WO2000020400A1 - Nouveaux composes et compositions pour le traitement de l'hepatite c - Google Patents

Nouveaux composes et compositions pour le traitement de l'hepatite c Download PDF

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Publication number
WO2000020400A1
WO2000020400A1 PCT/US1999/022850 US9922850W WO0020400A1 WO 2000020400 A1 WO2000020400 A1 WO 2000020400A1 US 9922850 W US9922850 W US 9922850W WO 0020400 A1 WO0020400 A1 WO 0020400A1
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Prior art keywords
alkyl
hydrogen
derivatives
isomers
compound
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PCT/US1999/022850
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English (en)
Inventor
Jason M. Hataye
Kenneth Rice
Emma J. Shelton
Jeffrey R. Spencer
Vivian R. Wang
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Axys Pharmaceuticals, Inc.
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Priority to AU10990/00A priority Critical patent/AU1099000A/en
Publication of WO2000020400A1 publication Critical patent/WO2000020400A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • C07F9/65068—Five-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • the present invention relates to a novel class of compounds which are effective in inhibiting the activity of serine proteases, particularly the hepatitis C virus protease NS3, and in treating hepatitis C viral infections.
  • the present invention also relates to methods for using the compounds in treating hepatitis C viral infections and methods for making and pharmaceutical compositions containing the compounds.
  • Viral hepatitis is a hepatocellular inflammatory disease caused by specific hepatotrophic viruses. The disease can range from acute hepatitis progressing to chronic persistent hepatitis and eventual cirrhosis. Parenterally transmitted non-A, non-B viral infections cause 90 to 95% of all transfusion-associated viral hepatitis and may account for as many as 300,000 cases of hepatitis per year in the United States. Hepatitis C virus (HCV) is the apparent causative agent for most non-A, non-B hepatitis infections and is most likely the leading cause of chronic liver disease in the Western world.
  • HCV Hepatitis C virus
  • the HCV genome encodes for a single polypeptide having approximately 3010 amino acids. Five nonstructural regions, NS1 to NS5, are encoded toward the 3'-end of the genome and several structural proteins are encoded near the 3 '-end of the genome.
  • the NS3 region encodes for a serine protease that, along with an associated cofactor NS4A, is involved in processing the HCV translation product into its individual functioning structural and nonstructural proteins. Hence, functional NS3 protease is a necessary component of HCV replication.
  • HCV hepatitis Patients with acute HCV hepatitis may recover without medical intervention. However, about half of all acute infections progress to chronic persistent hepatitis, which left untreated can lead to cirrhosis and eventual death. The hepatocellular inflammatory effects of the chronic HCV hepatitis can be ameliorated with corticosteroid treatments.
  • Antiviral agents such as acyclovir or interferon- ⁇ are used to treat HCV infection.
  • Interferon- ⁇ the only approved anti-HCV therapeutic agent, is expensive and must be administered by subcutaneous injection three times a week for up to six months. Interferon- ⁇ produces improvements in liver enzymes and histology; however, HCV RNA titer frequently remains high despite long term chemotherapy. Moreover, a significant population of patients relapse when drug therapy is stopped. The overall success in treating HCV hepatitis with interferon- ⁇ is about 25%.
  • NS3 serine protease is a rational target for designing new and effective anti-HCV chemotherapies.
  • Peptide-like NS3 protease inhibitors are known and described in PCT International Applications WO 98/17679 and WO 98/22496 as anti-HCV chemotherapeutic agents.
  • the discovery and development of low molecular weight, non -peptide inhibitors of the NS3 serine protease will provide a highly effective means for treating HCV infections.
  • This application relates to a compound of Formula I:
  • nl is O, 1, 2, 3 or 4; n2 is 0, 1, 2 or 3;
  • X 3 is -O-, -S-, -S(O)- -S(O) 2 - -C(O)- -NR 8 - or -CR 8 R 9 -, wherein R 8 is hydrogen, halo, (C,. 6 )alkyl or together with R 9 forms (C 2 . 6 )alkylene or (C,.
  • R 9 is hydrogen, halo, (C,_ 6 )alkyl or as defined above, wherein any 1 to 3 carbon atoms with a free valence comprising R 8 and/or R 9 optionally independently are substituted with halo, tri(C, .6 )alkylammonio, -NR 10 R 10 , -C(O)NR 10 R 10 , -OR 10 , -C(O)OR 10 or -OC(O)R 10 , wherein
  • R 10 at each occurrence independently is hydrogen or (C, .6 )alkyl
  • R 1 at each occurrence independently is (C [ . 6 )alkyl, (C 1.6 )alkyloxy, (C,_ 6 )alkanoyloxy, (C, .6 )alkylthio, halo, hydroxy or mercapto and bonded to any annular carbon atom with a free valence comprising B;
  • R 3 is cyano, -R 11 , -CR 12 R 12 NR n R 13 , -C(NR 13 )R", -C(O)R", -C(NR 13 )NR n R 13 , -C(O)NR"R 13 , -C(O)OR u , -S(O)R", -S(O) 2 R' ⁇ -S(O) 2 NR ⁇ R 13 or -S(O) 2 OR n and bonded to any annular atom with a free valence comprising B, wherein:
  • R" is hydrogen, (C ⁇ alkyl, cyclo(C 3 . 6 )alkyl(C 0 . 3 )alkyl, heterocyclo(C 3 . 6 )alkyl(C 0 . 3 )alkyl, (C 6 . 10 )aryl(C 0.3 )alkyl, hetero(C 5 . 14 )aryl(C 0 . 3 )alkyl, polycyclo(C 9.10 )aryl(C 0.3 )alkyl or heteropolycyclo(C 8. , 0 )aryl(C 0 .
  • any alkyl moiety comprising R 11 optionally independently is substituted with 1 to 3 substitutents selected from -P(O)(OR 14 )OR 14 , -S(O) 2 OR 14 and -C(O)OR 14 and any 1 to 3 annular carbon atoms with free valences of any aromatic ring comprising R 11 optionally independently are substituted with halo, nitro, cyano, optionally halo-substituted (C,.
  • R 12 at each occurrence independently is hydrogen, (C,. 3 )alkyl or together with another R 12 and the carbon atom to which both are attached forms cyclopropyl and R 13 at each occurrence independently is hydrogen or (C,. 6 )alkyl; and R 4 is -R 15 , -OR 15 , -NR 15 R 16 , -SR 15 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 OR 15 , -S(O) 2 NR 15 R 16 ,
  • R 15 is (C, .6 )alkyl substituted with 1 to 2 radicals selected from -P(O)(OR 17 )OR 17 and -S(O) 2 OR 17 and optionally substituted with 1 to 2 radicals
  • R 17 is hydrogen or (C, .6 )alkyl
  • R 16 is hydrogen or (C,. 6 )alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.
  • a second aspect of this invention is a pharmaceutical composition which contains a compound of the invention or a N-oxide derivative, prodrug derivatives, individual isomer, mixture of isomers or pharmaceutically acceptable salt thereof in admixture with one or more suitable excipients.
  • a third aspect of this invention is a method of treating a patient infected with hepatitis C virus, which method comprises administering to the patient a therapeutically effective amount of a compound of the invention or a N-oxide derivative, prodrug derivative, individual isomer, mixture of isomers or pharmaceutically acceptable salt thereof.
  • a fourth aspect of this invention is the processes for preparing compounds of the invention and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof as set forth in "Detailed Description of the Invention".
  • Alkanoyl means the radical — C(O)R, wherein R is alkyl as defined in the Detailed
  • Alkyl for the purposes of this application, means a straight or branched, saturated or unsaturated aliphatic hydrocarbon radical having the number of carbon atoms indicated, and any ketone, thioketone or iminoketone thereof (e.g., (C [ .
  • (C 0 )alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, 3-oxopentyl, 3-thioxopentyl, 3-iminopentyl, etc.).
  • the term "(C 0 )alkyl", as in (C 6 _ 10 )aryl(C 0 . 3 )alkyl, means that the linking alkyl moiety does not exist and the aryl group is bonded directly to the point of attachment as a subsitutent.
  • Alkyloxy means the radical -OR, wherein R is alkyl as defined in the Detailed Description of the Invention, having the number of carbon atoms indicated (e.g.,
  • (C,. 6 )alkyloxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, .sec-butoxy, isobutoxy, tert-butoxy, vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethynyloxy, 1-propynyloxy, 2-propynyloxy, etc.).
  • “Ammonio" means the radical -NH 3 + .
  • Amino means the radical — NH 2 .
  • Aryl means an aromatic monocyclic or fused polycyclic hydrocarbon radical containing the number of carbon atoms indicated, wherein each ring contained therein is comprised of 6 annular members (e.g., (C 6 . 14 )aryl includes phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.).
  • Carbamoyl means the radical -C(O)NH 2 .
  • Carboxy means the radical -C(O)OH.
  • Cyano means the radical -CN.
  • Cycloalkyl means a saturated or unsaturated, monocyclic or fused polycyclic hydrocarbon radical containing the number of carbon atoms indicated, wherein each ring contained therein is comprised of 3 to 8 annular members, and any carbocyclic ketone, thioketone and iminoketone derivative thereof.
  • (C 3 _ 14 )cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, and the like.
  • “Deprotecting” refers to removing any protective groups present after the selective reaction has been carried out.
  • “Fused heterobicyclic radical” means a heterocyclic radical containing two fused rings having the number of annular members indicated, wherein at least two annular members of one ring are common to the second ring, and the carbocyclic ketone and thioketone derivatives thereof.
  • heterobicyclic radical containing from 8 to 12 annular atoms includes lH-benzimidazol-2-yl, lH-naphtho[2,3- ⁇ i]imidazol-2-yl, lH-imidazo[4,5-/]quinolin-2-yl, lH-imidazo[4,5-b]pyridin-2-yl, 2,6-dioxo-2,3,6,7-tetrahydro- lH-purin-8-yl, 2,6-dithioxo-2,3,6,9-tetrahydro-lH-purin-8-yl, 7H-purin-8-yl, l,6-dihydrocyclopentaimidazol-2-yl, 4-quinolin-2-yl, and the like.
  • Free valence when referring to atoms in the compounds of the invention, means that the atom(s) referred has the capacity to form a bond with another molecule, other than hydrogen, and, thus, comprise a substituted atom.
  • the reference when referring to a compound of the invention by formula and the attachement of a free valence not designated, it is to be understood that the reference is to all attachments possible, including to hydrogen, optional bonds or optional substituents.
  • the compound of Formula ⁇ , infra., in which the annullar atom X 8 is N refers to instances wherein the indicated nitrogen atom is attached to an annular carbon atom (i.e., when the optional bond is present) and a hydrogen atom (i.e., when the optional bond is absent).
  • Halo means fluoro, chloro, bromo or iodo.
  • Heteroaryl means an aromatic monocyclic or fused polycyclic divalent radical having the number of annular atoms indicated, wherein each ring contained therein is comprised of 5 to 6 annular members and one or more of the annular atoms is a heteroatom moiety, as defined in the Detailed Description of the Invention, and each ring contained therein is comprised of 5 to 6 annular members (e.g., hetero(C 5 .
  • aryl includes thienyl, furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxaxolyl, indolyl, benzo[b]thienyl, isobenzofuranyl, purinyl, isoquinolyl, pterdinyl, perimidinyl, imidazolyl, pyridyl, pyrazolyl, pyrazinyl, quinolyl, etc.).
  • Heterocycloalkyl means cycloalkyl, as defined above, except one or more of the annular carbon atoms indicated are replaced by a heteroatom moiety, as defined in the Detailed Description of the Invention, and any carbocyclic ketone, thioketone or iminoketone derivative thereof.
  • heterocyclo(C 5 . 14 )alkyl includes piperidyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, quinuclidinyl, morpholinyl, and the like.
  • Heterocycloalkylene means cycloalkylene, as defined above, except one or more of the annular carbon atoms indicated is replaced by a heteroatom moiety, as defined in the Detailed Description of the Invention, and any carbocyclic ketone, thioketone or iminoketone derivative thereof.
  • heterocyclo(C 3. )alkylene includes piperidylene, pyrrolidinylene, pyrrolinylene, imidazolidinylene, quinuclidinylene, morpholinylene, and the like.
  • Heteropolycycloaryl means polycycloaryl, as defined below, except one or more of the annular carbon atoms indicated are replaced by a heteroatom moiety, as set defined in the Detailed Description of the Invention, and any carbocyclic ketone, thioketone or iminoketone derivative thereof.
  • heteropolycyclo(C 8 . 10 )alkyl includes
  • Haldroxy means the radical —OH.
  • Iminoketone means the derivative -C(NR)— , wherein R is hydrogen or alkyl as defined in the Detailed Description of the Invention.
  • “Isomers” mean compounds of the invention having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed
  • enantiomers or sometimes “optical isomers".
  • a carbon atom bonded to four nonidentical substituents is termed a "chiral center”.
  • a compound with one chiral center has two enantiomeric forms of opposite chirality is termed a "racemic mixture”.
  • a compound that has more than one chiral center has 2" " ' enantiomeric pairs, where n is the number of chiral centers.
  • Compounds with more than one chiral center may exist as either an individual diasteromer or as a mixture of diastereomers, termed a "diastereomeric mixture". When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center.
  • Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
  • the substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog and the absolute descriptor R or 5 is cited in parenthesis followed by a hyphen and the chemical name of the compound.
  • Compounds of the invention that contain a chiral center can exist as individual stereoisomers or mixtures of stereoisomers. For the purposes of the this application when referring to a compound of the invention by name or by formula and the configuration is not designated, it is to be understood that the reference is to all possible configurations of the compound and the mixtures, racemic or otherwise, thereof.
  • Ketone means the derivative -C(O)— .
  • Leaving group has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under alkylating conditions, and includes, halogen, hydroxy, alkyloxy, alkylsulfonloxy (e.g., mesyloxy, ethanesulfonyloxy, etc.), arylsulfonyloxy (e.g., benzenesulfonyloxy and tosyloxy, thienyloxy), dihalophosphinoyloxy, tetrahalophosphaoxy, and the like.
  • alkylsulfonloxy e.g., mesyloxy, ethanesulfonyloxy, etc.
  • arylsulfonyloxy e.g., benzenesulfonyloxy and tosyloxy, thienyloxy
  • dihalophosphinoyloxy tetrahalopho
  • N-oxide derivatives means derivatives of compounds of the invention in which nitrogens are in an oxidized state (i.e., O ⁇ ) and which possess the desired pharmacological activity.
  • the N-oxide derivatives of compounds of the invention can be prepared by methods known to those of ordinary skill in the art.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” means salts of compounds of the invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenes
  • Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
  • Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
  • Phosphono means the radical -P(O)(OH) 2 .
  • Polycycloaryl means a fused polycyclic radical containing the number of carbon atoms indicated, wherein at least one, but not all, of the fused rings comprising the radical is aromatic and each ring contained therein is comprised of five to six annular members, and any carbocyclic ketone and thioketone derivative thereof. For example, polycyclo(C 9 .
  • aryl includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, 2,4-dioxo-l,2,3,4-tetrahydronaphthyl, and the like.
  • Prodrug derivatives means derivatives of compounds of the invention which are converted in vivo to the corresponding non-derivatized form of a compound of the invention. Suitable prodrug derivatives include those compounds of the invention in which one or more nitrogen and/or oxygen atoms with a free valence are substituted with a group which is readily cleavable by in vivo processes.
  • prodrug derivatives of compounds of the invention may contain one or more N-substituted amino groups (e.g., — ⁇ H 2 (R 19 )), N-substituted nitrogen atoms incorporated into an aliphatic, alicyclic or aromatic structure (e.g., - ⁇ (R 19 )-), N-substituted imino or amidino groups (e.g., -C( ⁇ R 19 )H, -C(NR 19 )NH 2 or -C(NH)NHR 19 ), N-substituted guanidino groups (e.g., - ⁇ HC( ⁇ R 19 ) ⁇ HR 19 ,
  • N-substituted amino groups e.g., — ⁇ H 2 (R 19 )
  • N-substituted nitrogen atoms incorporated into an aliphatic, alicyclic or aromatic structure e.g., - ⁇ (R 19 )-
  • R 19 is (i) -C(O)R 20 or -CH(R 21 )OC(O)R 20 , wherein R 20 is (C,. 10 )alkyl, (C 0 )alkyloxy, carbamoyl, (C 0 )alkylcarbamoyl, di(C 0 )alkylcarbamoyl, j.-2-(C, .10 )alkanoyloxyphenylvinyl, 3-(C, .10 )alkanoyloxybutyryl, (C 3 .
  • R 21 is hydrogen or (C 1 . 10 )alkyl; (ii) -X 7 -R 22 , wherein X 7 is (C 0 )alkylene and R 22 is carboxy; or (iii) -C(O)OCH(R 23 )OC(O)R 24 , wherein R 23 is hydrogen, (C,. 10 )alkyl or (C 3 . 10 )cycloalkyl and R 24 is (C 0 )alkyl or (C 3 . 10 )cycloalkyl.
  • prodrug derivatives of compounds of the invention may contain one or more N-hydroxylated imino or amidino groups (e.g., -C( ⁇ OR 25 )H, -C(NOR 25 )NH 2 or -C(NH)NHOR 25 ) or N-hydroxylated guanidino groups (e.g., - ⁇ HC( ⁇ OR 25 ) ⁇ H 2 , -NHC(NH)NHOR 25 ), in which R 25 is hydrogen, methyl,
  • R 26 is (C M0 )alkyl or (C 3 . 10 )cycloalkyl and R 27 is hydrogen or (C,. 10 )alkyl; N-substituted hydroxy groups (e.g.,-OR 28 ), in which R 28 is -C(O)R 19 or -CH(R 20 )OC(O)R 19 , wherein R 19 and R 20 are as defined above; and/or ester derivatives of carboxylic acids (e.g., -C(O)OR 29 ), phosphonic acids (e.g., -P(O)(OR 29 )) and sulfonic acids (e.g., -S(O) 2 OR 29 wherein R 29 is (C M0 )alkyl, (C 3.10 )cycloalkyl or -C(O)OCH(R 2 )OC(O)R 24 , wherein
  • Protective group has the meaning conventionally associated with it in synthetic organic chemistry, i.e., a group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site and which can be readily removed after the selective reaction is completed.
  • Protected derivatives means derivatives of compounds of the invention in which a reactive site or sites are blocked with protective groups.
  • Protected derivatives of compounds of the invention are useful in the preparation of compounds of the invention.
  • Suitable protective groups for reactive nitrogen atoms include tert-butoxycarbonyl, benzyloxycarbonyl and any other suitable amino protective groups (e.g., see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981).
  • “Therapeutically effective amount” means that amount which, when administered to a patient is effective for treating a disease.
  • Thioketone means the derivative -C(S)-.
  • Treatment refers to any administration of a compound of the present invention and includes:
  • 6-(l-carboxy-2-phosphonoethylcarbamoyl)-l -methyl- lH-benzoimidazol-2-yl and X 3 is -C ⁇ 2 (C ⁇ 3 )- is named 2-( ⁇ 2-[l-(lH-benzoimidazol-2-yl)-ethyl]-3-methyl- 3H-benzoimidazole-5-carbonyl ⁇ -amino)-3-phosphono-propionic acid.
  • a preferred aspect of the Invention is a compound of Formula I in which A together with B and C together with D comprise fused heterobicyclic radicals wherein A and C each contain 5 annular members and B and D each contain 6 annular members and X 1 and X 2 and X 4 and X 5 are adjacent members of an oxazol-2-yl, lH-imidazol-2-yl or thiazol-2-yl ring.
  • a preferred aspect of the Invention are compounds of Formula II:
  • nl is O, 1, 2, 3 or 4
  • n2 is 0, 1, 2 or 3
  • X 8 is C, N, CR 3 or NR 3 , wherein R 3 is cyano, (C,. 6 )alkyl, -C(O)R", -C(O)NR u R 13 or -C(O)OR u , wherein R 11 independently is hydrogen, (C ⁇ alkyl or (C )aryl(C 0 alkyl, R 13 is hydrogen or (C [ . 6 )alkyl and any alkyl moiety comprising R 11 optionally independently is substituted with 1 to 3 substitutents selected from -P(O)(OR 14 )OR 14 , -S(O) 2 OR 14 and -C(O)OR 14 , wherein R 14 at each occurrence independently is hydrogen or (C,. 6 )alkyl; provided that when X 8 is NR 3 the adjacent optional bond is not present and, unless indicated otherwise, any free valence of an annular atom is occupied by a hydrogen atom;
  • R 1 and R 2 at each occurrence independently are (C,. 6 )alkyl, (C,. 6 )alkyloxy, halo or hydroxy and bonded to any annular carbon atom with a free valence;
  • R 4 is -C(O)NR 15 R 16 , wherein:
  • R 15 is (C,. 6 )alkyl substituted with 1 to 2 radicals selected from -P(O)(OR 17 )OR 17 and -S(O) 2 OR 17 and optionally substituted with 1 to 2 -C(O)OR 17 groups, wherein R 17 is hydrogen or (C,.
  • R 16 is hydrogen or (C,_ 6 )alkyl
  • R° is (C, .6 )alkyl optionally substituted with one to two substituents independently selected from halo, tr C ⁇ alkylammonio, -NR 7 R 7 , -C(O)NR 7 R 7 , -OR 7 , -C(O)OR 7 , -OC(O)R 7 or -S(O) 2 OR 7 , wherein R 7 at each occurrence independently is hydrogen or (C,. 6 )alkyl; and
  • R 8 and R 9 independently are hydrogen, halo or (C, .6 )alkyl, wherein any 1 to 3 carbon atoms with a free valence comprising R 8 and/or R 9 optionally independently are substituted with halo, tri(C, .6 )alkylammonio, -NR 10 R 10 , -C(O)NR 10 R 10 , -OR 10 , -C(O)OR 10 or
  • R 10 at each occurrence independently is hydrogen or (C,. 6 )alkyl.
  • a preferred aspect of the invention are compounds of Formula II in which both of the optional bonds are present, nl and n2 each are 0, X 8 is N or CR 3 , R° is (C )alkyl, R 8 is hydrogen or methyl and R 9 is hydrogen; preferably wherein R 3 is acetyl, benzyloxycarbonyl, cyano or -C(O)NR u R 13 , wherein R 11 and R 13 independently are hydrogen or methyl.
  • a preferred aspect of the invention are compounds of Formula II in which neither of the optional bonds are present, nl and n2 are 0, X 8 is NR 3 , R 6 is (C M )alkyl, R 8 is hydrogen or methyl and R 9 is hydrogen; preferably wherein R 3 is acetyl, benzyloxycarbonyl or -C(O)NR u R 13 , wherein R u and R 13 independently are hydrogen or methyl.
  • a preferred aspect of the invention are compounds of Formula II in which both of the optional bonds are present, nl is 0, 1, 2, 3 or 4; n2 is 0; X 8 is C; R 1 at each occurrence is chloro, fluoro or hydroxy; R 6 is (C,. 4 )alkyl; R 8 is hydrogen or methyl; and R 9 is hydrogen.
  • the compounds of the invention are serine protease inhibitors and/or are intermediates useful in the preparation of the compounds of the invention.
  • the compounds inhibit HCV protease NS-3 and, as such, are useful in treating HCV infections.
  • the compounds of the invention may be administered alone to treat patients with
  • compositions and Administration HCV infections or in combination with other anti-viral agents such as ⁇ -, ⁇ - or ⁇ -interferons, ribavirin, amantadine and the like.
  • compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic agent.
  • a therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • therapeutically effective amounts of a compound of the invention may range from 1 microgram per kilogram body weight ( ⁇ g/kg) per day to 10 milligram per kilogram body weight (mg/kg) per day, typically 10 ⁇ g/kg/day to 1 mg/kg/day. Therefore, a therapeutically effective amount for a 80 kg human patient may range from 80 ⁇ g/day to 100 mg/day, typically 0.1 mg/day to 10 mg/day.
  • compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of the invention in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient.
  • excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like.
  • Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.).
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose and glycols.
  • compositions of a compound of the invention for treating an infection will comprise from
  • the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required.
  • Representative pharmaceutical formulations containing a compound of the invention are described in Example 26.
  • the compounds of the present invention are synthesized using standard techniques and reagents known to and used by those of skill in the art. It will be noted that the linkages between the various functional groups generally comprise carbon linked to the nitrogen of an amide or carbamate, the oxygen of a carbamate or the carbon of a carbonyl.
  • L is a leaving group
  • D together with the vinylene moiety to which it is fused comprise a monocyclic or fused bicyclic divalent radical containing from 5 to 15 annular atoms, wherein each ring contains 5 to 7 annular atoms and each annular atom optionally is a heteroatom
  • R 29 is -OH, -NHR 6 or -SH
  • X 9 is -O-, -NR 6 - or -S- and n2, n3, n4,
  • A, B, X 1 , X 2 , X 3 , X 5 , R 1 , R 2 , R 3 , R 4 and R 6 are as defined in the Summary of the Invention.
  • Compounds of Formula I in which X 4 and X 5 are adjacent members of an oxazol-2-yl, lH-imidazol-2-yl or thiazol-2-yl ring can be prepared by reacting a compound of Formula 1 , or a protected derivative thereof, with a compound of Formula 2, or a protected derivative thereof, and then deprotecting if necessary.
  • the reaction between the compounds of Formulae 1 and 2 may be carried out neat, but preferably is carried out in the presence of l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU) or polyphosphoric acid, at 160 to 200°C, preferably 180-190°C, and requires 1 to 5 hours to complete.
  • DMPU l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone
  • polyphosphoric acid at 160 to 200°C, preferably 180-190°C, and requires 1 to 5 hours to complete.
  • Deprotection can be effected by any means which removes the protective group and gives the desired product in reasonable yield.
  • R 30 is -OH, -NHR 5 or -SH
  • X 9 is -O-, -NR 5 - or -S- and n2, n3, n4, B, C, X 1 , X 3 , X 4 , X 5 , R 1 , R 2 , R 3 , R 4 and R 6 are as defined in the Summary of the Invention.
  • Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, high-pressure liquid chromatography (HPLC), or a combination of these procedures.
  • suitable separation and isolation procedures can be had by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can, of course, be used.
  • Nuclear magnetic resonance (NMR) spectra were recorded on a General Electric "QE Plus" spectrometer (300 MHZ).
  • Infrared (IR) spectra were recorded on a Perkin-Elmer 1600 Fourier Transform IR (FTIR).
  • Analytical HPLC was performed on a Ultrafast Microprotein Analyzer, Michrom BioResources, Inc. equipped with a PLRP column, 1mm x 150mm.
  • Preparative HPLC was performed on a Gilson LC using a VYDAC 1x25 cm C 18 reverse phase (RP) column or a Waters Prep LC2000 system using a Vydac 5x25 cm C 18 RP column.
  • Mass spectra (MS) were obtained on a Finnigan SSQ 710 with an ESI source by direct infusion or by HPLC MS (Ultrafast Microprotein Analyzer, C lg column 2mm X 150 mm).
  • Compounds of the invention in which R 3 is carbamoyl can be prepared by treating a compound of the invention in which R 3 is cyano with acid (e.g., hydrobromic acid) in a suitable solvent (e.g., acetic acid) for 5 to 8 hours at room temperature, then adding water to the reaction mixture and allowing 2 to 3 days for formation of the corresponding amide.
  • acid e.g., hydrobromic acid
  • suitable solvent e.g., acetic acid
  • the compounds of the invention may be prepared as pharmaceutically acceptable acid addition salts by reacting the free base forms of a compound of The invention with a pharmaceutically acceptable inorganic or organic acid.
  • the pharmaceutically acceptable base addition salts of the compounds of the invention may be prepared by reacting the free acid forms of compounds of the invention with pharmaceutically acceptable inorganic or organic bases.
  • Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of the invention are set forth in the definitions section of this application.
  • the salt forms of the compounds of The invention may be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of The invention can be prepared from the corresponding base addition salt or acid addition salt form.
  • compounds of the invention in an acid addition salt form may be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.).
  • a suitable base e.g., ammonium hydroxide solution, sodium hydroxide, etc.
  • Compounds of The invention in a base addition salt form may be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).
  • N-oxides of compounds of the invention can be prepared by methods known to those of ordinary skill in the art.
  • N-oxides can be prepared by treating an unoxidized form of the compound of The invention with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, met -chloroperoxybenzoic acid, etc.) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as methylene chloride) at approximately 0°C.
  • an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, met -chloroperoxybenzoic acid, etc.
  • a suitable inert organic solvent e.g., a halogenated hydrocarbon such as methylene chloride
  • Compounds of the invention in unoxidized form can be prepared from N-oxides of compounds of The invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80°C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.
  • an inert organic solvent e.g., acetonitrile, ethanol, aqueous dioxane, etc.
  • Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art. For further details on prodrugs and their preparation see Saulnier et ⁇ /.(1994), Bioorganic and Medicinal Chemistry Letters. 4:1985)..
  • Compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diasteromeric derivatives of compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
  • the diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
  • an aspect of this Invention is a process for preparing a compound of Formula I, which process comprises: (a) reacting a compound of Formula 2:
  • L is a leaving group
  • D together with the vinylene moiety to which it is fused comprise a monocyclic or fused bicyclic divalent radical containing from 5 to 15 annular atoms, wherein each ring contains 5 to 7 annular atoms and each annular atom optionally is a heteroatom
  • R 29 is -OH, —NHR 6 or -SH and nl, n2, n3,
  • A, B, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 and R 6 are as defined in the Summary of the Invention, to give a compound of Formula 4 :
  • 3,4-Dinitro-benzoic acid amide (3.5 g, 16.6 mmol) was taken into methanol (100 mL and added to 10% palladium on carbon (1.0 g) under a nitrogen atmosphere. The mixture was then hydrogenated at 60 psi using a Parr apparatus over 8 hours.
  • 3,4-diamino-benzoic acid amide (756 mg, 5.0 mmol), prepared as in Example 1, was taken into glacial acetic acid (5 mL) followed by addition of 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (1.47 g, 7.5 mmol), prepared as in Example 2, and the mixture was warmed to 70 °C for one hour. The mixture was concentrated in vacuo and the residue partitioned with saturated aqueous sodium hydrogen carbonate (10 mL) and ethyl acetate
  • 3-Methylamino-4-nitro-benzoic acid (5.0 g, 25.5 mmol), prepared as in Example 4, was taken up into a 2: 1 methanol and tetrahydrofuran solution (300 mL) and added to 10% palladium on carbon (1 g) under a nitrogen atmosphere. The mixture was hydrogenated at 60 psi using a Parr apparatus over 8 hours.
  • 2-Amino-3-phosphonopropionic acid 56 mg, 0.33 mmol
  • N-methyl- N-(trimethylsilyl)trifluoroacetamide 1.0 mL, 5.4 mmol
  • the solution was then concentrated in vacuo to a colorless oil and subsequently taken into DMF solution (0.5 mL).
  • the mixture was treated with EDC (0.10 g, 0.52 mmol), and N,N-diisopropylethylamine (0.18 mL, 1.0 mmol), and allowed to gradually warm to 20° C. After 16 hours, the solvent was removed under reduced pressure. The residue was suspended in chloroform, washed with saturated ⁇ a ⁇ CO 3 , NaCl, and dried (Na 2 SO 4 ). The solvent was removed under reduced pressure, and the crude material was purified by silica gel chromatography using an isocratic eluant consisting of 90/10/1 chloroform methanol/acetic acid.
  • Ethyl 2-cyanopropionate (100 g 0.29 mol) was dissolved in ethanol (65mL) and the solution cooled to 0° C followed by saturation with dry hydrogen chloride gas. The mixture was allowed to warm to room temperature and stir over 24 hours at which point the reaction was again cooled to 0° C and saturated with hydrogen chloride gas. The mixture was allowed to warm to room temperature and stirred another 24 hours.
  • Solid sodium chloride was added in sufficient quantity to saturate the aqueous phase which was extracted with ethyl acetate 3x and the organic layers combined.
  • the insoluble residue was then taken into a minimum of water and neutralized by addition of an excess of solid sodium bicarbonate and the aqueous mixture was extracted with ethyl acetate lx.
  • the organic layer was combined with the previously obtained ethyl acetate solution and the combined ethyl acetate solutions dried over anhydrous magnesium sulfate. Filtration and concentration afforded an orange oil (32g) which slowly crystallized.
  • the hydrochloride salt is obtained by precipitation with ethyl ether and filtration to give 2-(3H-imidazo[4,5-c]pyridin-2-yl)-propionic acid ethyl ester hydrochloride (12.5 g) as a white hygroscopic solid; ' ⁇ -NMR (300 MHZ, d 6 -DMSO): 9.40 (s, IH), 8.59 (d, IH), 8.15 (d,
  • 3H-imidazo[4,5-c]pyridine-5-carboxylic acid benzyl ester 911 mg, 2.0 mmol was dissolved in methanol (25 mL) and the solution added to 10% palladium on carbon under a nitrogen atmosphere. The mixture was hydrogenated at 60 psi using a Parr apparatus for 12 hours. The mixture was then acidified to p ⁇ 2 by dropwise addition of 4 M hydrogen chloride in dioxane solution and filtered. The organic solution was concentrated in vacuo to afford
  • o-Phenylenediamine (11.0 g, 0.10 mol) and 2-ethoxycarbonimidoyl-propionic acid ethyl ester (25.5 g, 0.12 mol), prepared as in Example 14, were combined in acetic acid (30 mL) with cooling sufficient to maintain a temperature of 20° C. The mixture was allowed to stir for 3 hours, then poured over cracked ice. The slurry was brought to pH 10-11 with K 2 CO 3 , and stirred for 3 hours to allow for crystallization. The solid material was isolated by filtration, rinsed with water and dried.
  • the solution was added to stirring ethyl acetate, and a brown solid was isolated by filtration and rinsed with ethyl acetate.
  • the material was purified by C18 reversed-phase ⁇ PLC (2 ⁇ 27% MeCN/ ⁇ 2 O containing 0.1% TFA, over 50 min.). Appropriate fractions were pooled, and the solvent was removed under reduced pressure. The product was re-lyophilized from 0.1 M Hydrochloric acid.
  • HCV NS3 protease (1 to 3 nM), NS3 cofactor NS4a (10 ⁇ M), ZnCl 2 (5 ⁇ M), Tris (50 mM; pH 7.5), glycerol (50%), TWEEN-20® (polyoxyethylenesorbitan monolaurate; 0.05%) and test compound (varying concentrations) was incubated for 15 minutes at room temperature (21 to 24 °C) in 96-well microtiter plates.
  • the quenced fluorescence substrate acetyl-Asp-Glu-Asp(Edans)-Glu-Glu-Abu- ⁇ [COO]-Ala-Ser- Lys(Dabcyl)-NH 2 (AnaSpec, Inc., San Jose, CA, U.S.A.) was added to a final concentration of 1.5 ⁇ M.
  • the hydrolysis of the fluorescent substrate was followed spectrophotometrically at 485 nanometers after excitation at 355 nanometers (Taliani, M., Bianchi, E., Narjes, F., Fossatelli, M., Urbani, C.S., De Francesco, R., and Pessi, A., (1996) Anal. Biochem.
  • the velocity of the NS3 catalyzed hydrolysis was determined from the linear portion of the progress curves using a fMax Microplate Reader (Molecular Devices, Sunnyvale, CA, U.S.A.) interfaced with a Macintosh PowerPC computer.
  • Apparent inhibition constants K were calculated from the progress curves using the software package Batch K; (Biokin Ltd., Madison, WI, (Kuzmic, P. (1996) Anal. Biochem. 237, 260273) which provides a parametric method for determining inhibitor potency using a transformation of a tight binding inhibition model (Morrison, J.F. (1969) Biochem. Biophys. Acta 185, 269-286).
  • EXAMPLE 26 The following are representative pharmaceutical formulations containing a compound vention.
  • Citric Acid Monohydrate 1.05 mg

Abstract

L'invention porte sur de nouveaux dérivés bihétérocycliques inhibiteurs des protéases sérines, sur leurs sels pharmacocompatibles et sur leurs N-oxydes, ainsi que sur leur emploi comme agents thérapeutiques, et sur leur procédé de fabrication.
PCT/US1999/022850 1998-10-05 1999-10-04 Nouveaux composes et compositions pour le traitement de l'hepatite c WO2000020400A1 (fr)

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US6642204B2 (en) 2002-02-01 2003-11-04 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor tri-peptides
US6653295B2 (en) 2000-12-13 2003-11-25 Bristol-Myers Squibb Company Inhibitors of hepatitis C virus NS3 protease
EP1468107A2 (fr) * 2001-10-15 2004-10-20 Beckman-Coulter, Inc. Procedes et reactifs permettant des dosages cellulaires ameliores
WO2004091782A1 (fr) 2003-04-17 2004-10-28 Ecocat Oy Catalyseur comprenant un oxyde d'aluminium pour le traitement des gaz emis
WO2006033703A1 (fr) * 2004-07-27 2006-03-30 Gilead Sciences, Inc. Imidazo[4,5-d]pyrimidines, procedes d'utilisation et de preparation correspondants
EP1650203A1 (fr) * 2000-09-11 2006-04-26 Chiron Corporation Procédé de pröparation des dérivés quinéolinone benzimidazol-2-yliques.
US7091184B2 (en) 2002-02-01 2006-08-15 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor tri-peptides
US7119072B2 (en) 2002-01-30 2006-10-10 Boehringer Ingelheim (Canada) Ltd. Macrocyclic peptides active against the hepatitis C virus
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US7504378B2 (en) 2002-10-25 2009-03-17 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
US7511157B2 (en) 2004-07-20 2009-03-31 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor dipeptide analogs
US7585845B2 (en) 2003-05-21 2009-09-08 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor compounds
US7642235B2 (en) 2003-09-22 2010-01-05 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
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WO2010017401A1 (fr) * 2008-08-07 2010-02-11 Bristol-Myers Squibb Company Inhibiteurs du virus de l’hépatite c
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EP2399988A2 (fr) 2006-08-11 2011-12-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Système de culture cellulaire pour la réplication du virus de l'hépatite C par l'activation ou l'inhibition de récepteur farnésoïde X (FXR) et méthode de diagnostic pour l'infection avec VHC
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US9796705B2 (en) 2009-12-22 2017-10-24 Merck Sharp & Dohme Corp. Fused tricyclic compounds and methods of use thereof for the treatment of viral diseases
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US7119072B2 (en) 2002-01-30 2006-10-10 Boehringer Ingelheim (Canada) Ltd. Macrocyclic peptides active against the hepatitis C virus
US7091184B2 (en) 2002-02-01 2006-08-15 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor tri-peptides
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US7838527B2 (en) 2002-11-13 2010-11-23 Novartis Vaccines And Diagnostics, Inc. Methods of treating cancer and related methods
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US7659263B2 (en) 2004-11-12 2010-02-09 Japan Tobacco Inc. Thienopyrrole compound and use thereof as HCV polymerase inhibitor
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WO2007119889A1 (fr) 2006-04-18 2007-10-25 Japan Tobacco Inc. Nouveau compose de piperazine et son utilisation en tant qu'inhibiteur de la polymerase du vhc
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