US20050119189A1 - Inhibitors of serine proteases, particularly HCV NS3-NS4A protease - Google Patents
Inhibitors of serine proteases, particularly HCV NS3-NS4A protease Download PDFInfo
- Publication number
- US20050119189A1 US20050119189A1 US10/943,265 US94326504A US2005119189A1 US 20050119189 A1 US20050119189 A1 US 20050119189A1 US 94326504 A US94326504 A US 94326504A US 2005119189 A1 US2005119189 A1 US 2005119189A1
- Authority
- US
- United States
- Prior art keywords
- aliphatic
- independently
- ring
- cycloalkyl
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- DNVSKRLSTIVKED-UHFFFAOYSA-N CS(C)NC1CC1 Chemical compound CS(C)NC1CC1 DNVSKRLSTIVKED-UHFFFAOYSA-N 0.000 description 1
- CCPQGEWYRYGLLE-UHFFFAOYSA-N [H]N(C(=O)C(=O)C(C)(C)C)C(C)C.[H]N(C(=O)C(=O)C(C)(C)C)C1=CC=CC=C1.[H]N(C(=O)C(=O)C(C)(C)C)C1=NOC(C)=C1.[H]N(C(=O)C(=O)C(C)(C)C)C1CC1.[H]N(C(=O)C(=O)C(C)(C)C)C1CCCC1.[H]N(C(=O)C(=O)C(C)(C)C)C1CCCCC1.[H]N(CC(C)C)C(=O)C(=O)C(C)(C)C.[H]N(CC1=CC=CC=C1)C(=O)C(=O)C(C)(C)C.[H]N(CC1CCCCC1)C(=O)C(=O)C(C)(C)C Chemical compound [H]N(C(=O)C(=O)C(C)(C)C)C(C)C.[H]N(C(=O)C(=O)C(C)(C)C)C1=CC=CC=C1.[H]N(C(=O)C(=O)C(C)(C)C)C1=NOC(C)=C1.[H]N(C(=O)C(=O)C(C)(C)C)C1CC1.[H]N(C(=O)C(=O)C(C)(C)C)C1CCCC1.[H]N(C(=O)C(=O)C(C)(C)C)C1CCCCC1.[H]N(CC(C)C)C(=O)C(=O)C(C)(C)C.[H]N(CC1=CC=CC=C1)C(=O)C(=O)C(C)(C)C.[H]N(CC1CCCCC1)C(=O)C(=O)C(C)(C)C CCPQGEWYRYGLLE-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
-
- 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
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to compounds that inhibit serine protease activity, particularly the activity of hepatitis C virus NS3-NS4A protease. As such, they act by interfering with the life cycle of the hepatitis C virus and are also useful as antiviral agents.
- the invention further relates to pharmaceutical compositions comprising these compounds either for ex vivo use or for administration to a patient suffering from HCV infection.
- the invention also relates to processes for preparing the compounds and methods of treating an HCV infection in a patient by administering a pharmaceutical composition comprising a compound of this invention.
- HCV hepatitis C virus
- the HCV genome encodes a polyprotein of 3010-3033 amino acids [Q. L. Choo, et. al., “Genetic Organization and Diversity of the Hepatitis C Virus.” Proc. Natl. Acad. Sci. USA, 88, pp. 2451-2455 (1991); N. Kato et al., “Molecular Cloning of the Human Hepatitis C Virus Genome From Japanese Patients with Non-A, Non-B Hepatitis,” Proc. Natl. Acad. Sci. USA, 87, pp. 9524-9528 (1990); A. Takamizawa et. al., “Structure and Organization of the Hepatitis C Virus Genome Isolated From Human Carriers,” J.
- the HCV nonstructural (NS) proteins are presumed to provide the essential catalytic machinery for viral replication.
- the NS proteins are derived by proteolytic cleavage of the polyprotein [R. Bartenschlager et. al., “Nonstructural Protein 3 of the Hepatitis C Virus Encodes a Serine-Type Proteinase Required for Cleavage at the NS3/4 and NS4/5 Junctions,” J. Virol., 67, pp. 3835-3844 (1993); A. Grakoui et.
- the HCV NS protein 3 contains a serine protease activity that helps process the majority of the viral enzymes, and is thus considered essential for viral replication and infectivity. It is known that mutations in the yellow fever virus NS3 protease decrease viral infectivity [Chambers, T. J. et. al., “Evidence that the N-terminal Domain of Nonstructural Protein NS3 From Yellow Fever Virus is a Serine Protease Responsible for Site-Specific Cleavages in the Viral Polyprotein”, Proc. Natl. Acad. Sci. USA, 87, pp. 8898-8902 (1990)].
- the first 181 amino acids of NS3 have been shown to contain the serine protease domain of NS3 that processes all four downstream sites of the HCV polyprotein [C. Lin et al., “Hepatitis C Virus NS3 Serine Proteinase: Trans-Cleavage Requirements and Processing Kinetics”, J. Virol., 68, pp. 8147-8157 (1994)].
- HCV NS3 serine protease and its associated cofactor, NS4A helps process all of the viral enzymes, and is thus considered essential for viral replication. This processing appears to be analogous to that carried out by the human immunodeficiency virus aspartyl protease, which is also involved in viral enzyme processing. HIV protease inhibitors, which inhibit viral protein processing, are potent antiviral agents in man, indicating that interrupting this stage of the viral life cycle results in therapeutically active agents. Consequently HCV NS3 serine protease is also an attractive target for drug discovery.
- Such inhibitors would have therapeutic potential as protease inhibitors, particularly as serine protease inhibitors, and more particularly as HCV NS3 protease inhibitors. Specifically, such compounds may be useful as antiviral agents, particularly as anti-HCV agents.
- the present invention addresses these needs by providing a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
- the invention also relates to compounds of formula I-1: or pharmaceutically acceptable salts thereof, wherein the variables are as defined herein.
- compositions that comprise the above compounds and the use thereof.
- Such compositions may be used to pre-treat invasive devices to be inserted into a patient, to treat biological samples, such as blood, prior to administration to a patient, and for direct administration to a patient.
- the composition will be used to inhibit HCV replication and to lessen the risk of or the severity of HCV infection.
- the invention also relates to processes for preparing the compounds of formula I.
- the present invention provides a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein:
- the present invention also provides a compound of formula I-1: or a pharmaceutically acceptable salt thereof, wherein:
- aryl as used herein means a monocyclic or bicyclic carbocyclic aromatic ring system. Phenyl is an example of a monocyclic aromatic ring system. Bicyclic aromatic ring systems include systems wherein both rings are aromatic, e.g., naphthyl, and systems wherein only one of the two rings is aromatic, e.g., tetralin. It is understood that as used herein, the term “(C6-C10)-aryl-” includes any one of a C6, C7, C8, C9, and C10 monocyclic or bicyclic carbocyclic aromatic ring system.
- bioisostere —CO 2 H as used in herein refers to a chemical moiety which may substitute for a carboxylic acid group in a biologically active molecule. Examples of such groups are disclosed in Christopher A. Lipinski, “Bioisosteres in Drug Design” Annual Reports in Medicinal Chemistry, 21, pp. 286-88 (1986), and in C. W. Thornber, “Isosterism and Molecular Modification in Drug Design” Chemical Society Reviews, pp. 563-580 (1979).
- Examples of such groups include, but are not limited to, —COCH 2 OH, —CONHOH, SO 2 NHR′, —SO 3 H, —PO(OH)NH 2 , —CONHCN, —OSO 3 H, —CONHSO 2 R′, —PO(OH) 2 , —PO(OH)(OR′), —PO(OH)(R′), —OPO(OH) 2 , —OPO(OH)(OR′), —OPO(OH)(R′), HNPO(OH) 2 , —NHPO(OH) (OR′), —NHPO(OH) (R′)
- heterocyclyl as used herein means a monocyclic or bicyclic non-aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from O, N, NH, S, SO, and SO 2 in a chemically stable arrangement.
- heterocyclyl one or both rings may contain said heteroatom or heteroatom groups.
- (C5-C10)-heterocyclyl- includes any one of a 5, 6, 7, 8, 9, and 10 atom monocyclic or bicyclic non-aromatic ring system having 1 to 3 heteroatoms or heteroatom groups in each ring selected from O, N, NH, and S in a chemically stable arrangement.
- heterocyclic rings examples include 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperid
- heteroaryl as used herein means a monocyclic or bicyclic aromatic ring system having 1 to 3 heteroatoms or heteroatom groups in each ring selected from O, N, NH, and S in a chemically stable arrangement.
- heteroaryl a monocyclic or bicyclic aromatic ring system having 1 to 3 heteroatoms or heteroatom groups in each ring selected from O, N, NH, and S in a chemically stable arrangement.
- heteroaryl rings examples include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl
- aliphatic as used herein means a straight chained or branched alkyl, alkenyl or alkynyl. It is understood that as used herein, the term “(C1-C12)-aliphatic-” includes any one of a C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, and C12 straight or branched alkyl chain of carbon atoms. It is also understood that alkenyl or alkynyl embodiments need at least two carbon atoms in the aliphatic chain.
- cycloalkyl or cycloalkenyl refers to a monocyclic or fused or bridged bicyclic carbocyclic ring system that is not aromatic.
- Cycloalkenyl rings have one or more units of unsaturation. It is also understood that as used herein, the term “(C3-C10)-cycloalkyl- or -cycloalkenyl-” includes any one of a C3, C4, C5, C6, C7, C8, C9, and C10 monocyclic or fused or bridged bicyclic carbocyclic ring. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, nornbornyl, adamantyl and decalin-yl.
- the carbon atom designations may have the indicated integer and any intervening integer.
- the number of carbon atoms in a (C1-C4)-alkyl group is 1, 2, 3, or 4. It should be understood that these designation refer to the total number of atoms in the appropriate group.
- the total number of carbon atoms and heteroatoms is 3 (as in aziridine), 4, 5, 6 (as in morpholine), 7, 8, 9, or 10.
- chemically stable arrangement refers to a compound structure that renders the compound sufficiently stable to allow manufacture and administration to a mammal by methods known in the art. Typically, such compounds are stable at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive condition, for at least a week.
- the radical is: wherein:
- the radical is: wherein:
- the radical is: wherein:
- the radical is: wherein:
- the radical is;
- the present invention provides a compound of formula IA: wherein:
- z is one, W is selected from: and R 6 and R 8 are as defined in any of the embodiments herein.
- W is selected from: and R 14 and R 15 are as defined in any of the embodiments herein.
- the radical is: wherein:
- the radical is: wherein:
- R 7 is hydrogen
- R 7 is hydrogen
- R 2 is hydrogen
- the radical is: wherein:
- the radical is: wherein:
- the radical is: wherein:
- the present invention provides a compound of formula IB: wherein:
- the present invention provides a compound of formula IB-1: wherein:
- z is one, W is selected from: and R 6 and R 8 are as defined in any of the embodiments herein.
- W is selected from: and R 14 and R 15 are as defined in any of the embodiments herein.
- the radical is: wherein:
- the present invention provides a compound of formula IC: wherein:
- z is 1, Z and Z′ are S, R 9 , R 9′ , R 11 , and R 11′ , are H, R 1 , R 2 , R 3 , R 4 , R 5 , R 5′ , R 7 , R 12 , and W are as defined in any of the embodiments herein and the fused benzo ring is optionally substituted with up to 3 J substituents, wherein J is as defined in any of the embodiments herein.
- z is 0, Z and Z′ are S, R 9 , R 9′ , R 11 , and R 11′ are H, R 1 , R 2 , R 3 , R 4 , R 5 , R 5′ , R 7 , R 12 , and W are as defined in any of the embodiments herein and the fused benzo ring is optionally substituted with up to 3 J substituents, wherein J is as defined in any of the embodiments herein.
- the present invention provides a compound of formula IC-1: wherein:
- z is 1, Z and Z′ are S, R 9 , R 9′ , R 11 , and R 11′ are H, R 1 , R 2 , R 3 , R 4 , R 5 , R 5′ , R 7 , R 12 , R 12′ , X, V, and W are as defined in any of the embodiments herein and the fused benzo ring is optionally substituted with up to 3 J substituents, wherein J is as defined in any of the embodiments herein.
- z is 0, Z and Z′ are S, R 9 , R 9′ , R 11 , and R 11′ are H, R 1 , R 2 , R 3 , R 4 , R 5 , R 5′ , R 7 , R 12 , R 12′ , X, V, and W are as defined in any of the embodiments herein and the fused benzo ring is optionally substituted with up to 3 J substituents, wherein J is as defined in any of the embodiments herein.
- z is one, W is selected from: and R 6 and R 8 are as defined in any of the embodiments herein.
- W is selected from: and R 14 and R 15 are as defined in any of the embodiments herein.
- the radical is: wherein:
- the radical is: wherein:
- the present invention provides a compound of formula ID: wherein:
- the present invention provides a compound of formula ID-1: wherein:
- z is 1.
- z is 0.
- z is one, W is selected from: and R 6 and R 8 are as defined in any of the embodiments herein.
- z is 0, w is selected from: and R 14 and R 15 are as defined in any of the embodiments herein.
- the radical is:
- the radical is: wherein the R 10′ group, is independently and optionally substituted with up to 3 substituents independently selected from J.
- the radical is:
- the radical is:
- the radical is:
- the radical is: wherein up to 5 atoms in R′ are optionally and independently substituted with J.
- the radical is:
- the radical is:
- the present invention provides a compound of formula IE: wherein:
- the present invention provides a compound of formula IE-1: wherein:
- z is 1.
- z is one, W is selected from: and R 6 and R 8 are as defined in any of the embodiments herein.
- W is selected from: and R 14 and R 15 are as defined in any of the embodiments herein.
- the radical is: wherein;
- the radical is:
- the radical is:
- the radical is:
- the present invention provides a compound of formula IF: wherein:
- the present invention provides a compound of formula IF-1: wherein:
- the present invention provides a compound of formula IF-2: wherein:
- W is selected from: and R 14 and R 15 are as defined in any of the embodiments herein.
- the radical is: wherein;
- the present invention provides a compound of formula IG: wherein:
- the present invention provides a compound of formula IG-1: wherein:
- z is 1.
- z is 0.
- z is one, W is selected from: and R 6 and R 8 are as defined in any of the embodiments herein.
- z is 0, w is selected from: and R 14 and R 15 are as defined in any of the embodiments herein.
- the radical is: wherein:
- the radical is:
- the present invention provides a compound of formula IH: wherein:
- the present invention provides a compound of formula 1H-1: wherein:
- z is 1.
- z is one, W is selected from: and R 6 and R 8 are as defined in any of the embodiments herein.
- W is selected from: and R 14 and R 15 are as defined in any of the embodiments herein.
- W in compounds of formula I or formula I-1 is: wherein in the W, the NR 6 R 6 is selected from —NH—(C1-C6 aliphatic), —NH—(C3-C6 cycloalkyl), —NH—CH(CH 3 )-aryl, or —NH—CH(CH 3 )-heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with up to 3 halogens.
- the NR 6 R 6 in the W radical is:
- the NR 6 R 6 in the W radical is:
- the NR 6 R 6 is:
- the NR 6 R 6 in the W radical is:
- the NR 6 R 6 in the W radical is:
- the present invention provides a compound of formula IJ: wherein:
- the present invention provides a compound of formula IJ-1: wherein:
- z is 1.
- W in compounds of formula I or formula I-1 is: wherein R 8 is as defined above.
- each R 8 together with the boron atom is a (C5-C10)-membered heterocyclic ring having no additional heteroatoms other than the boron and the two oxygen atoms.
- the heterocyclic ring is:
- W in compounds of formula I or formula I-1 is: wherein R 6 is as defined in any of the embodiments herein.
- W in compounds of formula I or formula I-1 is: wherein R 6 is as defined in any of the embodiments herein.
- W in compounds of formula I or formula I-1 is: wherein R 6 is as defined in any of the embodiments herein.
- the present invention provides a compound of formula Ij: wherein:
- z is 1.
- R 5′ is hydrogen and R 5 is:
- R 5′ is hydrogen and R 5 is:
- the present invention provides a compound of formula IK: wherein:
- the present invention provides a compound of formula IK-1: wherein:
- R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 9 , R 9′ , R 10 , R 10′ , R 11 , R 11′ , R 12′ , R 12 , X, and V are as defined in any of the embodiments herein, z is 1, and NR 6 R 6 is:
- R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 9 , R 9′ , R 10 , R 10′ , R 11 , R 11′ , R 12′ , R 12 , X, and V are as defined in any of the embodiments herein and z is 1.
- the present invention provides a compound of formula IK-2: wherein:
- W is selected from: and R 14 and R 15 are as defined in any of the embodiments herein.
- R 5′ and R 5 are:
- R 7 if present, and R 2 , R 4 , and R 12′ are each independently H, methyl, ethyl, or propyl.
- R 7 if present, and R 2 and R 4 are each H.
- the present invention provides a compound of formula IL: wherein:
- the present invention provides a compound of formula IL-1: wherein:
- R 1 , R 3 , R 6 , R 9 , R 9′ , R 10 , R 10′ , R 11 , R 11′ , R 12′ , R 12 , z, X, and V are as defined in any of the embodiments herein, and NR 6 R 6 is:
- z is one, R 1 , R 3 , R 6 , R 9 , R 9′ , R 10 , R 10′ , R 11 , R 11′ , R 12′ , R 12 , X, and V are as defined in any of the embodiments herein, and NR 6 R 6 is:
- the present invention provides a compound of formula IL-2: wherein:
- z is one, W is selected from: and R 6 and R 8 are as defined in any of the embodiments herein.
- W is selected from: and R 14 and R 15 are as defined in any of the embodiments herein.
- R 3 is:
- R 3 is:
- R 3 is:
- the present invention provides a compound of formula IM: wherein:
- the present invention provides a compound of formula IM-1: wherein:
- the present invention provides a compound of formula IM-2: wherein:
- the present invention provides a compound of formula IM-3: wherein:
- z is one, W is selected from: and R 6 and R 8 are as defined in any of the embodiments herein.
- W is selected from: and R 14 and R 15 are as defined in any of the embodiments herein.
- R 1 is:
- R 1 is:
- R 1 is cyclohexyl
- the present invention provides a compound of formula IN: wherein:
- the present invention provides a compound of formula IN-1: wherein:
- R 6 , R 9 , R 9′ , R 10 , R 10′ , R 11 , R 11′ , R 12′ , R 12 , X and V are as defined in any of the embodiments herein, and NR 6 R 6 is:
- the present invention provides a compound of formula IN-2: wherein:
- the present invention provides a compound of formula IN-3: wherein:
- z is one, W is selected from: and R 6 and R 8 are as defined in any of the embodiments herein.
- W is selected from: and R 14 and R 15 are as defined in any of the embodiments herein.
- optional J substituents on any substitutable nitrogen are selected from —R′, —N(R′) 2 , —N(R′)SO 2 R′, —SO 2 R′, —SO 2 N(R′) 2 , —C(O)R′, —C(O)OR′, —C(O)C(O)R′, —C(O)C(O)N(R′) 2 , —C(O)CH 2 C(O)R′, —C( ⁇ NH)N(R′) 2 , or —C(O)N(R′) 2 .
- no carbon atoms of R 1 , R 3 , R 5 , and R 5′ are replaced with N. NH, O, or S.
- these R 1 , R 3 , R 5 , and R 5′ groups have no J substituents.
- the compound is:
- the compounds of this invention may contain one or more asymmetric carbon atoms and thus may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention.
- Each stereogenic carbon may be of the R or S configuration.
- the compounds of this invention have the structure and stereochemistry depicted in compounds 1-12.
- Scheme 1 above provides a general route for the preparation of compounds of formula I, II, IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, IN, and IN wherein X-V is —C(O)C(O), W is —C(O)C(O)—N(R 6 ) 2 , R 2 , R 4 , and R 7 are H, and R 1 , R 3 , R 5 , R 5′ , R 9 , R 9′ , R 10 , R 10′ , R 11 , R 11′ , R 12 , and R 12′ are as described in any of the embodiments herein.
- Scheme 2 above provides a general route for the preparation of compounds of formula 26.
- commercially available amine 23 and sulfonyl chloride 24 are condensed and then hydrolyzed under basic conditions to provide intermediate acid 26.
- amine 23 and sulfonyl chloride 24 are condensed and then hydrolyzed under basic conditions to provide intermediate acid 26.
- suitable reagents may be used to prepare intermediate 26.
- Scheme 3 above provides a general route for the preparation of compounds of formula III and formula I.
- coupling of the acid 26 and amine 20 to give amide intermediate 27 may be accomplished using the conditions indicated or coupling reagents known to one of skill in the art.
- Subsequent oxidation of keto alcohol 27 with Dess Martin periodinane, or other oxidation conditions known to those skilled in the art affords compounds of formula III or formula I, wherein X-V is —C(O)S(O) 1-2 , W is —C(O)C(O)—N(R 6 ) 2 , R 2 , R 4 , and R 7 are H, and R 1 , R 3 , R 5 , R 5′ , R 9 , R 9′ , R 10 , R 10′ , R 11 , R 11′ , R 12 , and R 12′ are as described in any of the embodiments herein.
- Scheme 6 above provides a general route for the preparation of compounds of formula I and formula VI, wherein X-V is —S(O) 1-2 C(O)—, W is —C(O)C(O)—N(R 6 ) 2 , R 2 , R 4 , and R 7 are H, and R 1 , R 3 , R 5 , R 5′ , R 9 , R 9′ , R 10 , R 10′ , R 11 , R 11′ , R 12 , and R 12′ are as described in any of the embodiments herein.
- Chloroester 37 is prepared according to the methods described in J. Org. Chem ., pp. 2624-2629 (1979).
- Scheme 7 above provides a general route for the preparation of compounds of formula IB-1, formula IB, and formula IC, wherein X-V is —C(O)C(O)—, W is —C(O)C(O)—N(R 6 ) 2 , R 2 , R 4 , and R 7 are H, and n, Z, Z′, R 1 , R 3 , R 5 , R 5′ , R 9 , R 9′ , R 10 , R 10′ , R 11 , R 11′ , R 12 , and R 12′ are as described in any of the embodiments herein.
- other suitable and commercially available coupling reagents may be used to prepare intermediates 47, 49, 51, and 53.
- Boc-P3-OH may alternatively be substituted with the commercial CBz protected amino acids.
- Suitable deprotection conditions to remove the Cbz protecting groups are known to those skilled in the art.
- the oxidation of intermediate 53 to compounds of formula IB-1 may be accomplished using other suitable conditions known to the skilled artisan.
- Scheme 8 above provides a general route for the preparation of compounds of formula ID-1 and formula ID, wherein X-V is —C(O)C(O)—, W is —C(O)C(O)—N(R 6 ) 2 , R 2 , R 4 , and R 7 are H, and R 1 , R 3 , R 5 , R 5′ , R 6 , R 12 , and R 12′ are as described in any of the embodiments herein. As would be recognized by any skilled practitioner, other suitable and commercially available coupling reagents may be used to prepare intermediates 56, 58, 60, and 62.
- Boc-P3-OH may alternatively be substituted with the commercial CBz protected amino acids.
- Suitable deprotection conditions to remove the Cbz protecting groups are known to those skilled in the art.
- the oxidation of intermediate 62 to compounds of formula ID-1 may be accomplished using other suitable conditions known to the skilled artisan.
- Scheme 9 above provides a general route for the preparation of compounds of formula IE-1 and formula IE, wherein X-V is —C(O)C(O)—, W is —C(O)C(O)—N(R 6 ) 2 , R 2 R 4 , and R 7 are H, and R′, R 1 , R 3 , R 5 , R 5′ , R 6 , R 12 and R 12′ are as described in any of the embodiments herein.
- the steps used in scheme 9 could be modified by, for example, using different reagents or carrying out the reactions in a different order.
- other suitable and commercially available coupling reagents may be used to prepare intermediates 66, 67, 69, and 70.
- Cbz protected amino acids represented by, for instance, Cbz-P3-OH
- Cbz-P3-OH may alternatively be substituted with the commercial t-Boc protected amino acids.
- Suitable deprotection conditions to remove the Boc protecting groups are known to those skilled in the art.
- the oxidation of intermediate 70 to compounds of formula IE-1 may be accomplished using other suitable conditions known to the skilled artisan.
- Scheme 10 above depicts an alternative approach to preparing compounds of formulae IE-1 and IE of this invention wherein, X-V is —C(O)C(O)—, W is —C(O)C(O)—N(R 6 ) 2 , R 2 , R 4 , and R 7 are H, and R′, R 1 , R 3 , R 5 , R 5′ , R 6 , R 12 , and R 12′ are as described in any of the embodiments herein.
- a 4-hydroxyproline derivative 71 is reacted with a commercially available R′-halide (such an aryl chloride), represented by R′—X, in the presence of a suitable base (such as potassium t-butoxide) to provide a compound 72.
- R′-halide such an aryl chloride
- a suitable base such as potassium t-butoxide
- the compound 72 then may be carried on to compounds of formula IE-1 by routine methods.
- other suitable and commercially available coupling reagents may be used to prepare intermediates 74, 75, 76, and 77.
- the commercially available Boc protected amino acids represented by, for instance, Boc-P3-OH, may alternatively be substituted with the commercial CBz protected amino acids. Suitable deprotection conditions to remove the Cbz protecting groups are known to those skilled in the art.
- the oxidation of intermediate 77 to compounds of formula IE-1 may be accomplished using other suitable conditions known to the skilled artisan.
- Scheme 11 above provides a general route for the preparation of compounds of formula IF-1 and formula IF, wherein X-V is —C(O)C(O)—, W is —C(O)C(O)—N(R 6 ) 2 , R 2 , R 4 , and R 7 are H, and ring A, R 1 , R 3 , R 5 , R 5′ , R 6 , R 12 , and R 12′ are as described in any of the embodiments herein.
- the steps used in scheme 11 could be modified by, for example, using different reagents or carrying out the reactions in a different order.
- Scheme 12 above provides a synthetic route for the preparation of compound 84.
- Scheme 12 could be modified using techniques known to skilled practitioners to arrive at compound 84.
- other commercially available oxalamide esters may be converted into the corresponding acids by a route analogous to that described above.
- Scheme 13 provides a synthetic route for the preparation of non-commercially available oxalamide esters or oxalamide acids of interest. Scheme 13 may be modified using techniques known to skilled practitioners to arrive at compounds represented by formula 88.
- Scheme 14 above provides a synthetic route for the preparation of compound 1 from 89 (BOC-protected octahydro-indole-2-carboxylic acid).
- Intermediate 89 may be prepared from commercially available octahydro-indole-2-carboxylic acid (Bachem) according to the procedure described in PCT publication No. WO 03/087092 (the entire of contents of which is hereby incorporated by reference) and references cited therein.
- Scheme 14 could be modified using techniques known to skilled practitioners to arrive at compound 1.
- the experimental procedures to prepare compound 1 are further exemplified below in Example 2.
- Scheme 15 above provides a synthetic route for the preparation of Cbz-protected azabicyclo[2.2.1]heptane-3-carboxylic acid, compound 99 and the corresponding t-butyl ester, compound 100.
- the free acid 99 may be further elaborated by the route defined in scheme 1 above to prepare compounds of formulae I and IH.
- the t-butyl ester 100 may be further elaborated by a modification of schemes 9 or 10 above to give compounds of formulae I and IH.
- Scheme 16 above provides a general route for the preparation of compounds of formula IP and formula I-1, wherein R 5 is H, R 5′ is n-propyl, W is —C(O)C(O)—NH—C(R 14 )—C(O)—NH—C(R 15 )—Y, R 2 , R 4 , and R 7 are H, and ring A, X, V, R 1 , R 3 , R 5 , R 5′ , R 6 , R 9 , R 9′ , R 10 , R 10′ , R 11 , R 11′ , R 14 , R 15 , Y, z, R 12 , and R 12′ are as described in any of the embodiments herein.
- Various 3, 4, and 5-substituted proline analogues may either be purchased commercially or prepared according to known literature procedures.
- the starting 3-substituted proline analogues may be prepared according to the method of Holladay, M. W. et al., J. Med. Chem., 34, pp. 457-461 (1991).
- the cyclohexyl proline intermediates may be prepared by platinum oxide reduction of the commercially available phenyl substituted proline analogues. Such reduction conditions are well known to those skilled in the art.
- the starting 3,4-disubstituted proline analogues may be prepared according to the method of Kanamasa, S. et al., J. Org. Chem, 56, pp.
- one embodiment of this invention provides a process for preparing a compound of formula I, as defined in any of the embodiments herein, comprising the step of: reacting a compound of formula VII in the presence of a compound of formula VIII to provide a compound of formula IX: wherein:
- the 4-hydroxy group in formula VII may be converted to a leaving group.
- X is a nucleophilic oxygen which reacts with VII to provide IX.
- P1, P3, P4 refer to the residues of an HCV protease inhibitor as defined in the art and as are well known to skilled practitioners.
- the compound of formula IX may be carried on to a compound of formula I according to the methods described herein.
- Another embodiment of this invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula I or formula I-1 or pharmaceutically acceptable salts thereof.
- the compound of formula I or formula I-1 is present in an amount effective to decrease the viral load in a sample or in a patient, wherein said virus encodes a serine protease necessary for the viral life cycle, and a pharmaceutically acceptable carrier.
- salts of the compounds of this invention are preferably derived from inorganic or organic acids and bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, peroxine salt, sodium bicarbonate, sodium bicarbonate
- Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
- the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
- lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
- dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
- long chain halides such
- compositions and methods of this invention may also be modified by appending appropriate functionalities to enhance selective biological properties.
- modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
- compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
- ion exchangers alumina, aluminum stearate, lecithin
- serum proteins such as human serum albumin
- buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial g
- compositions of this invention are formulated for pharmaceutical administration to a mammal.
- said mammal is a human being.
- compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
- parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
- the compositions are administered orally or intravenously.
- Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
- the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides.
- Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
- These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
- a long-chain alcohol diluent or dispersant such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
- Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
- dosage levels of between about 0.01 and about 100 mg/kg body weight per day of the protease inhibitor compounds described herein are useful in a monotherapy for the prevention and treatment of antiviral, particularly anti-HCV mediated disease.
- dosage levels of between about 0.5 and about 75 mg/kg body weight per day of the protease inhibitor compounds described herein are useful in a monotherapy for the prevention and treatment of antiviral, particularly anti-HCV mediated disease.
- the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- a typical preparation will contain from about 5% to about 95% active compound (w/w). In one embodiment, such preparations contain from about 20% to about 80% active compound.
- compositions of this invention comprise a combination of a compound of formula I or formula I-1 and one or more additional therapeutic or prophylactic agents
- both the compound and the additional agent should be present at dosage levels of between about 10 to 100% of the dosage normally administered in a monotherapy regimen.
- the additional agent should be present at dosage levels of between about 10 to 80% of the dosage normally administered in a monotherapy regimen.
- compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
- carriers that are commonly used include lactose and corn starch.
- Lubricating agents such as magnesium stearate, are also typically added.
- useful diluents include lactose and dried cornstarch.
- aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
- compositions of this invention may be administered in the form of suppositories for rectal administration.
- suppositories may be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
- suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
- compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
- Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
- the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
- Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
- the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
- Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride.
- the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
- compositions of this invention may also be administered by nasal aerosol or inhalation.
- Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
- the pharmaceutical compositions are formulated for oral administration.
- compositions of this invention additionally comprise another anti-viral agent, preferably an anti-HCV agent.
- anti-viral agents include, but are not limited to, immunomodulatory agents, such as ⁇ -, ⁇ -, and ⁇ -interferons, pegylated derivatized interferon- ⁇ compounds, and thymosin; other anti-viral agents, such as ribavirin, amantadine, and telbivudine; other inhibitors of hepatitis C proteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors); inhibitors of other targets in the HCV life cycle, including helicase and polymerase inhibitors; inhibitors of internal ribosome entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors (e.g., compounds of U.S.
- PEG-Intron means PEG-Intron®, peginteferon alfa-2b, available from Schering Corporation, Kenilworth, N.J.;
- interferon means a member of a family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation, and modulate immune response, such as interferon alpha, interferon beta, or interferon gamma.
- the interferon is ⁇ -interferon.
- a therapeutic combination of the present invention utilizes natural alpha interferon 2a.
- the therapeutic combination of the present invention utilizes natural alpha interferon 2b.
- the therapeutic combination of the present invention utilizes recombinant alpha interferon 2a or 2b.
- the interferon is pegylated alpha interferon 2a or 2b.
- Interferons suitable for the present invention include:
- a protease inhibitor would be preferably administered orally. Interferon is not typically administered orally. Nevertheless, nothing herein limits the methods or combinations of this invention to any specific dosage forms or regime. Thus, each component of a combination according to this invention may be administered separately, together, or in any combination thereof.
- the protease inhibitor and interferon are administered in separate dosage forms.
- any additional agent is administered as part of a single dosage form with the protease inhibitor or as a separate dosage form.
- the specific amounts of each compound may be dependent on the specific amounts of each other compound in the combination.
- dosages of interferon are typically measured in IU (e.g., about 4 million IU to about 12 million IU).
- agents whether acting as an immunomodulatory agent or otherwise
- agents include, but are not limited to, interferon-alph 2B (Intron A, Schering Plough); Rebatron (Schering Plough, Inteferon-alpha 2B+Ribavirin); pegylated interferon alpha (Reddy, K. R. et al. “Efficacy and Safety of Pegylated (40-kd) interferon alpha-2a compared with interferon alpha-2a in noncirrhotic patients with chronic hepatitis C ( Hepatology, 33, pp. 433-438 (2001); consensus interferon (Kao, J.
- Interferons may ameliorate viral infections by exerting direct antiviral effects and/or by modifying the immune response to infection.
- the antiviral effects of interferons are often mediated through inhibition of viral penetration or uncoating, synthesis of viral RNA, translation of viral proteins, and/or viral assembly and release.
- non-immunomodulatory or immunomodulatory compounds may be used in combination with a compound of this invention including, but not limited to, those specified in WO 02/18369, which is incorporated herein by reference (see, e.g., page 273, lines 9-22 and page 274, line 4 to page 276, line 11).
- This invention may also involve administering a cytochrome P450 monooxygenase inhibitor.
- CYP inhibitors may be useful in increasing liver concentrations and/or increasing blood levels of compounds that are inhibited by CYP.
- any CYP inhibitor that improves the pharmacokinetics of the relevant NS3/4A protease may be used in a method of this invention.
- CYP inhibitors include, but are not limited to, ritonavir (WO 94/14436), ketoconazole, troleandomycin, 4-methylpyrazole, cyclosporin, clomethiazole, cimetidine, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, sertraline, indinavir, nelfinavir, amprenavir, fosamprenavir, saquinavir, lopinavir, delavirdine, erythromycin, VX-944, and VX-497.
- Preferred CYP inhibitors include ritonavir, ketoconazole, troleandomycin, 4-methylpyrazole, cyclosporin, and clomethiazole.
- ritonavir see U.S. Pat. No. 6,037,157, and the documents cited therein: U.S. Pat. No. 5,484,801, U.S. application Ser. No. 08/402,690, and International Applications WO 95/07696 and WO 95/09614).
- a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
- a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
- the amount of active ingredients will also depend upon the particular described compound and the presence or absence and the nature of the additional anti-viral agent in the composition.
- the invention provides a method for treating a patient infected with a virus characterized by a virally encoded serine protease that is necessary for the life cycle of the virus by administering to said patient a pharmaceutically acceptable composition of this invention.
- the methods of this invention are used to treat a patient suffering from a HCV infection. Such treatment may completely eradicate the viral infection or reduce the severity thereof.
- the patient is a human being.
- the methods of this invention additionally comprise the step of administering to said patient an anti-viral agent preferably an anti-HCV agent.
- anti-viral agents include, but are not limited to, immunomodulatory agents, such as ⁇ -, ⁇ -, and ⁇ -interferons, pegylated derivatized interferon- ⁇ compounds, and thymosin; other anti-viral agents, such as ribavirin, amantadine, and telbivudine; other inhibitors of hepatitis C proteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors); inhibitors of other targets in the HCV life cycle, including helicase and polymerase inhibitors; inhibitors of internal ribosome entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors (e.g., VX-497 and other IMPDH inhibitors disclosed in U.S. Pat. Nos. 5,807,876 and 6,498,178, mycophenolic acid and derivatives thereof
- Such additional agent may be administered to said patient as part of a single dosage form comprising both a compound of this invention and an additional anti-viral agent.
- the additional agent may be administered separately from the compound of this invention, as part of a multiple dosage form, wherein said additional agent is administered prior to, together with or following a composition comprising a compound of this invention.
- the present invention provides a method of pre-treating a biological substance intended for administration to a patient comprising the step of contacting said biological substance with a pharmaceutically acceptable composition comprising a compound of this invention.
- biological substances include, but are not limited to, blood and components thereof such as plasma, platelets, subpopulations of blood cells and the like; organs such as kidney, liver, heart, lung, etc; sperm and ova; bone marrow and components thereof, and other fluids to be infused into a patient such as saline, dextrose, etc.
- the invention provides methods of treating materials that may potentially come into contact with a virus characterized by a virally encoded serine protease necessary for its life cycle.
- This method comprises the step of contacting said material with a compound according to the invention.
- materials include, but are not limited to, surgical instruments and garments (e.g. clothes, gloves, aprons, gowns, masks, eyeglasses, footwear, etc.); laboratory instruments and garments (e.g. clothes, gloves, aprons, gowns, masks, eyeglasses, footwear, etc.); blood collection apparatuses and materials; and invasive devices, such as shunts, stents, etc.
- the compounds of this invention may be used as laboratory tools to aid in the isolation of a virally encoded serine protease.
- This method comprises the steps of providing a compound of this invention attached to a solid support; contacting said solid support with a sample containing a viral serine protease under conditions that cause said protease to bind to said solid support; and eluting said serine protease from said solid support.
- the viral serine protease isolated by this method is HCV NS3-NS4A protease.
- R t (min) refers to the HPLC retention time, in minutes, associated with the compound.
- the HPLC retention times listed were either obtained from the mass spec. data or using the following method:
- Ethyl oxanilate 83 (Aldrich, 1.0 g, 1.0 eq) in 12 mL of THF was treated dropwise with a 1N NaOH solution (5.70 mL, 1.1 eq) resulting in a white precipitate. After stirring for 3 hours at RT, 0.5N HCl and ethyl acetate were added, the organic layer separated, washed with 0.5N HCl and brine and then dried over sodium sulfate, filtered, and concentrated to give 712 mg (68%) of N-phenyl oxalamic acid 84 as a white solid with consistent analytical data.
- reaction mixture was concentrated in vacuo, diluted with ethyl acetate, the organic phase washed with 0.5N HCl, brine, saturated sodium bicarbonate solution, and brine, then dried over sodium sulfate, filtered, and concentrated in vacuo.
- Acid 84 (20 mg, 1.4 eq) in CH 2 Cl 2 (1 mL) was treated with PyBOP (53 mg, 1.2 eq) and NMM (0.028 mL, 3.0 eq) and stirred for 5 minutes. To this was added a solution of oxalamide (50 mg, 1.0 eq) and NMM (0.028 mL, 3.0 eq) in CH 2 Cl 2 (1 mL) and the mixture stirred at room temperature overnight. The mixture was diluted with ethyl acetate, the organic phase washed with 0.5N HCl, brine, saturated bicarbonate solution, and brine, then dried over sodium sulfate, filtered and concentrated in vacuo.
- Oxalamide 96 (24 mg, 1.0 eq) in CH 2 Cl 2 (1 mL) and t-BuOH (41 uL) was treated with Dess Martin periodinane (41 mg, 3.0 eq) and the suspension stirred at room temp. for 3 hours. Sodium thiosulfate was added and the mixture stirred for 15 minutes, then diluted with ethyl acetate, the organic phase washed with sodium bicarbonate solution and brine, then dried over anydrous sodium sulfate and concentrated in vacuo.
- HCV hepatitis C virus
- replicon cell monolayer was treated with a trypsin:EDTA mixture, removed, and then media A was diluted into a final concentration of 100,000 cells per ml wit. 10,000 cells in 100 ul were plated into each well of a 96-well tissue culture plate, and cultured overnight in a tissue culture incubator at 37° C.
- RNA virus such as Bovine Viral Diarrhea Virus (BVDV)
- BVDV Bovine Viral Diarrhea Virus
- RNA extraction reagents such as reagents from RNeasy kits
- Total RNA was extracted according the instruction of manufacturer with modification to improve extraction efficiency and consistency.
- total cellular RNA including HCV replicon RNA, was eluted and stored at ⁇ 80° C. until further processing.
- a Taqman real-time RT-PCR quantification assay was set up with two sets of specific primers and probe. One was for HCV and the other was for BVDV. Total RNA extractants from treated HCV replicon cells was added to the PCR reactions for quantification of both HCV and BVDV RNA in the same PCR well. Experimental failure was flagged and rejected based on the level of BVDV RNA in each well. The level of HCV RNA in each well was calculated according to a standard curve run in the same PCR plate. The percentage of inhibition or decrease of HCV RNA level due to compound treatment was calculated using the DMSO or no compound control as 0% of inhibition. The IC50 (concentration at which 50% inhibition of HCV RNA level is observed) was calculated from the titration curve of any given compound.
- Buffer 50 mM HEPES, pH 7.8; 20% glycerol; 100 mM NaCl
- Total assay volume was 100 ⁇ L.
- X1 conc. in Reagent ( ⁇ L) assay Buffer 86.5 see above 5 mM KK4A 0.5 25 ⁇ M 1 M DTT 0.5 5 mM DMSO or inhibitor 2.5 2.5% v/v 50 ⁇ M tNS3 0.05 25 nM 250 ⁇ M 5AB 20 25 ⁇ M (initiate)
- the buffer, KK4A, DTT, and tNS3 were combined; distributed 78 ⁇ L each into wells of 96 well plate. This was incubated at 30 C for ⁇ 5-10 min.
- test compound 2.5 ⁇ L was dissolved in DMSO (DMSO only for control) and added to each well. This was incubated at room temperature for 15 min.
- Solvent B HPLC grade acetonitrile+0.1% TFA Time Flow Max (min) % B (ml/min) press. 0 5 0.2 400 12 60 0.2 400 13 100 0.2 400 16 100 0.2 400 17 5 0.2 400
- Table 1 below depicts Mass Spec., HPLC, Ki and IC 50 data for certain compounds of the invention.
- Compounds with Ki's ranging from 0.25 ⁇ M to 1 ⁇ M are designated A.
- Compounds with Ki's ranging from 0.1 ⁇ M to 0.25 ⁇ M are designated B.
- Compounds with Ki's below 0.1 ⁇ M are designated C.
- Compounds with IC 50 's ranging from 0.25 ⁇ M to 1 ⁇ M are designated A.
- Compounds with IC 50 's ranging from 0.1 ⁇ M to 0.25 ⁇ M are designated B.
- Compounds with IC 50 's below 0.1 ⁇ M are designated C.
Priority Applications (3)
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US10/943,265 US20050119189A1 (en) | 2003-09-18 | 2004-09-17 | Inhibitors of serine proteases, particularly HCV NS3-NS4A protease |
US12/265,125 US8426359B2 (en) | 2003-09-18 | 2008-11-05 | Inhibitors of serine proteases, particularly HCV NS3-NS4A protease |
US13/851,303 US20130316945A1 (en) | 2003-09-18 | 2013-03-27 | Inhibitors of serine proteases, particularly hcv ns3-ns4a protease |
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US10/943,265 US20050119189A1 (en) | 2003-09-18 | 2004-09-17 | Inhibitors of serine proteases, particularly HCV NS3-NS4A protease |
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US12/265,125 Expired - Fee Related US8426359B2 (en) | 2003-09-18 | 2008-11-05 | Inhibitors of serine proteases, particularly HCV NS3-NS4A protease |
US13/851,303 Abandoned US20130316945A1 (en) | 2003-09-18 | 2013-03-27 | Inhibitors of serine proteases, particularly hcv ns3-ns4a protease |
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US13/851,303 Abandoned US20130316945A1 (en) | 2003-09-18 | 2013-03-27 | Inhibitors of serine proteases, particularly hcv ns3-ns4a protease |
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EP (1) | EP1664091A1 (fr) |
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AR (1) | AR045769A1 (fr) |
AU (1) | AU2004274468B2 (fr) |
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2004
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- 2004-09-17 WO PCT/US2004/030428 patent/WO2005028502A1/fr active Application Filing
- 2004-09-17 US US10/943,265 patent/US20050119189A1/en not_active Abandoned
- 2004-09-17 AR ARP040103367A patent/AR045769A1/es unknown
- 2004-09-17 JP JP2006527035A patent/JP4685775B2/ja not_active Expired - Fee Related
- 2004-09-17 CA CA002538791A patent/CA2538791A1/fr not_active Abandoned
- 2004-09-17 AU AU2004274468A patent/AU2004274468B2/en not_active Ceased
- 2004-09-17 TW TW093128277A patent/TW200526686A/zh unknown
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2008
- 2008-11-05 US US12/265,125 patent/US8426359B2/en not_active Expired - Fee Related
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2013
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Also Published As
Publication number | Publication date |
---|---|
US8426359B2 (en) | 2013-04-23 |
CA2538791A1 (fr) | 2005-03-31 |
JP2007536204A (ja) | 2007-12-13 |
AU2004274468A1 (en) | 2005-03-31 |
US20090291902A1 (en) | 2009-11-26 |
JP4685775B2 (ja) | 2011-05-18 |
TW200526686A (en) | 2005-08-16 |
EP1664091A1 (fr) | 2006-06-07 |
AR045769A1 (es) | 2005-11-09 |
WO2005028502A1 (fr) | 2005-03-31 |
US20130316945A1 (en) | 2013-11-28 |
AU2004274468B2 (en) | 2009-07-23 |
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