lanolin and reduced lanolin; hydrocarbons such as VASELINE®, squalene, squalane and liquid paraffin; long to medium chain fatty acids such as caprylic acid, lauric acid, stearic acid and oleic acid; higher alcohols such as lauryl alcohol, cetanol and stearyl alcohol; fatty acid esters such as butyl stearate and dtlauryl malonate; medium to long chain carboxylic acid esters of glycerin such as triolein and tristearin; glycerin-substituted carboxylic acid esters such as glycerin acetoacetate; and polyethylene glycols and its derivatives such as macrogols
  • the pharmaceutical composition of this invention may be prepared by uniformly mixing predetermined amounts of the active ingredient, the absorption aid and optionally the base, etc, in a stirrer or a grinding mill, if required at an elevated temperature.
  • the resulting composition may be formed into a suppository in unit dosage form by, for example, casting the mixture in a mold, or by forming it into a gelatin capsule using a capsule filling machine.
  • the compositions according to the present invention also can be administered as a nasal spray, nasal drop, solution, suspension, gel, ointment, cream or powder.
  • the administration of a composition can also include using a nasal tampon or a nasal sponge containing a composition of the present invention.
  • the nasal delivery systems that can be used with the present invention can take various forms including aqueous preparations, non-aqueous preparations and combinations thereof.
  • Aqueous preparations include, for example, aqueous gels, aqueous suspensions, aqueous liposomal dispersions, aqueous emulsions, aqueous microemulsions and combinations thereof.
  • Non-aqueous preparations include, for example, non-aqueous gels, nonaqueous suspensions, non-aqueous liposomal dispersions, non-aqueous emulsions, nonaqueous microemulsions and combinations thereof.
  • the various forms of the nasal delivery systems can include a buffer to maintain pH, a pharmaceutically acceptable thickening agent and a humectant.
  • the pH of the buffer can be selected to optimize the absorption of the therapeutic agent(s)across the nasal mucosa.
  • suitable forms of buffering agents can be selected such that when the formulation is delivered into the nasal cavity of a mammal, selected pH ranges are achieved therein upon contact with, e.g., a nasal mucosa.
  • the pH of the compositions may be maintained from about 2.0 to about 6.0. It is desirable that the pH of the compositions is one which does not cause significant irritation to the nasal mucosa of a recipient upon administration.
  • the viscosity of the compositions of the present invention can be maintained at a desired level using a pharmaceutically acceptable thickening agent.
  • Thickening agents that can be used in accordance with the present invention include methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof.
  • concentration of the thickening agent will depend upon the agent selected and the viscosity desired. Such agents can also be used in a powder formulation discussed above.
  • compositions of the present invention can also include a humectant to reduce or prevent drying of the mucus membrane and to prevent irritation thereof.
  • Suitable humectants that can be used in the present invention include sorbitol, mineral oil, vegetable oil and glycerol; soothing agents; membrane conditioners; sweeteners; and combinations thereof.
  • the concentration of the humectant in the present compositions will vary depending upon the agent selected.
  • One or more therapeutic and/or agents may be incorporated into the nasal delivery system or any other delivery system described herein.
  • composition formulated for topical administration may be iiquid or semi-solid
  • a gel, lotion, emulsion, cream, ointment, spray or aerosol may be provided in combination with a "finite" carrier, for example, a non-spreading material that retains its form, including, for example, a patch, bioadhesive, dressing or bandage. It may be aqueous or non-aqueous; it may be formulated as a solution, emulsion, dispersion, a suspension or any other mixture.
  • compositions provided herein may be applied topically or locally to various areas in the body of a patient.
  • topical application is intended to refer to application to the tissue of an accessible body surface, such as, for example, the skin (the outer integument or covering) and the mucosa (the mucous-producing, secreting and/or containing surfaces).
  • mucosal surfaces include the mucosal surfaces of the eyes, mouth (such as the lips, tongue, gums, cheeks, sublingual and roof of the mouth), larynx, esophagus, bronchial, nasal passages, vagina and rectum/anus; in some embodiments, preferably the mouth, larynx, esophagus, vagina and rectum/anus; in other embodiments, preferably the eyes, larynx, esophagus, bronchial, nasal passages, and vagina and rectum/anus.
  • local application refers to application to a discrete internal area of the body, such as, for example, a joint, soft tissue area (such as muscle, tendon, ligaments, intraocular or other fleshy internal areas), or other interna! area of the body.
  • a discrete internal area of the body such as, for example, a joint, soft tissue area (such as muscle, tendon, ligaments, intraocular or other fleshy internal areas), or other interna! area of the body.
  • soft tissue area such as muscle, tendon, ligaments, intraocular or other fleshy internal areas
  • local application refers to applications to discrete areas of the body.
  • desirable efficacy may involve, for example, penetration of therapeutic agent(s) of the invention into the skin and/or tissue to substantially reach systemic circulation or a peripheral or central locus.
  • the compositions may also contain a glycol, that is, a compound containing two or more hydroxy groups.
  • a glycol which may be particularly useful for use in the compositions is propylene glycol.
  • the glycol may be included in the compositions in a concentration of from greater than 0 to about 5 wt. %, based on the total weight of the composition.
  • the compositions are preferably formulated as a solution or a suspension in an aqueous-based medium, such as isotonically buffered saline or are combined with a biocompatible support or bioadhesive intended for internal administration.
  • Lotions which, for example, may be in the form of a suspension, dispersion or emulsion, contain an effective concentration of one or more of the compounds. The effective concentration is preferably to deliver an effective amount.
  • the compound of the present invention may find use at a concentration of between about 0.1-50% [by weight] or more of one or more of the compounds provided herein.
  • the lotions may contain, for example, [by weight] from 1% to 50% of an emollient and the balance water, a suitable buffer, and other agents as described above.
  • emollients known to those of skill in the art as suitable for application to human skin may be used. These include, but are not limited to, the following: (a) Hydrocarbon oils and waxes, including mineral oil, petrolatum, paraffin, ceresin, ozokerite, microcrystailine wax, polyethylene, and perhydrosqualene.
  • Silicone oils including dimethylpoiysiloxanes, methylphenylpolysiloxanes, water-soluble and alcohol-soluble silicone- glycol copolymers
  • Triglyceride fats and oils including those derived from vegetable, animal and marine sources. Examples include, but are not limited to, castor oil, safflower oil, cotton seed oil, corn oil, olive oil, cod liver oil, almond oil, avocado oil, palm oil, sesame oil, and soybean oil.
  • Acetoglyceride esters such as acetylated monoglycerides.
  • Ethoxylated glycerides such as ethoxylated glyceryl monostearate.
  • esters of fatty acids having 10 to 20 carbon atoms Methyl, isopropyl and butyl esters of fatty acids are useful herein. Examples include, but are not limited to, hexyl laurate, isohexyl laurate, isohexyl paimitate, isopropyl paimitate, isopropyl myristate, decyl oleate, isodecyl oleate, hexadecyl stearate, decyl stearate, isopropyi isostearate, diisopropyl adipate, diisohexyl adipate, dihexyldecyl adipate, diisopropy!
  • Alkenyl esters of fatty acids having 10 to 20 carbon atoms examples thereof include, but are not limited to, oleyl myristate, oleyl stearate, and oleyl oleate.
  • Suitable examples include, but are not limited to, peiargonic, lauric, myristic, palmitic, stearic, isostearic, hydroxystearic, oleic, linoleic, ricinoleic, arachidonic, behenic, and erucic acids, (t) Fatty alcohols having 10 to 22 carbon atoms, such as, but not limited to, lauryl, myristyi, cetyl, hexadecyl, stearyl, isostearyi, hydroxystearyf, oleyl, ricinoleyl, behenyl, erucyl, and 2-octyl dodecyl alcohols.
  • Fatty alcohol ethers including, but not limited to ethoxylated fatty alcohols of 10 to 20 carbon atoms, such as, but are not limited to, the lauryl, cetyl, stearyl, isostearyi, oleyl, and cholesterol alcohols having attached thereto from 1 to 50 ethylene oxide groups or 1 to 50 propylene oxide groups or mixtures thereof, (k) Ether-esters, such as fatty acid esters of ethoxylated fatty alcohols.
  • Lanolin and derivatives including, but not limited to, lanolin, lanolin oil, lanolin wax, lanolin alcohols, lanolin fatty acids, isopropyl lanolate, ethoxylated lanolin, ethoxylated lanolin alcohols, ethoxylated cholesterol, propoxylated lanolin alcohols, acetylated lanolin, acetylated lanolin alcohols, lanolin alcohols linoleate, lanolin alcohols ricinoleate, acetate of lanolin alcohols ricinoleate, acetate of ethoxylated alcohols-esters, hydrogenolysis of lanolin, ethoxylated hydrogenated lanolin, ethoxylated sorbitol lanolin, and liquid and semisolid lanolin absorption bases, (m) poiyhydric alcohols and polyether derivatives, including, but not limited to, propylene glycol, dipropylene glycol, polyethylene glycol
  • polyoxyethylene polyoxypropylene glycols poiyoxypropylene polyoxyethylene glycols, glycerol, ethoxylated glycerol, propoxylated glycerol, sorbitol, ethoxylated sorbitol, hydroxypropyl sorbitol, polyethylene glycol [M.W. 200-6000], methoxy polyethylene glycols 350, 550, 750, 2000, 5000, poly(ethylene oxide) homopolymers [M.W.
  • polyalkylene glycols and derivatives polyalkylene glycols and derivatives, hexylene glycol (2-methyi-2,4-pentanediol), 1 ,3-butylene glycol, 1 ,2,6,-hexanetrtol, ethohexadiol USP (2-ethyl-1 ,3-hexanediol), C 15 -C 18 vicinal glycol and poiyoxypropyte ⁇ e derivatives of trim ethylol propane, (n) poiyhydric alcohol esters, including, but not limited to, ethylene glycol mono- and di-fatty acid esters, diethylene glycol mono- and di- fatty acid esters, polyethylene glycol [M.W.
  • the lotions further preferably contain [by weight] from 1% to 10%, more preferably from 2% to 5%, of an emulsifier.
  • the emulsifiers can be nonionic, anionic or cationic. Examples of satisfactory nonionic emulsifiers include, but are not limited to, fatty alcohols having 10 to 20 carbon atoms, fatty alcohols having 10 to 20 carbon atoms condensed with 2 to 20 moles of ethylene oxide or propylene oxide, alkyl phenols with 6 to 12 carbon atoms in the alkyl chain condensed with 2 to 20 moles of ethylene oxide, mono- and di-fatty acid esters of ethylene oxide, mono- and di-fatty acid esters of ethylene glycol where the fatty acid moiety contains from 10 to 20 carbon atoms, diethylene glycol, polyethylene glycols of molecular weight 200 to 6000, propylene glycols of molecular weight 200 to 3000, glycerol, sorbitol, sorbitan,
  • Suitable anionic emulsifiers include, but are not limited to, the fatty acid soaps, e.g., sodium, potassium and triethanolamine soaps, where the fatty acid moiety contains from 10 to 20 carbon atoms.
  • Other suitable anionic emulsifiers include, but are not limited to, the alkali metal, ammonium or substituted ammonium alkyl sulfates, alkyl arylsulfonates, and alkyl ethoxy ether sulfonates having 10 to 30 carbon atoms in the alkyl moiety.
  • the alkyl ethoxy ether sulfonates contain from 1 to 50 ethylene oxide units.
  • cationic emulsifiers are quaternary ammonium, morpholinium and pyridinium compounds. Certain of the emollients described in preceding paragraphs also have emulsifying properties. When a lotion is formulated containing such an emollient, an additional emulsifier is not needed, though it can be included in the composition.
  • the balance of the lotion is water or a C 2 or C 3 alcohol, or a mixture of water and the alcohol.
  • the lotions are formulated by simply admixing all of the components together.
  • the compound is dissolved, suspended or otherwise uniformly dispersed in the mixture,
  • a thickening agent at a level from 1 % to 10% by weight of the composition.
  • suitable thickening agents include, but are not limited to: cross-linked carboxypolymethylene polymers, ethyl cellulose, polyethylene glycols, gum tragacanth, gum kharaya, xanthan gums and bentonite, hydroxyethyl cellulose, and hydroxypropyl cellulose.
  • Creams can be formulated to contain a concentration effective to deliver an effective amount of therapeutic agent(s) of the invention to the treated tissue, typically at between about 0.1 %, preferably at greater than 1% up to and greater than 50%, preferably between about 3% and 50%, more preferably between about 5% and 15% therapeutic agent(s) of the invention.
  • the creams also contain from 5% to 50%, preferably from 10% to 25%, of an emollient and the remainder is water or other suitable non-toxic carrier, such as an isotonic buffer.
  • the emollients, as described above for the lotions can also be used in the cream compositions.
  • the cream may also contain a suitable emulsifier, as described above.
  • the emulsifier is included in the composition at a level from 3% to 50%, preferably from 5% to 20%.
  • These compositions that are formulated as solutions or suspensions may be applied to the skin, or, may be formulated as an aerosol or foam and applied to the skin as a spray-on.
  • the aerosol compositions typically contain [by weight] from 25% to 80%, preferably from 30% to 50%, of a suitable propellant.
  • propellants are the chlorinated, fluorinated and chlorofluorinated lower molecular weight hydrocarbons. Nitrous oxide, carbon dioxide, butane, and propane are also used as propellant gases. These propellants are used as understood in the art in a quantity and under a pressure suitable to expel the contents of the container.
  • solutions and suspensions may also be topically applied to the eyes and mucosa.
  • Solutions particularly those intended for ophthalmic use, may be formulated as 0.01%-10% isotonic solutions, pH about 5-7, with appropriate salts, and preferably containing one or more of the compounds herein at a concentration of about 0.1%, preferably greater than 1%, up to 50% or more.
  • Suitable ophthalmic solutions are known [see, e.g., U.S. Pat. No, 5,116,868, which describes typical compositions of ophthalmic irrigation solutions and soiutions for topical application].
  • Such solutions which have a pH adjusted to about 7,4, contain, for example, 90-100 mM sodium chloride, 4-6 mM dibasic potassium phosphate, 4-6 mM dibasic sodium phosphate, 8-12 mM sodium citrate, 0.5-1.5 mM magnesium chloride, 1.5-2.5 mM calcium chloride, 15-25 mM sodium acetate, 10-20 mM D,L-sodium ⁇ -hydroxybutyrate and 5- 5.5 mM glucose.
  • Gel compositions can be formulated by simply admixing a suitable thickening agent to the previously described solution or suspension compositions.
  • suitable thickening agents have been previously described with respect to the lotions.
  • the gelled compositions contain an effective amount of therapeutic agent(s) of the invention, typically at a concentration of between about 0.1-50% by weight or more of one or more of the compounds provided herein.; from 5% to 75%, preferably from 10% to 50%, of an organic solvent as previously described; from 0.5% to 20%, preferably from 1% to 10% of the thickening agent; the balance being water or other aqueous or non-aqueous carrier, such as, for example, an organic liquid, or a mixture of carriers.
  • a compound or composition of the invention may be administered to a subject at least once per day, daily, every other day, every 6 to 8 days, weekly, bi-weekly, monthly, or bi-monthly.
  • the formulations can be designed and provided to create steady state plasma levels.
  • Steady state plasma concentrations can be measured using HPLC techniques, as are known to those of skill in the art.
  • Steady state is achieved when the rate of drug availability is equal to the rate of drug elimination from the circulation, in typical therapeutic and/or settings, the therapeutic agent(s) of the invention will be administered to patients either on a periodic dosing regimen or with a constant infusion regimen.
  • the concentration of drug in the plasma will tend to rise immediately after the onset of administration and will tend to fail over time as the drug is eliminated from the circulation by means of distribution into cells and tissues, by metabolism, or by excretion.
  • Steady state will be obtained when the mean drug concentration remains constant over time.
  • the pattern of the drug concentration cycle is repeated identically in each interval between doses with the mean concentration remaining constant.
  • the mean drug concentration will remain constant with very little oscillation.
  • the achievement of steady state is determined by means of measuring the concentration of drug in plasma over at least one cycle of dosing such that one can verify that the cycle is being repeated identically from dose to dose.
  • maintenance of steady state can be verified by determining drug concentrations at the consecutive troughs of a cycle, just prior to administration of another dose.
  • steady state can be verified by any two consecutive measurements of drug concentration.
  • Example 1 Preparation of Example 1: ⁇ 4-(4-(2-(Phenylamino)-6-2,2 I 2-trifluoroethoxy)pyrimidin-4- ylam ⁇ no)piperidin-1-lsulfonyl)phenyl)(pyrrolidin-1-yl)methanone
  • Example 2 4-(4-(4-fluorophenethyl)piperazin-1-y1)-6-(2,2,2-trifluoro ethoxy)-N-(3-(trifluorornethyl)phenyl)pyrimidin-2-amine [0179]
  • Example 3 4- ⁇ 4-(4-fluorobenzyl)p ⁇ perazin-1-yl)-6-(2,2,2-tr ⁇ fluoro ethoxy)-N-
  • Furfuryl amine (143 mg, 1.5 mmol) was added to a solution of 2 (400 mg, 1.5 mmol) and DIPEA (0.26 m!_, 1.5 mmot) in THF (10 ml_) at room temperature. The mixture was stirred for 24 hours at room temperature (TLC control), diluted with water and extracted with dichloromethane. The combined organic phases were concentrated at reduced pressure.
  • Furfuryl amine (143 mg, 1.5 mmol) was added to a solution of 3 (400 mg, 1.5 mmol) and DIPEA (0.26 mL, 1.5 mmol) in THF (10 mL) at room temperature. The mixture was stirred for 24 hours at room temperature (TLC control), diluted with water and extracted with dichloromethane. The combined organic phases were concentrated at reduced pressure.
  • the first approach started from benzenecarboxamidine or aminecarboxamtdine by introducing aryl or amine at C6-position in the first step.
  • the carboxamidine cyclized with diethylmalonate and further underwent chlorinated-oxidation to form dichioroaldehyde 4.
  • cyclization of 4 with various hydrazines formed the pyrazole- pyrimidine core and also introduced an N1 substituent.
  • the mono-chlorine in 6 was replaced with various primary and secondary amines or boronic acids to generate libraries with C4 variation in libraries A, C, E, S, F, K, N, H, AB, wherein:
  • R1 alkyl and aryl (benzyl, Me, Et, Pr, Phenethyl, Piperidine ethyl);
  • R4 anilines (m-, p-arnidoanilines, m-sutfamidoanilines, m-suifoneanilines etc.), primary amines (1 -substituted piperidin-4-amines), secondary amines (substituted piperazines), substituted aryi;
  • R1 alkyl and aryl (benzyl, Me, Pr, o-C!-Phenyl, p-F-Phenyl);
  • R4 anilines (p-Me-aniline, m-Me-aniline, p-F-aniline, m-F-ani)ine, m- s ⁇ lfonyiamidoanilines), primary amines (1 -substituted piperidi ⁇ -4-amines, o-Me- benzylamine);
  • R6 anilines (3,4-diF-aniline, m-F-aniline, etc), primary amines (1 -substituted piperidin-4- amines), secondary amines (substituted piperazines, pyrrolidine), Ar, ethoxy-.
  • R4 OH, anilines, p-F-benzylamine
  • R6 m-, p-sulfonyiamidophenyls, m-amidophenyls.
  • R5 m-sulfonylamidophenyts
  • reaction was monitored by TLC.
  • the reaction mixture was cooled to RT, the precipitate was filtered, and the residue was concentrated under reduced pressure.
  • the key intermediate (8) was obtained as a white precipitate, it was crystallized from ether and dried giving 8 with quantitative yield (0.430 g).
  • LCMS analysis of the reaction mixture demonstrated the presence of starting material only in the case of primary amine, and about 70% of target compound in cases of secondary amine and substituted piperazine.
  • the target compounds were purified by column chromatography with methylene chloride as eluent giving white precipitates in yields of 10-55 %.
  • reaction mixture was added 1.38 g (4,51 mmol) of TEA and 3.76 mmol of amine. Reaction mixture was stirred at 80 0 C overnight. LCMS demonstrated total conversation of starting material. The reaction mixture was evaporated and purified by column chromatography.
  • Compound 7 Compound 6 (200 mg, 0.63 mmol), boronic acid (150 mg, 0.72 mmol), and triphenylphosphine (25 mg, 0.10 mmol) were charged into the flask containing 4 mL of dioxane and 1.5 mL of 2 M aqueous Na 2 CO 3 solution. After purging the mixture with Ar for 20 min, [Pd(PPh 3 ) 4 ] catalyst (36 mg, 0,03 mmol, 5 mo! %) was added. The reaction mixture was heated at 100 0 C for 4 h under an Ar atmosphere. After cooling of the reaction mixture to RT the solvent was removed under reduced pressure to produce yellow oil. The residue was washed with water (20 mL) and extracted with CHCI 3 (20 mL). The organic layer was isolated and purified by coiumn chromatography.
  • reaction mixture was poured into water acidified with HCI and the organic phase was extracted with chloroform twice.
  • the target compound was purified by column chromatography with methylene chloride-ethanol (100:1 ) as an eluent affording oily products in 5-30 % yield (3-15 mg).
  • the 4- and 6-positions were further derivatized by O- and N-nucleophiles.
  • the chlorine at 6-position was attacked by sodium ethoxide, furfurylamine and 4-methoxyaniline to provide intermediates 4a, 5a, 6a correspondingly.
  • the last chlorine was replaced by amines to give the desired compounds.
  • PCI5 (1.2 g) was stirred at refiuxing for 2 hours and then cooied to room temperature. POCI3 was removed at reduced pressure. Crushed ice was added to the residue and the obtained mixture was stirred at room temperature. The formed solid was collected by filtration, washed with water and dried in high vacuum to give compound 3. Yield 160 mg, 47%.

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Abstract

La présente invention concerne de nouveaux composés comprenant des pyrimidines, des pyrazolopyrimidines, et des imidazolopyrimidines substituées, leurs synthèses, et des compositions les comprenant, y compris des compositions pharmaceutiques, comprenant les nouvelles pyrimidines, pyrazolopyrimidines, imidazolpyrimidines et des composés analogues. De tels composés fonctionnent en inhibant l'entrée des virus de la famille des Flaviviridae, y compris le virus de l'hépatite C (VHC), à l'intérieur des cellules qui sont susceptibles d'être infectées par les virus. Ces composés sont utiles dans le traitement, la thérapie et/ou la prophylaxie de maladies virales et d'infections, y compris l'infection par le VHC.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102827085A (zh) * 2012-09-17 2012-12-19 符爱清 2,4,5-三氯嘧啶化合物的制备方法
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US8445490B2 (en) 2009-10-14 2013-05-21 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8476431B2 (en) 2008-11-03 2013-07-02 Itellikine LLC Benzoxazole kinase inhibitors and methods of use
US8586584B2 (en) 2009-10-14 2013-11-19 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8629150B2 (en) 2011-09-28 2014-01-14 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8637542B2 (en) 2008-03-14 2014-01-28 Intellikine, Inc. Kinase inhibitors and methods of use
US8697706B2 (en) 2011-10-14 2014-04-15 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8741884B2 (en) 2010-05-04 2014-06-03 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8765944B2 (en) 2010-08-19 2014-07-01 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
WO2014135507A1 (fr) * 2013-03-07 2014-09-12 F. Hoffmann-La Roche Ag Nouveaux dérivés de pyrazole
WO2014140065A1 (fr) * 2013-03-13 2014-09-18 Sanofi N-(4-(azaindazol-6-yl)phényl)sulfonamides et leur utilisation comme produits pharmaceutiques
US8916702B2 (en) 2012-02-06 2014-12-23 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8933066B2 (en) 2011-04-14 2015-01-13 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
WO2015005491A1 (fr) 2013-07-12 2015-01-15 国立大学法人京都大学 Procédé de criblage d'une substance capable d'inhiber l'épissage anormal provoquant l'apparition ou l'évolution d'une maladie
US8940752B2 (en) 2009-06-29 2015-01-27 Incyte Corporation Pyrimidinones as PI3K inhibitors
US8993580B2 (en) 2008-03-14 2015-03-31 Intellikine Llc Benzothiazole kinase inhibitors and methods of use
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WO2015057945A1 (fr) 2013-10-18 2015-04-23 Indiana University Research And Technology Corporation Effecteurs d'assemblage de virus de l'hépatite b
US9040547B2 (en) 2011-09-22 2015-05-26 Pfizer Inc. Pyrrolopyrimidine and purine derivatives
US9062055B2 (en) 2010-06-21 2015-06-23 Incyte Corporation Fused pyrrole derivatives as PI3K inhibitors
US9096600B2 (en) 2010-12-20 2015-08-04 Incyte Corporation N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors
US9096611B2 (en) 2008-07-08 2015-08-04 Intellikine Llc Kinase inhibitors and methods of use
US9108984B2 (en) 2011-03-14 2015-08-18 Incyte Corporation Substituted diamino-pyrimidine and diamino-pyridine derivatives as PI3K inhibitors
US9126948B2 (en) 2011-03-25 2015-09-08 Incyte Holdings Corporation Pyrimidine-4,6-diamine derivatives as PI3K inhibitors
US9133190B2 (en) 2012-11-08 2015-09-15 Pfizer Inc. Heteroaromatic compounds and their use as dopamine D1 ligands
US20150266882A1 (en) * 2012-10-19 2015-09-24 Origenis Gmbh Pyrazolo[4,3-d]pyrimidines as kinase inhibitors
US9193721B2 (en) 2010-04-14 2015-11-24 Incyte Holdings Corporation Fused derivatives as PI3Kδ inhibitors
US9199982B2 (en) 2011-09-02 2015-12-01 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
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US9290496B2 (en) 2013-11-21 2016-03-22 Pfizer Inc. Purine derivatives
US9295673B2 (en) 2011-02-23 2016-03-29 Intellikine Llc Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof
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US9868744B2 (en) 2014-04-25 2018-01-16 Pfizer Inc. Heteroaromatic compounds and their use as dopamine D1 ligands
US9868743B2 (en) 2013-02-07 2018-01-16 Bristol-Myers Squibb Company Macrocyclic molecules as HCV entry inhibitors
US9988401B2 (en) 2015-05-11 2018-06-05 Incyte Corporation Crystalline forms of a PI3K inhibitor
WO2018151326A1 (fr) 2017-02-20 2018-08-23 国立大学法人京都大学 Composition pharmaceutique et méthode de traitement pour une maladie génétique associée à des anomalies d'épissage
US10077277B2 (en) 2014-06-11 2018-09-18 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
WO2019024908A1 (fr) * 2017-08-04 2019-02-07 厦门大学 Composés penta- et hexa-hétérocycliques substitués, procédé de préparation correspondant, combinaison de médicaments et utilisation associées
US20190092778A1 (en) * 2016-09-30 2019-03-28 Asana Biosciences, Llc P2x3 and/or p2x2/3 compounds and methods
US10266530B2 (en) 2016-09-09 2019-04-23 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US10273228B2 (en) 2015-04-17 2019-04-30 Indiana University Research And Technology Corporation Hepatitis B viral assembly effectors
US10280164B2 (en) 2016-09-09 2019-05-07 Incyte Corporation Pyrazolopyridone compounds and uses thereof
WO2019090272A1 (fr) 2017-11-06 2019-05-09 Flx Bio, Inc. Modulateurs du récepteur de chimiokine pour le traitement de cancers positifs au virus epstein-barr
US10336759B2 (en) 2015-02-27 2019-07-02 Incyte Corporation Salts and processes of preparing a PI3K inhibitor
CN110437253A (zh) * 2019-08-06 2019-11-12 复旦大学 含联苯结构的二芳基嘧啶并环化合物及其制备方法和用途
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WO2020063636A1 (fr) * 2018-09-27 2020-04-02 苏州锐明新药研发有限公司 Composé de pyrazolopyrimidine et son procédé de préparation et son utilisation dans la préparation d'un médicament anticancéreux
CN111170992A (zh) * 2018-11-12 2020-05-19 新发药业有限公司 一种5,6-二氢吡啶-2(1h)-酮衍生物的制备方法
WO2020117972A1 (fr) * 2018-12-04 2020-06-11 The Board Of Regents Of The University Of Texas System Agents thérapeutiques ciblant la polypose adénomateuse colique (apc) mutante pour le traitement du cancer
US10722495B2 (en) 2017-09-08 2020-07-28 Incyte Corporation Cyanoindazole compounds and uses thereof
US10745388B2 (en) 2018-02-20 2020-08-18 Incyte Corporation Indazole compounds and uses thereof
US10752635B2 (en) 2018-02-20 2020-08-25 Incyte Corporation Indazole compounds and uses thereof
CN111732575A (zh) * 2020-08-03 2020-10-02 北京鑫开元医药科技有限公司 一种n-(3-(嘧啶-2-基)苯基)苯磺酰胺类衍生物、药物组合物、制备方法及应用
US10800761B2 (en) 2018-02-20 2020-10-13 Incyte Corporation Carboxamide compounds and uses thereof
US10851109B2 (en) 2014-02-11 2020-12-01 Mitokinin Llc Compositions and methods of using the same for treatment of neurodegenerative and mitochondrial disease
US10899755B2 (en) 2018-08-08 2021-01-26 Incyte Corporation Benzothiazole compounds and uses thereof
WO2021050900A1 (fr) 2019-09-13 2021-03-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibiteurs du récepteur de la tyrosine kinase pour le traitement de maladie ou de trouble sensible à la modulation de la protéine kinase
EP3800188A1 (fr) 2019-10-02 2021-04-07 Bayer AG Pyrazolopyrimidines substituées en tant qu'inhibiteurs d'irak4
US11014929B2 (en) 2016-09-09 2021-05-25 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US11066394B2 (en) 2019-08-06 2021-07-20 Incyte Corporation Solid forms of an HPK1 inhibitor
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US11111247B2 (en) 2018-09-25 2021-09-07 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US20210290625A1 (en) * 2019-04-18 2021-09-23 Université de Liège Pyrimidine derivatives for prevention and treatment of gram-negative bacterial infection, contamination and fouling
CN113979945A (zh) * 2021-11-15 2022-01-28 湖北理工学院 一种制备3-氨基吡唑-4-甲酰胺半硫酸盐的新方法
US11242343B2 (en) 2016-09-09 2022-02-08 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11299473B2 (en) 2018-04-13 2022-04-12 Incyte Corporation Benzimidazole and indole compounds and uses thereof
WO2022123310A1 (fr) * 2020-12-11 2022-06-16 Ildong Pharmaceutical Co., Ltd. Nouveaux composés en tant qu'inhibiteurs doubles du récepteur des androgènes et de la phosphodiestérase
US11406624B2 (en) 2017-02-15 2022-08-09 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11414419B2 (en) 2017-06-21 2022-08-16 Mitokinin, Inc. Substituted purines for the treatment of neurodegenerative and mitochondrial diseases
US11939307B2 (en) 2019-11-29 2024-03-26 Institute Of Medicinal Biotechnology, Chinese Academy Of Medical Sciences Phenylmethyl-piperazine derivatives and antiviral uses thereof
WO2024168106A3 (fr) * 2023-02-09 2024-10-10 Caraway Therapeutics, Inc. Modulateurs de trpml, leurs compositions et procédés d'utilisation
WO2024168104A3 (fr) * 2023-02-09 2024-10-17 Caraway Therapeutics, Inc. Modulateurs de trpml, leurs compositions et procédés d'utilisation
US12226418B2 (en) 2018-06-01 2025-02-18 Incyte Corporation Dosing regimen for the treatment of PI3K related disorders

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5478830A (en) * 1992-05-29 1995-12-26 The Du Pont Merck Pharmaceutical Company Fused-ring heterocycles for the treatment of atherosclerosis
JP2004506737A (ja) * 2000-08-18 2004-03-04 アグーロン　ファーマシューティカルズ，インコーポレイテッド ピラゾール化合物、薬剤組成物、およびｅｒａｂまたはｈａｄｈ２活性の調節または阻害方法
WO2005121107A1 (fr) * 2004-06-09 2005-12-22 F. Hoffmann-La Roche Ag Pyrazolopyrimidines
WO2006132460A1 (fr) * 2005-06-10 2006-12-14 Dong-A Pharmaceutical.Co., Ltd. Agent pour la prevention et le traitement des maladies du foie contenant un derive de la pyrazolopyrimidine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5478830A (en) * 1992-05-29 1995-12-26 The Du Pont Merck Pharmaceutical Company Fused-ring heterocycles for the treatment of atherosclerosis
JP2004506737A (ja) * 2000-08-18 2004-03-04 アグーロン　ファーマシューティカルズ，インコーポレイテッド ピラゾール化合物、薬剤組成物、およびｅｒａｂまたはｈａｄｈ２活性の調節または阻害方法
WO2005121107A1 (fr) * 2004-06-09 2005-12-22 F. Hoffmann-La Roche Ag Pyrazolopyrimidines
WO2006132460A1 (fr) * 2005-06-10 2006-12-14 Dong-A Pharmaceutical.Co., Ltd. Agent pour la prevention et le traitement des maladies du foie contenant un derive de la pyrazolopyrimidine

Cited By (173)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9359349B2 (en) 2007-10-04 2016-06-07 Intellikine Llc Substituted quinazolines as kinase inhibitors
US8993580B2 (en) 2008-03-14 2015-03-31 Intellikine Llc Benzothiazole kinase inhibitors and methods of use
US8637542B2 (en) 2008-03-14 2014-01-28 Intellikine, Inc. Kinase inhibitors and methods of use
US9637492B2 (en) 2008-03-14 2017-05-02 Intellikine Llc Benzothiazole kinase inhibitors and methods of use
US9096611B2 (en) 2008-07-08 2015-08-04 Intellikine Llc Kinase inhibitors and methods of use
US9828378B2 (en) 2008-07-08 2017-11-28 Intellikine Llc Kinase inhibitors and methods of use
US8476431B2 (en) 2008-11-03 2013-07-02 Itellikine LLC Benzoxazole kinase inhibitors and methods of use
US8476282B2 (en) 2008-11-03 2013-07-02 Intellikine Llc Benzoxazole kinase inhibitors and methods of use
US11401280B2 (en) 2009-06-29 2022-08-02 Incyte Holdings Corporation Pyrimidinones as PI3K inhibitors
US9975907B2 (en) 2009-06-29 2018-05-22 Incyte Holdings Corporation Pyrimidinones as PI3K inhibitors
US9434746B2 (en) 2009-06-29 2016-09-06 Incyte Corporation Pyrimidinones as PI3K inhibitors
US10829502B2 (en) 2009-06-29 2020-11-10 Incyte Corporation Pyrimidinones as PI3K inhibitors
US8940752B2 (en) 2009-06-29 2015-01-27 Incyte Corporation Pyrimidinones as PI3K inhibitors
US10428087B2 (en) 2009-06-29 2019-10-01 Incyte Corporation Pyrimidinones as PI3K inhibitors
US8586584B2 (en) 2009-10-14 2013-11-19 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8445490B2 (en) 2009-10-14 2013-05-21 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US9403847B2 (en) 2009-12-18 2016-08-02 Incyte Holdings Corporation Substituted heteroaryl fused derivatives as P13K inhibitors
US9193721B2 (en) 2010-04-14 2015-11-24 Incyte Holdings Corporation Fused derivatives as PI3Kδ inhibitors
US8741884B2 (en) 2010-05-04 2014-06-03 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US9062055B2 (en) 2010-06-21 2015-06-23 Incyte Corporation Fused pyrrole derivatives as PI3K inhibitors
US8765944B2 (en) 2010-08-19 2014-07-01 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US9527848B2 (en) 2010-12-20 2016-12-27 Incyte Holdings Corporation N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors
US9096600B2 (en) 2010-12-20 2015-08-04 Incyte Corporation N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors
US9815839B2 (en) 2010-12-20 2017-11-14 Incyte Corporation N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors
US9295673B2 (en) 2011-02-23 2016-03-29 Intellikine Llc Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof
US9108984B2 (en) 2011-03-14 2015-08-18 Incyte Corporation Substituted diamino-pyrimidine and diamino-pyridine derivatives as PI3K inhibitors
US9126948B2 (en) 2011-03-25 2015-09-08 Incyte Holdings Corporation Pyrimidine-4,6-diamine derivatives as PI3K inhibitors
US8933066B2 (en) 2011-04-14 2015-01-13 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US9802937B2 (en) 2011-04-21 2017-10-31 Origenis Gmbh Substituted pyrazolo{4,3-D}pyrimidines as kinase inhibitors
US11433071B2 (en) 2011-09-02 2022-09-06 Incyte Corporation Heterocyclylamines as PI3K inhibitors
US9730939B2 (en) 2011-09-02 2017-08-15 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
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US9040547B2 (en) 2011-09-22 2015-05-26 Pfizer Inc. Pyrrolopyrimidine and purine derivatives
US8629150B2 (en) 2011-09-28 2014-01-14 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8697706B2 (en) 2011-10-14 2014-04-15 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8916702B2 (en) 2012-02-06 2014-12-23 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US9309251B2 (en) 2012-04-02 2016-04-12 Incyte Holdings Corporation Bicyclic azaheterocyclobenzylamines as PI3K inhibitors
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US9944646B2 (en) 2012-04-02 2018-04-17 Incyte Holdings Corporation Bicyclic azaheterocyclobenzylamines as PI3K inhibitors
JP2015518870A (ja) * 2012-06-07 2015-07-06 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト ピラゾロピリミドン及びタンキラーゼのピラゾロピリドン阻害剤
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CN102887860B (zh) * 2012-09-29 2015-07-01 上海泰坦科技有限公司 4-氯-6-三氟甲基嘧啶类化合物的制备方法
US9422311B2 (en) 2012-10-18 2016-08-23 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US9637491B2 (en) * 2012-10-19 2017-05-02 Origenis Gmbh Pyrazolo[4,3-D]pyrimidines as kinase inhibitors
US20150266882A1 (en) * 2012-10-19 2015-09-24 Origenis Gmbh Pyrazolo[4,3-d]pyrimidines as kinase inhibitors
US9527843B2 (en) 2012-11-08 2016-12-27 Pfizer Inc. Heteroaromatic compounds and their use as dopamine D1 ligands
US9133190B2 (en) 2012-11-08 2015-09-15 Pfizer Inc. Heteroaromatic compounds and their use as dopamine D1 ligands
JP2016503049A (ja) * 2012-12-20 2016-02-01 ユーシービー バイオファルマ エスピーアールエル 治療用に活性なピラゾロ−ピリミジン誘導体
US9624245B2 (en) 2013-02-07 2017-04-18 Bristol-Myers Squibb Company Macrocyclic compounds as HCV entry inhibitors
US9868743B2 (en) 2013-02-07 2018-01-16 Bristol-Myers Squibb Company Macrocyclic molecules as HCV entry inhibitors
WO2014135507A1 (fr) * 2013-03-07 2014-09-12 F. Hoffmann-La Roche Ag Nouveaux dérivés de pyrazole
KR20210019578A (ko) * 2013-03-07 2021-02-22 에프. 호프만-라 로슈 아게 신규 피라졸 유도체
JP2016510054A (ja) * 2013-03-07 2016-04-04 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ 新規ピラゾール誘導体
US9512132B2 (en) 2013-03-07 2016-12-06 Hoffmann-La Roche Inc. Pyrazole compounds as CB2 agonists
AU2014224784B2 (en) * 2013-03-07 2018-03-08 F. Hoffmann-La Roche Ag Novel pyrazol derivatives
JP2019055986A (ja) * 2013-03-07 2019-04-11 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ 新規ピラゾール誘導体
US9745322B2 (en) 2013-03-07 2017-08-29 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
EA027935B1 (ru) * 2013-03-07 2017-09-29 Ф. Хоффманн-Ля Рош Аг Новые производные пиразола
KR102369407B1 (ko) 2013-03-07 2022-03-02 에프. 호프만-라 로슈 아게 신규 피라졸 유도체
KR102219160B1 (ko) 2013-03-13 2021-02-23 사노피 N-(4-(아자인다졸-6-일)-페닐)-설폰아미드 및 약제로서의 그의 용도
WO2014140065A1 (fr) * 2013-03-13 2014-09-18 Sanofi N-(4-(azaindazol-6-yl)phényl)sulfonamides et leur utilisation comme produits pharmaceutiques
CN105189502A (zh) * 2013-03-13 2015-12-23 赛诺菲 N-(4-(氮杂吲唑-6-基)-苯基)-磺酰胺及其作为药物的用途
CN105189502B (zh) * 2013-03-13 2017-05-31 赛诺菲 N‑(4‑(氮杂吲唑‑6‑基)‑苯基)‑磺酰胺及其作为药物的用途
RU2671864C2 (ru) * 2013-03-13 2018-11-07 Санофи N-(4-(азаиндазол-6-ил)-фенил)-сульфонамиды и их применение в качестве лекарственных средств
TWI629275B (zh) * 2013-03-13 2018-07-11 賽諾菲公司 Ｎ－（４－（氮雜吲唑－６－基）－苯基）－磺醯胺及其作為醫藥之用途
KR20150130443A (ko) * 2013-03-13 2015-11-23 사노피 N-(4-아자인다졸-6-일)-페닐)-설폰아미드 및 약제로서의 그의 용도
US9718825B2 (en) 2013-03-13 2017-08-01 Sanofi N-(4-(azaindazol-6-yl)-phenyl)-sulfonamides and their use as pharmaceuticals
JP2016514116A (ja) * 2013-03-13 2016-05-19 サノフイ Ｎ−（４−（アザインダゾール−６−イル）−フェニル）−スルホンアミド類及び医薬としてのそれらの使用
US9580435B2 (en) 2013-05-02 2017-02-28 Hoffmann-La Roche Inc. Pyrrolo[2,3-D]pyrimidine derivatives as CB2 receptor agonists
US9505762B2 (en) 2013-05-02 2016-11-29 Hoffmann-La Roche Inc. Purine derivatives as CB2 receptor agonists
JPWO2015005491A1 (ja) * 2013-07-12 2017-03-02 国立大学法人京都大学 疾病の発症又は進行の一因となる異常スプライシングを抑制できる物質のスクリーニング方法
WO2015005491A1 (fr) 2013-07-12 2015-01-15 国立大学法人京都大学 Procédé de criblage d'une substance capable d'inhiber l'épissage anormal provoquant l'apparition ou l'évolution d'une maladie
US20160152620A1 (en) * 2013-07-12 2016-06-02 Kyoto University Method for screening substance capable of inhibiting abnormal splicing causative of onset or progress of disease
US9879014B2 (en) 2013-07-12 2018-01-30 Kyoto University Method for screening substance capable of inhibiting abnormal splicing causative of onset or progress of disease
EP3057592A4 (fr) * 2013-10-18 2017-04-19 Indiana University Research And Technology Corporation Effecteurs d'assemblage de virus de l'hépatite b
CN105828823A (zh) * 2013-10-18 2016-08-03 美国印第安纳大学研究和技术公司 乙型肝炎病毒组装效应物
US10220034B2 (en) 2013-10-18 2019-03-05 Indiana University Research And Technology Corporation Hepatitis B viral assembly effectors
WO2015057945A1 (fr) 2013-10-18 2015-04-23 Indiana University Research And Technology Corporation Effecteurs d'assemblage de virus de l'hépatite b
US9290496B2 (en) 2013-11-21 2016-03-22 Pfizer Inc. Purine derivatives
US10851109B2 (en) 2014-02-11 2020-12-01 Mitokinin Llc Compositions and methods of using the same for treatment of neurodegenerative and mitochondrial disease
AU2019202922B2 (en) * 2014-02-11 2020-12-03 Mitokinin, Inc. Compositions and methods of using the same for treatment of neurodegenerative and mitochondrial disease
US9688698B2 (en) 2014-04-25 2017-06-27 Pfizer Inc. Heteroaromatic compounds and their use as dopamine D1 ligands
US9868744B2 (en) 2014-04-25 2018-01-16 Pfizer Inc. Heteroaromatic compounds and their use as dopamine D1 ligands
US10077272B2 (en) 2014-04-25 2018-09-18 Pfizer Inc. Heteroaromatic compounds and their use as dopamine D1 ligands
US10479803B2 (en) 2014-06-11 2019-11-19 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
US11130767B2 (en) 2014-06-11 2021-09-28 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
US10077277B2 (en) 2014-06-11 2018-09-18 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
US11999751B2 (en) 2014-06-11 2024-06-04 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
EP4115882A1 (fr) 2015-01-16 2023-01-11 The General Hospital Corporation Composés permettant d'améliorer l'épissage d'arnm
WO2016115434A1 (fr) 2015-01-16 2016-07-21 The General Hospital Corporation Composés pour améliorer l'épissage de l'arnm
US10676475B2 (en) 2015-01-16 2020-06-09 The General Hospital Corporation Compounds for improving mRNA splicing
US11702417B2 (en) 2015-01-16 2023-07-18 The General Hospital Corporation Compounds for improving mRNA splicing
US10336759B2 (en) 2015-02-27 2019-07-02 Incyte Corporation Salts and processes of preparing a PI3K inhibitor
US11084822B2 (en) 2015-02-27 2021-08-10 Incyte Corporation Salts and processes of preparing a PI3K inhibitor
US12024522B2 (en) 2015-02-27 2024-07-02 Incyte Corporation Salts and processes of preparing a PI3K inhibitor
US10273228B2 (en) 2015-04-17 2019-04-30 Indiana University Research And Technology Corporation Hepatitis B viral assembly effectors
US9732097B2 (en) 2015-05-11 2017-08-15 Incyte Corporation Process for the synthesis of a phosphoinositide 3-kinase inhibitor
US10125150B2 (en) 2015-05-11 2018-11-13 Incyte Corporation Crystalline forms of a PI3K inhibitor
US9988401B2 (en) 2015-05-11 2018-06-05 Incyte Corporation Crystalline forms of a PI3K inhibitor
US11014929B2 (en) 2016-09-09 2021-05-25 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US10266530B2 (en) 2016-09-09 2019-04-23 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US10934288B2 (en) 2016-09-09 2021-03-02 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US10435405B2 (en) 2016-09-09 2019-10-08 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11795166B2 (en) 2016-09-09 2023-10-24 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11242343B2 (en) 2016-09-09 2022-02-08 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11542265B2 (en) 2016-09-09 2023-01-03 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US11891388B2 (en) 2016-09-09 2024-02-06 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US10280164B2 (en) 2016-09-09 2019-05-07 Incyte Corporation Pyrazolopyridone compounds and uses thereof
US12077543B2 (en) * 2016-09-30 2024-09-03 Asana Biosciences, Llc P2X3 and/or P2X2/3 compounds and methods
US20220227774A1 (en) * 2016-09-30 2022-07-21 Asana Biosciences, Llc P2x3 and/or p2x2/3 compounds and methods
US10611768B2 (en) * 2016-09-30 2020-04-07 Asana Biosciences, Llc P2X3 and/or P2X2/3 compounds and methods
US11339169B2 (en) * 2016-09-30 2022-05-24 Asana Biosciences, Llc P2X3 and/or P2X2/3 compounds and methods
US20190092778A1 (en) * 2016-09-30 2019-03-28 Asana Biosciences, Llc P2x3 and/or p2x2/3 compounds and methods
US11406624B2 (en) 2017-02-15 2022-08-09 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US12023338B2 (en) 2017-02-20 2024-07-02 Kyoto University Pharmaceutical composition and treatment method for genetic disease associated with splicing abnormalities
WO2018151326A1 (fr) 2017-02-20 2018-08-23 国立大学法人京都大学 Composition pharmaceutique et méthode de traitement pour une maladie génétique associée à des anomalies d'épissage
US11414419B2 (en) 2017-06-21 2022-08-16 Mitokinin, Inc. Substituted purines for the treatment of neurodegenerative and mitochondrial diseases
CN107383014A (zh) * 2017-06-21 2017-11-24 南方医科大学 一种1H‑吡唑并[3,4‑d]嘧啶类化合物及其制备方法和应用
CN110997669A (zh) * 2017-08-04 2020-04-10 厦门大学 取代五元并六元杂环类化合物、其制备方法、药物组合及其用途
US11352354B2 (en) 2017-08-04 2022-06-07 Xiamen University Substituted penta-fused hexa-heterocyclic compounds, preparation method therefor, drug combination and use thereof
WO2019024908A1 (fr) * 2017-08-04 2019-02-07 厦门大学 Composés penta- et hexa-hétérocycliques substitués, procédé de préparation correspondant, combinaison de médicaments et utilisation associées
JP7050093B2 (ja) 2017-08-04 2022-04-07 厦▲門▼大学 置換５員および６員複素環式化合物、その調製方法、薬剤の組み合わせおよびその使用
CN110997669B (zh) * 2017-08-04 2022-12-27 厦门大学 取代五元并六元杂环类化合物、其制备方法、药物组合及其用途
AU2018309245B2 (en) * 2017-08-04 2021-03-04 Xiamen University Substituted penta- and hexa-heterocyclic compounds, preparation method therefor, drug combination and use thereof
JP2020529968A (ja) * 2017-08-04 2020-10-15 厦▲門▼大学 置換５員および６員複素環式化合物、その調製方法、薬剤の組み合わせおよびその使用
US10722495B2 (en) 2017-09-08 2020-07-28 Incyte Corporation Cyanoindazole compounds and uses thereof
WO2019090272A1 (fr) 2017-11-06 2019-05-09 Flx Bio, Inc. Modulateurs du récepteur de chimiokine pour le traitement de cancers positifs au virus epstein-barr
US11730736B2 (en) 2017-11-06 2023-08-22 Rapt Therapeutics, Inc. Anticancer agents
US11492354B2 (en) 2018-02-20 2022-11-08 Incyte Corporation Indazole compounds and uses thereof
US10745388B2 (en) 2018-02-20 2020-08-18 Incyte Corporation Indazole compounds and uses thereof
US10800761B2 (en) 2018-02-20 2020-10-13 Incyte Corporation Carboxamide compounds and uses thereof
US10752635B2 (en) 2018-02-20 2020-08-25 Incyte Corporation Indazole compounds and uses thereof
US11731958B2 (en) 2018-02-20 2023-08-22 Incyte Corporation Carboxamide compounds and uses thereof
US11299473B2 (en) 2018-04-13 2022-04-12 Incyte Corporation Benzimidazole and indole compounds and uses thereof
US12226418B2 (en) 2018-06-01 2025-02-18 Incyte Corporation Dosing regimen for the treatment of PI3K related disorders
US11866426B2 (en) 2018-08-08 2024-01-09 Incyte Corporation Benzothiazole compounds and uses thereof
US10899755B2 (en) 2018-08-08 2021-01-26 Incyte Corporation Benzothiazole compounds and uses thereof
US11111247B2 (en) 2018-09-25 2021-09-07 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
WO2020063636A1 (fr) * 2018-09-27 2020-04-02 苏州锐明新药研发有限公司 Composé de pyrazolopyrimidine et son procédé de préparation et son utilisation dans la préparation d'un médicament anticancéreux
US12054488B2 (en) 2018-09-27 2024-08-06 Suzhou Raymon Pharmaceuticals Company, Ltd. Pyrazolopyrimidine compound and preparation method therefor and use thereof in preparation of anti-cancer drug
CN110950868A (zh) * 2018-09-27 2020-04-03 苏州锐明新药研发有限公司 吡唑并嘧啶化合物及制备方法与制备抗癌症药物的应用
CN110950868B (zh) * 2018-09-27 2022-05-13 苏州锐明新药研发有限公司 吡唑并嘧啶化合物及制备方法与制备抗癌症药物的应用
CN110698432A (zh) * 2018-11-07 2020-01-17 中国医学科学院医药生物技术研究所 苯甲基哌嗪类化合物及其制备方法和在抗病毒中的应用
CN110698432B (zh) * 2018-11-07 2023-02-03 中国医学科学院医药生物技术研究所 苯甲基哌嗪类化合物及其制备方法和在抗病毒中的应用
CN111170992A (zh) * 2018-11-12 2020-05-19 新发药业有限公司 一种5,6-二氢吡啶-2(1h)-酮衍生物的制备方法
CN111170992B (zh) * 2018-11-12 2021-05-14 新发药业有限公司 一种5,6-二氢吡啶-2(1h)-酮衍生物的制备方法
WO2020117972A1 (fr) * 2018-12-04 2020-06-11 The Board Of Regents Of The University Of Texas System Agents thérapeutiques ciblant la polypose adénomateuse colique (apc) mutante pour le traitement du cancer
US20210290625A1 (en) * 2019-04-18 2021-09-23 Université de Liège Pyrimidine derivatives for prevention and treatment of gram-negative bacterial infection, contamination and fouling
US11066394B2 (en) 2019-08-06 2021-07-20 Incyte Corporation Solid forms of an HPK1 inhibitor
US11787784B2 (en) 2019-08-06 2023-10-17 Incyte Corporation Solid forms of an HPK1 inhibitor
CN110437253A (zh) * 2019-08-06 2019-11-12 复旦大学 含联苯结构的二芳基嘧啶并环化合物及其制备方法和用途
WO2021050900A1 (fr) 2019-09-13 2021-03-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibiteurs du récepteur de la tyrosine kinase pour le traitement de maladie ou de trouble sensible à la modulation de la protéine kinase
WO2021064077A1 (fr) 2019-10-02 2021-04-08 Bayer Aktiengesellschaft Pyrazolopyrimidines substituées en tant qu'inhibiteurs d'irak4
EP3800188A1 (fr) 2019-10-02 2021-04-07 Bayer AG Pyrazolopyrimidines substituées en tant qu'inhibiteurs d'irak4
US11939307B2 (en) 2019-11-29 2024-03-26 Institute Of Medicinal Biotechnology, Chinese Academy Of Medical Sciences Phenylmethyl-piperazine derivatives and antiviral uses thereof
CN111732575A (zh) * 2020-08-03 2020-10-02 北京鑫开元医药科技有限公司 一种n-(3-(嘧啶-2-基)苯基)苯磺酰胺类衍生物、药物组合物、制备方法及应用
CN111732575B (zh) * 2020-08-03 2020-12-11 北京鑫开元医药科技有限公司 一种n-(3-(嘧啶-2-基)苯基)苯磺酰胺类衍生物、药物组合物、制备方法及应用
US11787812B2 (en) 2020-12-11 2023-10-17 Ildong Pharmaceutical Co., Ltd. Substituted pyrazolo[4,3-d]pyrimidines and imidazo[5,1 -f][1,2,4]triazines as androgen receptor and phosphodiesterase dual inhibitors
WO2022123310A1 (fr) * 2020-12-11 2022-06-16 Ildong Pharmaceutical Co., Ltd. Nouveaux composés en tant qu'inhibiteurs doubles du récepteur des androgènes et de la phosphodiestérase
CN113292452A (zh) * 2021-06-01 2021-08-24 山东京博生物科技有限公司 一种氰基乙酰胺的合成方法
CN113979945A (zh) * 2021-11-15 2022-01-28 湖北理工学院 一种制备3-氨基吡唑-4-甲酰胺半硫酸盐的新方法
WO2024168106A3 (fr) * 2023-02-09 2024-10-10 Caraway Therapeutics, Inc. Modulateurs de trpml, leurs compositions et procédés d'utilisation
WO2024168104A3 (fr) * 2023-02-09 2024-10-17 Caraway Therapeutics, Inc. Modulateurs de trpml, leurs compositions et procédés d'utilisation

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