WO2004113365A9 - Inhibiteurs de la tripeptide hepatite c serine protease - Google Patents

Inhibiteurs de la tripeptide hepatite c serine protease

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Publication number
WO2004113365A9
WO2004113365A9 PCT/US2004/015803 US2004015803W WO2004113365A9 WO 2004113365 A9 WO2004113365 A9 WO 2004113365A9 US 2004015803 W US2004015803 W US 2004015803W WO 2004113365 A9 WO2004113365 A9 WO 2004113365A9
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WIPO (PCT)
Prior art keywords
vinyl
butyl
compound
formula
tboc
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PCT/US2004/015803
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English (en)
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WO2004113365A3 (fr
WO2004113365A2 (fr
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Priority claimed from US10/849,107 external-priority patent/US7273851B2/en
Publication of WO2004113365A2 publication Critical patent/WO2004113365A2/fr
Publication of WO2004113365A3 publication Critical patent/WO2004113365A3/fr
Publication of WO2004113365A9 publication Critical patent/WO2004113365A9/fr

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  • the present invention relates to novel tripeptides having activity against hepatitis C virus (HCV) and useful in the treatment of HCV infections. More particularly, the invention relates to tripeptide compounds, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
  • HCV hepatitis C virus
  • HCV is the principal cause of non-A, non-B hepatitis and is an increasingly severe public health problem both in the developed and developing world. It is estimated that the virus infects over 200 million people worldwide, surpassing the number of individuals infected with the human immunodeficiency virus (HIV) by nearly five fold. HCV infected patients, due to the high percentage of individuals inflicted with chronic infections, are at an elevated risk of developing cirrhosis of the liver, subsequent hepatocellular carcinoma and terminal liver disease. HCV is the most prevalent cause of hepatocellular cancer and cause of patients requiring liver transplantations in the western world.
  • HIV human immunodeficiency virus
  • anti-HCV therapeutics There are considerable barriers to the development of anti-HCV therapeutics, which include, but are not limited to, the persistence of the virus, the genetic diversity of the virus during replication in the host, the high incident rate of the virus developing drug-resistant mutants, and the lack of reproducible infectious culture systems and small-animal models for HCV replication and pathogenesis. In a majority of cases, given the mild course of the infection and the complex biology of the liver, careful consideration must be given to antiviral drugs, which are likely to have significant side effects.
  • NS3 hepatitis C non-structural protein-3
  • HCV hepatitis C non-structural protein-3
  • the active site of the NS3 protease remains highly conserved thus making its inhibition an attractive mode of intervention.
  • Recent success in the treatment of HIV with protease inhibitors supports the concept that the inhibition of NS3 is a key target in the battle against HCV.
  • HCV is a flaviridae type RNA virus.
  • the HCV genome is enveloped and contains a single strand RNA molecule composed of circa 9600 base pairs. It encodes a polypeptide comprised of approximately 3010 amino acids.
  • the HCV polyprotein is processed by viral and host peptidase into 10 discreet peptides which serve a variety of functions. There are three structural proteins, C, El and E2.
  • the P7 protein is of unknown function and is comprised of a highly variable sequence.
  • NS2 is a zinc-dependent metalloproteinase that functions in conjunction with a portion of the NS3 protein.
  • NS3 incorporates two catalytic functions (separate from its association with NS2): a serine protease at the N-terminal end, which requires NS4A as a cofactor, and an ATP-ase-dependent helicase function at the carboxyl terminus.
  • NS4A is a tightly associated but non-covalent cofactor of the serine protease.
  • the NS3.4A protease is responsible for cleaving four sites on the viral polyprotein.
  • the NS3-NS4A cleavage is autocatalytic, occurring in cis.
  • the remaining three hydrolyses, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B all occur in trans.
  • NS3 is a serine protease which is structurally classified as a chymotrypsin-like protease. While the NS serine protease possesses proteolytic activity by itself, the HCV protease enzyme is not an efficient enzyme in terms of catalyzing polyprotein cleavage. It has been shown that a central hydrophobic region of the NS4A protein is required for this enhancement.
  • NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficacy at all of the sites.
  • a general strategy for the development of antiviral agents is to inactivate virally encoded enzymes, including NS3, that are essential for the replication of the virus.
  • Current efforts directed toward the discovery of NS 3 protease inhibitors were reviewed by S. Tan, A. Pause, Y. Shi, N. Sonenberg, Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov., 1, 867-881 (2002).
  • HCV protease inhibitors More relevant patent disclosures describing the synthesis of HCV protease inhibitors are: US 2003/0008828; WO 00/59929 (2000); WO 03/006490 (2003); WO 99/07733 (1999); WO 00/09543 (2000); WO 99/50230 (1999); U.S. Patent No. 5,861 ,297 (1999).
  • the present invention relates to novel tripeptide compounds and methods of treating a hepatitis C infection in a subject in need of such therapy with said tripeptide compounds.
  • the present invention further relates to pharmaceutical compositions comprising the compounds of the present invention, or pharmaceutically acceptable salts, esters, or prodrugs thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • a and B are independently selected from R 1 , -C(O)R,, -C(O)OR,, -C(O)NR 3 R 4 , - C(S)NR 3 R 41 Or -S(O) n R 1 ;
  • G is selected from -R 1 , -OR,, -C(O)R 1 , -C(O)OR 1 , -C(O)NR 3 R 4 , -NR 3 R 4 , or - N(R 3 )S(O) n R 1 ;
  • W is selected from a suitable leaving group, a substituted or unsubstituted heterocyclic, or a substituted or unsubstituted heteroaromatic;
  • Each R i is independently selected from: hydrogen, deuterium, acyl, silane, a substituted or unsubstituted, saturated or unsaturated aliphatic group, a substituted or unsubstituted, saturated or unsaturated alicyclic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted heterocyclic group;
  • Each of R 3 and R 4 is independently selected from: hydrogen, acyl, ester, optionally substituted amino acyl, a substituted or unsubstituted, saturated or unsaturated aliphatic group, a substituted or unsubstituted, saturated or unsaturated alicyclic group, a substituted or unsubstituted aromatic group, a
  • R 5 and R 6 are independently selected from: hydrogen, deuterium, acyl, silane, a substituted or unsubstituted, saturated or unsaturated aliphatic group, a substituted or unsubstituted, saturated or unsaturated alicyclic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, or a substituted or unsubstituted heterocyclic group alkoxy, alkyl amine, hydroxy, hydroxyl amine, carboxy, ester, amine; m is 0, 1 , or 2; n is 0, 1, or 2; and s is 1, 2, 3 or 4.
  • a first embodiment of the invention is a compound represented by Formula I as described above, or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient.
  • Representative subgenera of the invention include, but are not limited to: A compound of formula I, wherein W is OMs (-O-Mesylate).
  • X and Y are independently selected from: H, halogen, Q-C 6 alkyl, C 3 -Q 2 cycloalkyl, -CH 2 -alkylamino, -CH 2 -dialkylamino, -CH 2 -arylamino,
  • X and Y taken together with the carbon atoms occupying the 4 and 5 positions of the triazole ring, to which X and Y are attached, form a cyclic moiety selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
  • Q is selected from the group consisting of: absent, -CH 2 -, -0-, -NH-,
  • Q' is selected from the group consisting of: absent, -CH 2 -, and -NH-;
  • Y is selected from the group consisting of: H, C]-C 6 alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and M is independently selected from -R
  • Rx, R Y , and Rz are independently selected from the group consisting of H, N 3 , halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, alkylamino, dialkylamino, C]-C 6 alkynyl, substituted alkynyl, aryl, substituted aryl, -S-aryl, — S-substituted aryl, -O-aryl, -O— substituted aryl, NH-aryl, NH-substituted aryl, diarylamino, diheteroarylamino, arylalky], substituted arylalkyl, heteroaryl, substituted heteroaryl, -S-heteroaryl, -S-substituted heteroaryl, -O-heteroaryl, -O-substituted heteroaryl, — NH- heteroaryl,
  • the pharmaceutical compositions of the present invention may further contain other anti-HCV agents.
  • anti-HCV agents include, but are not limited to, ⁇ -interferon, ⁇ -interferon, ribavirin, and amantadine.
  • the pharmaceutical compositions of the present invention may further contain other HCV protease inhibitors.
  • compositions of the present invention may further comprise inhibitor(s) of other targets in the HCV life cycle, including, but not limited to, helicase, polymerase, metalloprotease, and internal ribosome entry site (IRES).
  • inhibitor(s) of other targets in the HCV life cycle including, but not limited to, helicase, polymerase, metalloprotease, and internal ribosome entry site (IRES).
  • the present invention includes methods of treating hepatitis C infections in a subject in need of such treatment by administering to said subject a therapeutically effective amount of the pharmaceutical compositions of the present invention.
  • the present invention contemplates the use of said the compounds of the instant invention or said pharmaceutical compositions for pre-treatment of invasive devices to be inserted into a subject or to treat biological samples, such as blood, prior to administration to a subject.
  • the pharmaceutical compositions of the present invention can be used to inhibit HCV replication and to lessen the risk of or the severity of HCV infection.
  • Another embodiment of the invention provides methods of treating materials that may have come in 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 of the present invention.
  • Such materials include, but are not limited to, surgical instruments and garments; blood collection apparatuses and materials and invasive devices, such as shunts, stents, etc.
  • the compounds of the present 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.
  • the present invention contemplates processes by which to make any compound delineated herein by any synthetic method disclosed herein.
  • An "aliphatic group” is non-aromatic moiety that may contain any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen, sulfur or other atoms, and optionally contain one or more units of unsaturation, e.g., double and/or triple bonds.
  • An aliphatic group may be straight chained, branched or cyclic and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms.
  • aliphatic groups include, for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Such aliphatic groups may be further substituted.
  • Suitable aliphatic or aromatic substituents include, but are not limited to, the following suitable substituents: -F, -Cl, -Br, -I, -OH, protected hydroxy, aliphatic ethers, aromatic ethers, oxo, -NO 2 , -CN, -CHO, imine, oxime, -C
  • C 2 -Ci 2 alkenyl or "C 2 -C 6 alkenyl,” as used herein, denote a monovalent group derived from a hydrocarbon moiety containing from two to twelve or two to six carbon atoms having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, alkadienes and the like.
  • substituted alkenyl refers to a "C 2 -Ci 2 alkenyl” or "C 2 -C 6 alkenyl” group as previously defined, substituted by one, two, three or more aliphatic substituents.
  • C 2 -Ci 2 alkynyl or "C 2 -C 6 alkynyl,” as used herein, denote a monovalent group derived from a hydrocarbon moiety containing from two to twelve or two to six carbon atoms having at least one carbon-carbon triple bond by the removal of a single hydrogen atom.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1 - propynyl, 1-butynyl, and the like.
  • substituted alkynyl refers to a "C 2 -Ci 2 alkynyl” or "C 2 -C 6 alkynyl” group as previously defined, substituted by one, two, three or more aliphatic substituents.
  • Ci-C 6 alkoxy refers to a Ci-C 6 alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom.
  • Q- C 6 -alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentoxy and n-hexoxy.
  • halo and halogen, as used herein, refer to an atom selected from fluorine, chlorine, bromine and iodine.
  • aryl or “aromatic” as used herein, refer to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and the like.
  • substituted aryl or “substituted aromatic,” as used herein, refer to an aryl or aromatic group substituted by one, two, three or more aromatic substituents.
  • arylalkyl refers to an ary] group attached to the parent compound via a Ci-C 3 alkyl or CpC 6 alkyl residue. Examples include, but are not limited to, benzyl, phenethyl and the like.
  • substituted arylalkyl refers to an arylalkyl group, as previously defined, substituted by one, two, three or more aromatic substituents.
  • heteroaryl or “heteroaromatic,” as used herein, refer to a mono-, bi-, or iri-cyclic aromatic radical or ring having from five to ten ring atoms of which at least one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized.
  • Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxaliny], and the like.
  • the heteroaromatic ring may be bonded to the chemical structure through a carbon or hetero atom.
  • substituted heteroaryl or “substituted heteroaromatic,” as used herein, refer to a heteroaryl or heteroaromatic group, substituted by one, two, three, or more aromatic substituents.
  • C 3 -Ci 2 -cycloalkyl or "alicyclic,” as used herein, denotes a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom. Examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl.
  • C 3 -Ci 2 -cycloalkyl or "substituted alicyclic,” as used herein, refers to an alicyclic group substituted by one, two, three or more aliphatic substituents.
  • heterocyclic refers to a non- aromatic ring, comprising three or more ring atoms, or a bi- or tri-cyclic group fused system, where (i) each ring contains between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 double bonds and each 6- membered ring has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (iv) any of the above rings may be fused to a benzene ring, and (v) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted.
  • heterocycloalkyl groups include, but are not limited to, [l,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, and tetrahydrofuryl.
  • substituted heterocycloalkyl or "substituted heterocyclic,” as used herein, refers to a heterocyclic group, as previously defined, substituted by one, two, three or more aliphatic substituents.
  • heteroarylalkyl to a heteroaryl group attached to the parent compound via a Ci-C 3 alkyl or CpC 6 alkyl residue.
  • heteroarylalkyl examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl and the like.
  • substituted heteroarylalkyl refers to a heteroarylalkyl group, as previously defined, substituted by independent replacement of one, two, or three or more aromatic substituents.
  • heterocycle refers to a heteroaromatic or a heterocyclic group as previously defined.
  • substituted heterocycle refers to a heterocycle group, as previously defined, substituted by independent replacement of one, two, or three or more aromatic substituents.
  • alkylamino refers to a group having the structure -NH(Ci-Ci 2 alkyl).
  • dialkylamino refers to a group having the structure -N(C)-Ci 2 alkyl) (C]- Ci 2 alkyl) and cyclic amines.
  • dialkylamino are, but not limited to, dimethyl amino, diethylamino, methylethylamino, piperidino, morpholino and the like.
  • alkoxycarbonyl represents an ester group, i.e., an alkoxy group, attached to the parent molecular moiety through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the like.
  • carboxydehyde refers to a group of formula -CHO.
  • carboxamide refers to a group of formula -C(O)NH(Ci- Ci 2 alkyl) or - C(O)N(Ci-C 12 alkyl) (C, -Cj 2 alkyl), -C(O)NH 2 , NHC(O)(C 1 -C 12 alkyl), N(C 1 - C 12 alkyl)C(O)(Ci-C 12 alkyl) and the like.
  • hydroxy protecting group refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
  • hydroxyl protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4- bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert- butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbony], 2,2,2- trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, l,l-dimethyl-2-propenyl, 3-methyl- 3 -butenyl, allyl, benzyl, para-methoxy
  • Preferred hydroxyl protecting groups for the present invention are acetyl (Ac or -C(O)CH 3 ), benzoyl (Bz or - C(O)C 6 H 5 ), and trimethylsilyl (TMS or-Si(CH 3 ) 3 ).
  • protected hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzyloxycarbonyl, 4- nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, l,l-dimethyl-2-prop
  • Preferred hydroxyl protecting groups for the present invention are acetyl (Ac or -C(O)CH 3 ), benzoyl (Bz or - C(O)C 6 H 5 ), and trimethylsilyl (TMS or-Si(CH 3 ) 3 ).
  • amino protecting group refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed. Amino protecting groups as known in the are described generally in T. H. Greene and P.G. M.
  • amino protecting groups include, but are not limited to, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and the like.
  • protected amino refers to an amino group protected with an amino protecting group as defined above.
  • acyl includes residues derived from acids, including but not limited to carboxylic acids, carbamic acids, carbonic acids, sulfonic acids, and phosphorous acids. Examples include aliphatic carbonyls, aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphatic sulfinyls, aromatic phosphates and aliphatic phosphates.
  • aprotic solvent refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor.
  • Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether.
  • hydrocarbons such as hexane and toluene
  • halogenated hydrocarbons such as, for example, methylene chloride, ethylene chloride, chloroform, and the like
  • heterocyclic compounds such as, for example, tetrahydrofuran and N-methylpyrrolidinone
  • ethers such as diethyl ether, bis-methoxymethyl ether.
  • protic solvent refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example.
  • Further discussions of protic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification. 4th ed., edited by John A. Riddick et al, Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.
  • the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art.
  • the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • the solvents, temperatures, reaction durations, etc. delineated herein are for purposes of illustration only and one of ordinary skill in the art will recognize that variation of the reaction conditions can produce the desired bridged macrocyclic products of the present invention.
  • Synthetic chemistry transformations and protecting group methodologies protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may 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.
  • a given biological system e.g., blood, lymphatic system, central nervous system
  • the compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- , or as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art.
  • any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon- heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.
  • pharmaceutically acceptable salt refers to those salts of the compounds formed by the process of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al.
  • salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • suitable organic acid examples include, but are not limited to, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamo
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • ester refers to esters of the compounds formed by the process of the present invention which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • prodrugs refers to those prodrugs of the compounds formed by the process of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention.
  • Prodrug as used herein means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula I.
  • prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8: 1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American
  • subject refers to an animal.
  • the animal is a mammal. More preferably the mammal is a human.
  • a subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.
  • biological sample(s) means a substance of biological origin intended for administration to a subject.
  • biological samples 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, and the like; sperm and ova; bone marrow and components thereof; or stem cells.
  • This invention also encompasses pharmaceutical compositions containing, Jason, this sentence is awkward, and methods of reducing the hepatitis C viral load in a subject through administering, pharmaceutically acceptable prodrugs of compounds of the present invention.
  • compounds having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of formula I.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters.
  • Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
  • Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including, but not limited to, ether, amine and carboxylic acid functionalities.
  • Suitable concentrations of reactants are 0.01M to 1OM, typically 0.1M to IM.
  • Suitable temperatures include -1O 0 C to 25O 0 C, typically -78°C to 150 0 C, more typically -78 0 C to 100 0 C, still more typically 0 0 C to 100 0 C
  • Reaction vessels are preferably made of any material which does not substantial interfere with the reaction. Examples include glass, plastic, and metal.
  • the pressure of the reaction can advantageously be operated at atmospheric pressure.
  • the atmospheres includes, for example, air, for oxygen and water insensitive reactions, or nitrogen or argon, for oxygen or water sensitive reactions.
  • compositions of this invention comprise a combination of a compound of the formulae described herein 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 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
  • the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.
  • the term "pharmaceutically acceptable carrier or excipient” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminun hydroxide; algin
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P.
  • injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and g
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • viral infections are treated or prevented in a subject, such as a human or lower mammal, by administering to the subject therapeutically effective amount of a compound of the present invention, in such amounts and for such time as is necessary to achieve the desired result.
  • An additional method of the present invention is the treatment of biological samples with a therapeutically effective amount of a compound of composition of the present invention in such amounts and for such time as is necessary to achieve the desired result.
  • a therapeutically effective amount" of a compound of the invention is meant a sufficient amount of the compound to treat or prevent hepatitis C infections in a subject, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
  • Another embodiment of the present invention is a method of treating a biological sample by contacting said biological sample with a therapeutically effective amount of a compound or pharmaceutical composition of the present invention.
  • the therapeutic method of the invention further comprises a co-therapeutic treatment regimen comprising administering a therapeutically effective amount of an anti-hepatitis C virus agent or inhibitor of the hepatitis C virus life cycle, in combination with a therapeutically effective amount of the compositions of the invention to treat disease in a patient.
  • a "co-therapeutic treatment regimen” means a treatment regimen wherein two drugs are administered simultaneously, in either separate or combined formulations, or sequentially at different times separated by minutes, hours or days, but in some way act together to provide the desired therapeutic response. Any known anti-hepatitis C virus agent or HCV life cycle inhibitor suitable for the treating the particular disease and the particular patient may be used in accordance with the invention.
  • Such suitable anti -hepatitis C virus agents include but are not limited to ⁇ -interferon, ⁇ - interferon, ribavarin, and adamantine.
  • Suitable HCV life cycle inhibitors include helicase, polymerase, metalloprotease, and IRES
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary.
  • 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.
  • the subject may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • the total daily therapeutically effective dose of the compounds of this invention administered to a subject in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.
  • the compounds of the formulae described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug.
  • the methods delineated herein contemplate administration of a therapeutically effective amount of compound or compound composition to achieve the desired or stated effect.
  • the pharmaceutical compositions of this invention will be administered from about 1 to about 6 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).
  • such preparations may contain from about 20% to about 80% active compound. Lower or higher doses than those recited above may be required.
  • Specific dosage and treatment regimens 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 status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician.
  • 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. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • HCV protease activity and inhibition is assayed using an internally quenched fluorogenic substrate.
  • a DABCYL and an EDANS group are attached to opposite ends of a short peptide. Quenching of the EDANS fluorescence by the DABCYL group is relieved upon proteolytic cleavage. Fluorescence was measured with a Molecular Devices Fluoromax (or equivalent) using an excitation wavelength of 355 nm and an emission wavelength of 485 nm.
  • the assay is run in Corning white half-area 96-well plates (VWR 29444-312 [Corning 3693]) with full-length NS3 HCV protease Ib tethered with NS4A cofactor (final enzyme concentration 1 to 15 nM).
  • the assay buffer is complemented with 10 ⁇ M NS4A cofactor Pep 4A (Anaspec 25336 or in-house, MW 1424.8).
  • RET Sl (Ac-Asp-Glu-Asp(EDANS)- Glu-Glu- AbU-[COO] Ala-Ser-Lys-(DABCYL)-NH 2 ,..AnaSpec 22991, MW 1548.6) is used as the fluorogenic peptide substrate.
  • the assay buffer contained 50 mM Hepes at pH 7.5, 30 mM NaCl and 10 mM BME. The enzyme reaction is followed over a 30 minutes time course at room temperature in the absence and presence of inhibitors.
  • HCV Inh 1 (Anaspec 25345, MW 796.8) Ac-Asp-Glu-Met- Glu-Glu-Cys-OH, [-20 0 C] and HCV Inh 2 (Anaspec 25346, MW 913.1) Ac-Asp-Glu- Dif-Cha-Cys-OH, were used as reference compounds.
  • HCV Cell Based Assay Quantification of HCV replicon RNA in cell lines
  • RNA is extracted and purified from cells using Qiagen Rneasy 96 Kit (Catalog No. 74182).
  • primers specific for HCV mediate both the reverse transcription (RT) of the HCV RNA and the amplification of the cDNA by polymerase chain reaction (PCR) using the TaqMan One-Step RT-PCR Master Mix Kit (Applied Biosystems catalog no. 4309169).
  • the nucleotide sequences of the RT-PCR primers which are located in the NS5B region of the HCV genome, are the following: HCV Forward primer "RBNS5bfor”: 5'GCTGCGGCCTGTCGAGCT SEQ ID No: 1 HCV Reverse primer "RBNS5Brev”: 5'CAAGGTCGTCTCCGCATAC SEQ ID No. 2
  • Detection of the RT-PCR product was accomplished using the Applied Biosystem (ABI) Prism 7700 Sequence Detection System (SDS) that detects the fluorescence that is emitted when the probe, which is labeled with a fluorescence reporter dye and a quencher dye, is processed during the PCR reaction.
  • SDS Sequence Detection System
  • the increase in the amount of fluorescence is measured during each cycle of PCR and reflects the increasing amount of RT-PCR product.
  • quantification is based on the threshold cycle, where the amplification plot crosses a defined fluorescence threshold. Comparison of the threshold cycles of the sample with a known standard provides a highly sensitive measure of relative template concentration in different samples (ABI User Bulletin #2 December 11; 1997).
  • the data is analyzed using the ABI SDS program version 1.7.
  • the relative template concentration can be converted to RNA copy numbers by employing a standard curve of HCV RNA standards with known copy number (ABI User Bulletin #2 December 1 1 , 1997).
  • the RT-PCR product was detected using the following labeled probe: 5' FAM-CGAAGCTCCAGGACTGCACGATGCT-TAMRA SEQ ID NO: 1
  • FAM Fluorescence reporter dye.
  • TAMRA: Quencher dye.
  • the RT reaction is performed at 48 0 C for 30 minutes followed by PCR.
  • GAPDH messenger RNA glyceraldehydes-3-phosphate dehydrogenase
  • the GAPDH copy number is very stable in the cell lines used.
  • GAPDH RT-PCR is performed on the same exact RNA sample from which the HCV copy number is determined.
  • the GAPDH primers and probes, as well as the standards with which to determine copy number, is contained in the ABI Pre-Developed TaqMan Assay Kit (catalog no. 4310884E).
  • the ratio of HCV/GAPDH RNA is used to calculate the activity of compounds evaluated for inhibition of HCV RNA replication.
  • HCV replicon RNA levels in Huh-1 1- 7 or 9-13 cells was determined by comparing the amount of HCV RNA normalized to GAPDH (e.g. the ratio of HCV/GAPDH) in the cells exposed to compound versus cells exposed to the 0% inhibition and the 100% inhibition controls. Specifically, cells were seeded
  • DMSO 50% inhibition control
  • IU/ml Interferon-alpha 2b 100 international units, IU/ml Interferon-alpha 2b in media/1 %DMSO or 3) media/1 %DMS0 containing a fixed concentration of compound.
  • 96 well plates as described above were then incubated at 37 0 C for 3 days (primary screening assay) or 4 days (IC50 determination).
  • A, B and C values are expressed as the ratio of HCV RNA/GAPDH RNA as determined for each sample in each well of a 96 well plate as described above. For each plate the average of 4 wells were used to define the 100% and 0% inhibition values. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one of ordinary skill in the art. All publications, patents, published patent applications, and other references mentioned herein are hereby incorporated by reference in their entirety
  • BOP is benzotriazol-l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate
  • DMAP for N,N-dimethylaminopyridine
  • DME for ethylene glycol dimethyl ether
  • HMBA 4-Hydroxymethylbenzoic acid AM resin
  • KHMDS is potassium bis(trimethylsilyl) amide
  • TMS for trimethyl silyl
  • TPP or PPh 3 for triphenylphosphine
  • tBOC or Boc for tert-butyloxy carbonyl.
  • Compounds of formula 3 may be prepared by dissolving 0.041 mmol of compound 2 and 0.123mmol of a nucleophilic heterocycle (W) in 3ml of DMF, adding 0.246mmol of cesium carbonate (80mg), and reacting at 70 0 C for 12 hours. The reaction mixture is then extracted with EtOAc and washed with IM sodium bicarbonate (2x30ml) and water (2x3OmI). The resulting organic solution is concentrated in vacuo to dryness.
  • W nucleophilic heterocycle
  • Example compounds 1-133 are prepared from the mesylate compound 2 and the appropriate substituted or unsubstituted heterocycle via the replacement method delineated above: Example 1.
  • R 5 is t-butyl, and R 6 is vinyl
  • Example 39 Compound of Formula I, wherein A is -S(O) 2 -Ri, wherein R] is cyclopentyl,
  • R 6 is vinyl
  • R 6 is vinyl
  • W is v JL
  • X is phenyl
  • Y is phenyl
  • R 5 is t-butyl
  • R 6 is vinyl
  • R 6 is vinyl
  • Example 48 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 49 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W m
  • Example 51 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 52 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 54 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 55 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 56 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 57 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 58 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 59 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 62 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 63 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • M 4-(p-trifluoromethoxyphenyl)phenyl
  • Rs is t-butyl
  • R 6 is vinyl
  • Example 64 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 65 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 66 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 67 Compound of Formula I, wherein A is tBOC, B is H, G is OEt, W is
  • Example 71 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 72 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • R 6 is vinyl
  • Example 73 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 74 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 75 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 77 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 78 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 79 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 80 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • R 6 is vinyl
  • Example 81 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 82 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 84 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 85 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 86 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 87 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 88 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • R 6 is vinyl
  • Example 90 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 91 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 92 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 93 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 94 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • R 6 is vinyl;
  • Example 95 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 96 Compound of Formula 1, wherein A is tBOC, B is H, G is OH, W is
  • Example 97 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 98 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 99 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 100 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 101 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 103 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 104 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 105 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 107 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 108 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • R O is vinyl;
  • Example 110 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 111 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 112 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 1 13 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 1 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 115 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 117 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • R 5 is t-butyl, and R 6 is vinyl
  • R 5 is t-butyl, and R 6 is vinyl
  • R 5 is t-butyl, and R 6 is vinyl
  • R 5 is t-butyl, and R 6 is vinyl
  • Example 127 Compound of Formula I, wherein A is -S(O) 2 -Ri, wherein R] is cyclopentyl,
  • Example 128 Compound of Formula I, wherein A is tBOC, B is H, G is -0-CH 2 -
  • Example 129 Compound of Formula I, wherein A is tBOC, B is H, G is -NHS(O) 2 -CH 2 -
  • Example compounds 133-168 are prepared from the tri-peptide precursor compound If and the appropriate substituted or unsubstituted heterocycle via Mitsunobu conditions:
  • Example 134 Compound of Formula I, wherein A is tBOC, B is H, G is OEt, W is
  • R 6 is vinyl;
  • Example 135. Compound of Formula I, wherein A is tBOC, B is H, G is OEt, W is
  • Rx is thiophen-3-yl
  • Ry is thiophen-3-yl
  • Rz is hydrogen
  • R 5 is t-butyl
  • R 6 is vinyl
  • Example 136 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Rx is thiophen-3-yl
  • R Y is thiophen-3-yl
  • Rz is hydrogen
  • R 5 is t-butyl
  • R 6 is vinyl
  • Example 137 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • R x is phenyl
  • R ⁇ is phenyl
  • R z is hydrogen
  • R 6 is vinyl
  • Example 138 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Rx is 4-(trifluoromethoxy)phenyl
  • R ⁇ is 4-(trifluoromethoxy)phenyl
  • Rz is hydrogen
  • R 5 is t-butyl
  • R 6 is vinyl
  • Example 139 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • R x is 4-(methanesulfonyl)phenyl
  • R ⁇ is 4-(methanesulfonyl)phenyl
  • R z is hydrogen
  • R 5 is t-butyl
  • R 6 is vinyl
  • Example 140 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 141 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 142 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 143 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 144 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 146 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 147. Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 148 Compound of Formula I, wherein A is tBOC, B is H, G is OEt, W is
  • Example 150 Compound of Formula I, wherein A is tBOC, B is H, G is OEt, W is
  • Rx is bromo
  • Ry is pyrrolid-1-yl
  • R z is hydrogen
  • R 5 is t- butyl
  • R 6 is vinyl
  • Example 151 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • R 6 is vinyl
  • Example 152 Compound of Formula I, wherein A is tBOC, B is H, G is OEt, W is
  • Example 154 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 156 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • R x is bromo
  • Ry is mercapto— 2-pryrimidine
  • Rz is hydrogen
  • Example 159 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 160 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 161 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is
  • Example 162 Compound of Formula I, wherein A is tBOC, B is H, G is OH, W is

Abstract

L'invention concerne des composés de formule (I), ou un sel, ester pharmaceutiquement acceptable, ou pro-médicament de ceux-ci, inhibant l'activité de la sérine protéase, en particulier l'activité du virus de l'hépatite C (HCV) NS3-NS4A protéase. En conséquence, les composés selon l'invention interfèrent avec le cycle de vie du virus de l'hépatite C et sont également utilisés comme agents antiviraux. L'invention concerne en outre des compositions pharmaceutiques comprenant les composés précités, pour l'administration à un sujet souffrant d'une infection HCV. L'invention concerne en outre des procédés de traitement d'une infection HCV chez un sujet, par administration d'une composition pharmaceutique comprenant les composés de l'invention.
PCT/US2004/015803 2003-06-05 2004-05-19 Inhibiteurs de la tripeptide hepatite c serine protease WO2004113365A2 (fr)

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